Clinical Pharmacology & Therapeutics Revision Notes

Clinical Pharmacology and
Therapeutics (CPT) Revision
Notes
By Dr Garry KJ Pettet MBBS/BSc
Revision 2 (January 2006)

Contents
.........................................................................Preface 1
.........................................................Drug development 2
...................................................Adverse drug reactions 5
...........................................................Drug interactions 7
..............................Pharmacodynamics/pharmacokinetics 9
..................................Prescribing in renal / liver disease 12
.............................................................Rheumatology 16
.........................................................Gastroenterology 22
....................................................................Antivirals 27
...........................................................Asthma / COPD 30
..................................................................Analgesics 35
..........................................................The failing heart 38
..............................................................Endocrinology 46
.........................................................................Lipids 57
......................................................................Clotting 60
............................................................Mood disorders 68
..................................................Anti-arrhythmic drugs 74
...............................................................Hypertension 81
........................................................Antibiotic therapy 83
..................................................................Antibiotics 86
.....................................................................Diabetes 95
Copyright Dr Garry KJ Pettet 2005 - 2009
www.garrypettet.com

....................................................................Epilepsy 101
...................................................................Migraine 107
.......................................................Multiple sclerosis 109
....................................................Parkinson’s disease 110
...............................Drug-induced movement disorders 115
......................................................Myasthenia gravis 117
...................................................................Diuretics 119
........................................................Muscle relaxants 122
..............................................................Anti-emetics 124
....................................................................The eye 127
.......................................Antipsychotics (neuroleptics) 130
........................Drugs in the elderly, young or pregnant 134
.............................................Cytotoxic chemotherapy 137
............................................................Anti-malarials 141
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Preface
I wrote these notes as a final year medical student in the UK as I found it
very difficult to find a good single text to use for my CPT revision.
I used the following textbooks in writing these notes:
- British National Formulary (BNF 47 March 2004)
- Clinical medicine 5th
edition (Kumar, Clark)
- Hands-on-guide to clinical pharmacology (Chatu, Milson & Tofield)
- Medical pharmacology at a glance 4th
edition (Neal)
- Oxford handbook of clinical medicine 6th
edition (Longmore, Wilkinson
& Rajagopalan)
- Pharmacology 4th
edition (Rang, Dale, Ritter)
I have made sure that everything that has been mentioned in our lectures is
in these notes. We must thank the following lecturers, as some of their
material may well be in these notes:
- Dr Chris Bench
- Dr Neil Chapman
- Dr Anton Emmanuel
- Dr Michael Feher
- Dr Alun Hughes
- Prof Sebastian Johnston
- Prof John MacDermot
- Dr Janice Main
- Dr Vias Markides
- Dr Jamil Mayet
- Dr Andrew Rice
- Dr Stephen Robinson
- Dr Mike Schachter
- Dr Tom Sensky
- Prof Peter Sever
- Dr Colin Tench
- Dr Simon Thom
- Dr Roxaneh Zamegar
I would also like to thank Dr Wajid Hussain for proofreading the section on
anti-arrhythmics.
Although every effort has been made to ensure the accuracy of these notes, I
take no responsibility for errors within (but please let me know as I have to
revise from these as well!).
Dr Garry Pettet
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Drug development
Surrogate markers:
• A biological measurement which substitutes for the therapeutic end-
point
• Examples:
o BP and stroke
o Cholesterol and coronary disease
• Characteristics of a “good” surrogate:
o Biological feasibility
o Dose-related response to intervention
o Easy to measure
o Reproducible
o Specific / sensitive
o High predictive value
o Acceptable by experts / regulatory authorities
Types of clinical trials:
• Open:
o Subject and researcher know what they are getting
• Single-blind:
o The subjects do not know what they are getting
• Double-blind:
o No one knows what they are getting (during the trial)
• PROBE:
o Prospective
o Randomised
o Open-labelled
o Blinded
o End-point
o This is used for large, complex studies with several treatments.
It is an open trial where those who analyse the results do not
know who got what treatment
The phases of a clinical trial:
• Phase 1:
o Healthy volunteers (not for cancer / HIV trials)
o Few subjects (< 50)
o Looks at pharmacokinetics / pharmacodynamic activity / safety
• Phase 2:
o Patients with the target disease
o More subjects (100 – 200)
o Usually single-blind trials
o Looks again at pharmacokinetics / safety (note, these may be
different than in healthy volunteers)
• Phase 3:
o Patients
o Much larger (> 1000)
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o Usually double-blind or PROBE
o May be parallel or crossover
o Multi-centre
o May use either “hard” (e.g. MI) or “surrogate” end-points
• Phase 4:
o Post-marketing
o Surveillance for:
 Adverse drug reactions
 Rare side-effects
 Drug interactions
Parallel vs crossover studies:
• Parallel study:
o Most randomised controlled trials (RCTs) are parallel
• Crossover study:
o Need fewer subjects
o Should normally be used in chronic stable diseases and the
interventions should have a rapid onset and short duration
o Beware of order effects:
 Carry-over effects
 Period effects:
• Changes in the patient’s disease over time
Power:
• Is the study large enough to answer the study’s question?
• Type 1 error (α):
o Chance of finding 2 treatments are different when they are not
o Usually:
 α = 0.05 (i.e. p < 0.05)
• Type 2 error (β):
o Chance of finding 2 treatments are equal when they are not
o Usually:
 β = 0.1 or 0.2 (arbitrary)
• Power = 1 - β (i.e. 80 – 90% usually)
• The higher we set β (i.e. the greater our power) the more expensive
the trial becomes as we need more subjects
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A
B
A
B

“Intention to treat” vs “per protocol” analysis:
• Intention to treat:
o Ignore whether the subjects actually take the medication (i.e.
just assume they did)
• Per protocol:
o Only analyse data from subjects who actually took the
medication
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Adverse drug reactions
Significance:
• 3 – 40% of inpatient admissions
• Affects 10 – 20% of hospital patients
• 4th
most common cause of death in US hospital patients
• Up to 30 – 60% are preventable
Types of adverse drug reaction (ADR):
• Type 1:
o “Predictable” reactions
o Common
o Dose-related
o A consequence of the known pharmacology of the drug
• Type 2:
o “Idiosyncratic” reactions
o Rare
o Usually not dose-related
o Allergies
o Pharmacogenetic variations
Classification of ADRs:
• Augmented pharmacological effect
• Bizarre
• Chronic
• Delayed
• End-of-treatment
Determinants of ADRs:
• Drug:
o Pharmacodynamics
o Pharmacokinetics
o Dose
o Formulation
o Route of administration
• Patient:
o Age
o Co-morbidity
o Organ dysfunction
o Genetic predisposition
• Environment:
o Mistakes
Allergies vs psuedoallergies:
• Allergies:
o Type I (anaphylaxis):
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 Penicillins
 Contrast media (anaphylactoid)
o Type II (cytotoxic antibodies – blood dyscrasias):
 Haemolytic anaemia:
• Methyldopa
• Penicillin
• Sulphonamides
 Agranulocytosis:
• Carbimazole
• Clozapine
 Thrombocytopenia:
• Quinidine
• Heparin
o Type III (immune complex formation):
 Penicillin
 Sulphonamides
o Type IV (cell mediated):
 Topical antibiotics
• Pseudoallergies:
o Looks like an allergy but is not immune-mediated
o Examples:
 Aspirin - bronchospasm
 ACE inhibitors – cough
Long-term ADRs:
• Withdrawal:
o Opiates
o Benzodiazepines
o Corticosteroids
• Rebound:
o Clonidine
o β-blockers
• Adaptive:
o Neuroleptics
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Drug interactions
Liver enzyme inducers (cytochrome P450):
• Carbamazepine
• Phenobarbitone
• Phenytoin
• Rifampicin
Liver enzyme inhibitors (cytochrome P450):
• Cimetidine
• Ciprofloxacin
• Grapefruit juice
• Macrolide antibiotics:
o Erythromycin
• Omeprazole
Important drugs metabolised by the liver (cytochrome P450):
• Carbamazepine
• Cyclosporin A
• Combined oral contraceptive (COC) pill
• Phenytoin
• Theophylline
• Warfarin
Some important drugs interacting with warfarin:
• Drugs increasing the effect of warfarin:
o Alcohol
o Amiodarone
o Antibiotics (many – reduced vitamin K absorption)
o Cimetidine
o Omeprazole
o Simvastatin
• Drugs decreasing the effect of warfarin:
o Carbamazepine
o COC pill
o Rifampicin
Interactions with diuretics:
• General:
o Potentiate:
 ACE inhibitors
 Lithium
o Metabolic:
 Hypokalaemia enhances digoxin efficacy
 β-blockers potentiate hypokalaemic effects of diuretics
• Loop:
o Increased risk of ototoxicity with the aminoglycosides
• Potassium-sparing:
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o Risk of hyperkalaemia with ACE inhibitors
Drugs affecting gastric emptying and hence drug absorption:
• Increase emptying:
o Metoclopramide
• Decrease emptying:
o Atropine
Impairment of drug excretion:
• Probenicid:
o Competes with Penicillins for renal tubular excretion, leads to
increased concentration of penicillins (can be beneficial)
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Pharmacodynamics/pharmacokinetics
Half-life (t1/2):
• The time taken for the concentration of drug in plasma (or blood) to
fall to half it’s original value
• Drugs with a short t1/2 may have a long duration of action:
o So-called “cell-trapping”
o E.g. omeprazole
Volume of distribution (Vd):
• This is the apparent volume into which the drug is distributed
Vd = dose / (initial apparent plasma concentration)
• Is used to calculate the clearance of a drug
• Is high for lipid-soluble drugs
• Is low for water-soluble drugs
• Values of Vd:
o < 5L drug retained within the vascular system
o < 15L drug is restricted to the extracellular fluid (ECF)
o > 15L indicates the drug is distributed throughout the
total body water
Clearance:
• The volume of plasma (or blood) cleared of drug per unit time
• Depends on drug lipid solubility
• Clearance (but not t1/2) provides an indication of the ability of the liver
and kidneys to dispose of the drug
First vs zero order kinetics:
• First-order kinetics:
o A metabolic process that depends on the drug concentration at
any given time is called a first-order process
o I.e. a non-saturable process
• Zero-order kinetics:
o If any enzyme system responsible for drug metabolism becomes
saturated, then the rate of elimination proceeds at a constant
rate and is unaffected by an increase in the concentration of the
drug
o I.e. a saturable process
o Examples include:
 Phenytoin
 Ethanol
o The importance of zero-order kinetics is that you could double
the dose, but the plasma concentration would not double (may
increase to an enormous extent)
Bioavailability:
• The proportion of administered drug reaching the systemic circulation
• IV drugs have 100% bioavailability
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• Drugs with high bioavailability:
o Ciprofloxacin (near 100%)
• Drugs with low bioavailability:
o Bisphosphonates (~15%)
First-pass metabolism:
• Also known as pre-systemic metabolism
• This is drug metabolism that occurs before the drug reaches the
system circulation
• Occurs in the liver and gut wall
• Some drugs undergo extensive first-pass metabolism:
o Levodopa
o Lignocaine
o Morphine
o Nitrates (e.g. GTN)
o Propranolol
o Verapamil
• Is generally a nuisance for two reasons:
o A larger dose is needed when it is given orally
o Marked individual variations occur
Post-systemic metabolism:
• The main purpose is to increase water-solubility of the drug
• Phase I:
o Three types of reaction:
 Oxidation:
• Most important are the P450 enzymes
• Xanthine oxidase metabolises 6-mercaptopurine
• Monoamine oxidase inactivates 5-HT, NA, tyramine
 Reduction / Hydrolysis
o Usually produces a more reactive compound that will be acted
on by phase II components
o May activate a prodrug – examples:
 Levodopa  dopamine
 Enalapril  enalaprilat
 Azathioprine  6-mercaptopurine
 Methlydopa  α-methyl-noradrenaline
 Carbimazole  methimazole
• Phase II:
o Conjugation of a drug or phase I metabolite with an
endogenous substance to form a more polar, easily excreted,
compound
o May be either:
 Glucuronidation
 Sulphation
 Acetylation (does not alter water-solubility)
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 Glutathione
Loading doses:
• In practice, a steady state concentration is effectively achieved after
three plasma half-times
• Faster attainment of the steady state is achieved by starting with a
larger dose – a loading dose
Therapeutic drug monitoring:
• Why?
o To investigate lack of drug efficacy
o Possible poor compliance
o Suspected toxicity
o Prevention of toxicity
• Type of drugs:
o Narrow therapeutic index (TI)
o Uncertain dose / concentration relationship
o Defined plasma concentrations with no active metabolites
• Examples:
o Not warfarin (this measures the INR, not drug concentration!)
o Antibiotics (aminoglycosides, vancomycin)
o Anticonvulsants (carbamazepine, phenytoin)
o Aminophylline / theophylline
o Cyclosporin A
o Digoxin
o Lithium
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Prescribing in renal / liver disease
Important drugs whose elimination is affected by renal impairment
• Half-lives are approximate ranges when renal impairment present
• Amoxicillin (t1/2 2 – 14 hours):
o Applies to most penicillins
o Toxic effects:
 Seizures (especially in meningitis)
 Rashes are more common in renal impairment
• Atenolol (t1/2 6 – 100 hours):
o Contraindicated in:
 Asthmatics
 Severe heart failure
 Peripheral vascular disease
o Toxic effects:
 Bradycardia
 Confusion
 Hypotension
• Captopril (t1/2 2 – 14 hours):
o Toxic effects:
 ⇓ GFR
 Angioedema
 Cough:
• Probably due to a direct effect on sensory afferents
• Not bradykinin
 GI disturbances
 Hypotension
 Taste disturbances
• Digoxin (t1/2 36 – 90 hours):
o Requires therapeutic drug monitoring (TDM)
o Toxic effects:
 Dysrhythmias (VT, heart block)
 Gynaecomastia
 Nausea (severe) / vomiting
 Xanthopsia (distortion of yellow colour vision)
• Gentamicin (t1/2 2½ - >50 hours):
o Increased risk of toxicity when:
 Dehydrated (important as septic patients usually are)
 Hyponatraemic
o Toxic effects:
 Nephrotoxicity (renal tubular damage)
 Ototoxicity (can be irreversible)
Vitamin D and the kidney:
• Vitamin D has to undergo two hydroxylation reactions within the body
to become active
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• Kidney forms the 1-hydroxy form of vitamin D and requires the
enzyme 1α-hydroxylase
• In renal impairment, the above step may not happen
• Bone disease caused by renal disease is termed renal
osteodystrophy:
o Loss of vitamin D activity
o ⇑ PTH activity
• Replacing vitamin D:
o Alfacalcidol (the 1-hydroxylated form, thus negating need for
1α-hydroxylase)
o Calcitriol (the active 1, 25-hydroxylated form) – rarely used
Nephrotoxic drugs:
• ACE inhibitors:
o ⇓ GFR (if the arterial perfusion pressure is low):
 Renal artery stenosis (especially bilaterally)
 Coarctation of the aorta
• Cyclosporin A:
o Used in renal transplants
o Is a substrate for P450 (levels may be increased by other drugs)
o ⇓ GFR
o Damages tubular function
• Gentamicin:
o Renal tubular damage
• Lithium:
o Nephrogenic diabetes insipidus
o Renal tubular damage
• NSAIDs:
o ⇓ GFR
o Papillary necrosis:
 Loss of PG-mediated vasodilatation
o Na+
retention
• Others:
o Urate stones:
 Anticancer drugs (tumour lysis syndrome)
o Myoglobinuria:
 Alcohol
 Statins
Drugs to watch when patient has impaired hepatic synthetic function:
• Hypoalbuminaemia:
o Drugs which bind to albumin and are cleared by the liver:
 Diazepam
 Phenytoin
 Tolbutamide
• A1-acidic glycoprotein deficiency:
o Binds basic drugs:
 Chlorpromazine
 Imipramine
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 Quinidine
• Reduced synthesis of clotting factors:
o Warfarin:
 If the liver is synthesising even less of factors II, VII, IX
and X then warfarin’s effects will be potentiated
o Antibiotics:
 Interfere with vitamin K production in the gut by bacteria
 May compound the above problem
Drugs to watch in a patient with current / recent hepatic encephalopathy:
• Antidepressants:
o Tricyclic antidepressants (TCAs) are safest (but use a ⇓ dose)
o Avoid monoamine oxidase inhibitors (MAOIs):
 Idiosyncratic hepatotoxicity
• Anti-psychotics:
o Chlorpromazine
• Anxiolytics / hypnotics:
o Oxazepam / temazepam are the safest
o Avoid chlormethiazole (especially IV)
• Opiates:
o Can precipitate coma
o Even low levels are dangerous
Drugs with a high first-pass metabolism:
• These drugs will not be metabolised as much in liver impairment (if
given orally), thus the dose should be ⇓
• Chlorpromazine
• Chlormethiazole
• Imipramine
• Morphine / pethidine
• Propranolol
• Verapamil
Hepatotoxic drugs:
• Cholestasis:
o Chlorpromazine (reversible cholestasis)
o Sulphonylureas (e.g. glibenclamide)
o Carbimazole
• Hepatocellular necrosis:
o Antibiotics:
 Isoniazid
 Rifampicin
 Nitrofurantoin
o Anticonvulsants:
 Can cause liver damage at normal doses in some patients
 Carbamazepine
 Phenytoin
 Valproate
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o Anti-hypertensives:
 Hydralazine:
• Also causes a SLE-like syndrome (ssDNA Abs)
 Methyldopa
o Halothane (repeated exposures)
o Paracetamol (overdose)
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Rheumatology
Drug treatment of osteoarthritis (OA):
• Simple analgesics:
o Paracetamol (as good as Ibuprofen in early disease)
• Topical therapy:
o NSAIDs (e.g. ibuleve)
o Capsaicin:
 Potent pain-producing agent
 After a few applications, the pain-producing effect
disappears and nociceptive responses to other stimuli
disappear as well – hence it’s use here
• Glucosamine
• Systemic NSAIDs
Drug treatment of rheumatoid arthritis (RA):
• NSAIDs
• COX-II inhibitors:
o Indications:
 Age >65 years
 Previous history of DU / GU or GI bleed
 Large doses of NSAID required to control pain
o Absolute contraindications:
 Established IHD
 Cerebrovascular disease
 Heart failure (NYHA II – IV)
• Gastroprotection (if on NSAID / long-term steroids):
o H2-receptor antagonists
o Proton pump inhibitors (PPIs)
o Misoprostol
• Disease modifying anti-rheumatic drug (DMARD):
o Persisting synovitis >6 weeks
o Several may have to be tried to find the right one:
 Methotrexate
 Sulphasalazine
 Gold
 Penicillamine
 Hydroxychloroquine
• Anti-TNFα therapy:
o Progressive RA after 2 DMARD failures
• Steroids are controversial but useful in acute flares
Drug treatment of osteoporosis:
• Bisphosphonates:
o Are the mainstay of treatment
• Calcium supplements
• Vitamin D
• Calcitonin (may be considered)
• HRT no longer has role
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Glucosamine:
• Unclear mechanism of action
• Probably similar efficacy to simple NSAIDs
• Better tolerated than NSAIDs but not free of side-effects:
o Headache
o Rash
o Drowsiness
Non-steroidal anti-inflammatory drugs (NSAIDs):
• (Non- selectively) inhibit cyclo-oxygenase (COX)
• COX converts arachidonic acid (derived from membrane phospholipids)
into endoperoxides
• The endoperoxides are further converted into:
o Prostaglandins (PGs):
 Potentiate the activity of other pain mediators
 Vasodilatation
o Thromboxane A2:
 Platelet aggregation
 Vasoconstriction
o Prostacyclin:
 Inhibits platelet aggregation
 Vasodilatation
• There are 2 isoforms of COX - COX-I and COX-II:
o COX-I is a constitutional enzyme and is important in the
maintenance of the protective GI mucus barrier in the stomach
and of renal blood flow
o COX-II is expressed at sites of inflammation
• NSAIDs are:
o Analgesic
o Antipyretic (inhibits the rise in brain PGs that cause pyrexia)
o Anti-inflammatory (at higher doses)
• Adverse effects:
o GI:
 Peptic ulceration (major adverse effect)
o Renal:
 Reduced renal blood flow
 Sodium retention - hypertension
 Interstitial nephritis
 Hyperkalaemia
 Papillary necrosis (chronic use)
o Other:
 Bronchospasm (especially in asthmatics)
 Allergies
Aspirin as a NSAID:
• Aspirin is a NSAID but the large doses required to control the
inflammation in the arthritides led to an unacceptable number of
adverse effects
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• It irreversibly inactivates COX – activity returns only when new
enzyme is synthesised:
o Hence it’s effectiveness in platelets (cannot synthesise new
enzyme)
Paracetamol as a NSAID:
• Like aspirin, paracetamol is a NSAID
• It’s mechanism of action is not fully understood and it has no anti-
inflammatory activity
• It works, act least partly, by reducing COX tone:
o This activity is only seen in areas of low peroxide concentration
o Hence, paracetamol works best when there is little or no
leucocyte infiltration (as leucocytes produce high levels of
peroxide)
Relative risk of GI toxicity with NSAIDs:
• From least toxic to most toxic:
o Ibuprofen
o Diclofenac
o Aspirin
o Naproxen
o Indomethacin
o Ketoprofen
COX-II inhibitors:
• E.g. Celecoxib (Rofecoxib (Vioxx) has been withdrawn in the UK))
• No better at improving symptoms of pain / inflammation than NSAIDs
• 50% reduction in GI:
o Ulceration
o Perforation
o Bleeds
• (Probable) increased risk of:
o Myocardial infarction
o Stroke
Methotrexate:
• Indications:
o Malignancy
o Psoriasis (when conventional therapy fails)
o Rheumatoid arthritis
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• Mechanism of action:
o Inhibits dihydrofolate reductase
o Leads to a reduction in the production of tetrahydrofolic acid
(which is essential for nucleic acid synthesis)
o Prevents cells from dividing
• Administer concurrent folic acid to minimise symptoms
o Nausea
o Fatigue
o Pneumonitis (rare but can be life-threatening)
• Contraindications:
o Renal / hepatic impairment
o Pregnancy
• Interactions:
o NSAIDs / probenicid:
 Reduce the excretion of methotrexate
Sulphasalazine:
• Mechanism of action in RA is unknown
o Nausea / abdominal discomfort
o Reduced sperm count
o Marrow suppression
o Salicylate allergy
o Renal impairment
Gold:
o Proteinuria
o Hepatitis
Penicillamine:
o Proteinuria
o Reduction in taste
o SLE
o Penicillin allergy
o SLE
Hydroxychloroquine:
o Rash
o Retinopathy (rare)
o Tinnitus
• Cautions:
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o Hepatic impairment
• Very toxic in overdose
Anti-TNFα therapy:
• TNFα is the major mediator of inflammation
• Used in RA when patient has failed to respond to >=2 DMARDs
(including methotrexate)
• Can be either:
o Soluble TNFα receptors (etanercept)
o Anti-TNFα receptors (infliximab)
• Reduce inflammation, inhibit progression and improve radiological
Sharp score (a measure of radiological RA severity)
o Local reactions
o Increased risk of infections:
 Especially tuberculosis (need to screen before therapy)
o Demyelination syndromes
o SLE-like syndrome:
 Avoid in SLE-sufferers
o Worsening of pre-existing heart failure
• Other disease indications:
o Ankylosing spondylitis
o Psoriatic arthritis
o Crohn’s disease
Bisphosphonates:
• E.g. alendronate, pamidronate
• Are enzyme-resistant analogues of pyrophosphate
• Bind to hydroxyapatite crystals and reduce bone resorption (via
inhibition of osteoclasts)
• Indications:
o Osteoporosis (both primary and steroid-induced)
o Paget’s disease
o Malignant hypercalcaemia
o Alendronate can cause oesophagitis:
 Swallow the tablet whole with a full glass of water on an
empty stomach and remain upright for at least 30 mins
Vitamin D supplementation:
• Usually given as ergocalciferol (vitamin D2 – the usual dietary source
of vitamin D)
• Is a fat-soluble vitamin so bile salts are necessary for absorption
o Hypercalcaemia
• Interactions:
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o Some anticonvulsants (carbamazepine, phenytoin) increase the
requirement of vitamin D
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Gastroenterology
Drug treatment of GORD / PUD:
• Antacids
• Acid suppression:
o H2-receptor antagonists
o Proton pump inhibitors (PPIs)
• Helicobacter pylori eradication
Drug treatment of constipation (laxatives):
• Bulk laxatives
• Stimulant laxatives
• Osmotic agents
• Stool softeners
• Suppositories / enemas
• Novel:
o Motilin analogues (e.g. erythromycin)
o 5-HT4 antagonists (e.g. tegaserod)
o Probiotics
Drug treatment of diarrhoea:
• General:
o Opioids (e.g. loperamide)
• Autonomic neuropathy (e.g. diabetes):
o Clonidine
o Octreotide (for secretory diarrhoea)
• Bacterial overgrowth:
o Treat underlying cause
o Cyclical antibiotics if above fails (e.g. neuropathy)
• Pancreatic insufficiency (e.g. diabetes, chronic pancreatitis):
o Pancreatin + acid-suppressant (e.g. PPI)
Drug treatment of Crohn’s disease:
• Acute exacerbations:
o Steroids (oral / rectal / IV)
o Elemental diet
o Anti-TNFα therapy (infliximab):
 Severe (especially fistulating) disease
• Maintenance:
o 5-Aminosalicylic acid (5-ASA) compounds
o Azathioprine (if 5-ASA fails)
o Methotrexate (if azathioprine intolerant)
Drug treatment of ulcerative colitis:
• Acute exacerbations:
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o Rectal 5-ASA (evidence shows benefit over steroids)
o Steroids (oral / rectal / IV)
• Maintenance:
o 5-ASA compounds
Antacids:
• Increase gastric pH (this increases rate of emptying thus action is
short)
• All antacids can interfere with drug absorption – should be taken
separately
• Sodium bicarbonate:
o Only useful water-soluble antacid
o May cause metabolic alkalosis
• Magnesium hydroxide:
o May cause diarrhoea
• Aluminium hydroxide:
o May cause constipation
• Alginate-containing compounds (e.g. Gaviscon):
o Form a “raft” on top of stomach contents and prevent reflux
H2-receptor antagonists:
• E.g. ranitidine, cimetidine
• Block histamine receptors on the gastric parietal cell membrane and
reduce acid secretion
• Indications:
o GORD
o PUD
• Adverse effects (mainly cimetidine):
o Liver enzyme inhibitor (increases levels of):
 Anticonvulsants (carbamazepine, phenytoin, valproate)
 Theophylline
 Warfarin
o Hyperprolactinaemia
o Anti-androgenic activity (gynaecomastia)
Proton pump inhibitors (PPIs):
• E.g. omeprazole, lansoprazole
• Inactive at neutral pH but are activated in the stomach and irreversibly
inhibit the H+
/K+
-ATPase (proton pump)
• Are more effective than H2-receptor antagonists and more cost-
effective
• Indications:
o GORD
o PUD
o Zollinger-Ellison syndrome
o Liver enzyme inhibitor (increases levels of):
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 Phenytoin
 Warfarin
• Cautions:
o Achlorhydria is associated with gastric cancer – unsure of long-
term effects of acid suppression
H. pylori eradication therapy:
• One PPI and two antibiotics for two weeks
• Usual combination (but there are many):
o Omeprazole
o Clarithromycin
o Amoxicillin (or metronidazole)
• Resistance to metronidazole is common
Bulk laxatives:
• E.g. bran, ispaghula
• Only good for mild constipation
• Are usually indigestible polysaccharides
• Increase the volume of the intestinal contents – thus stimulating
peristalsis by stretching mechanoreceptors
• Gradual onset of action (~1 week)
• Increase stool output as a function of initial stool weight:
o If stool volume is low initially then won’t see much of an
increase
o Exacerbates bloating in slow-transit constipations
Stimulant laxatives:
• E.g. bisacodyl, picosulphate, senna
• Are inactive glycosides that are activated in the colon by bacteria
• Once in colon – have direct stimulant effect on the myenteric plexus:
o Smooth muscle contraction (peristalsis)
• Also increase secretion of water and electrolytes
• Rapid onset of action (~8 hours) – give in evening for morning stool
o Colic
o Colonic atony
o Hypokalaemia
o Pseudomelanosis coli (colonic pigmentation with chronic use)
o Unpredictable effect
Osmotic agents:
• E.g. Lactulose, magnesium salts
• Poorly absorbed solutes that maintain a large stool volume by osmosis
• Lactulose:
o Is a disaccharide (fructose-galactose)
o Cannot be cleaved by human disaccharidases – is cleaved by
bacteria in the colon
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o These sugars are poorly absorbed by the colon and act as
osmotic laxatives
• Onset of action:
o Salts – hours
o Lactulose – 2 or 3 days
o Cramps
o Flatulence
o Hypermagnesaemia (especially in renal impairment) with Mg
salts
Stool softeners:
• E.g. sodium docusate, arachis oil
• Act like detergents in the colon and facilitate mixing of fat and water
in the stool
o Passive faecal leakage
• Not effective enough to be used on their own
Suppositories / enemas:
• E.g. glycerine suppositories, phosphate enemas
• Probably as effective as oral osmotic laxatives
Opioids and diarrhoea:
• E.g. loperamide, codeine, morphine
• Stimulate µ-receptors on myenteric neurones and lead to
hyperpolarization:
o Inhibits Ach release from myenteric plexus and reduces
peristalsis
• Loperamide is most appropriate as it does not cross the blood-brain
barrier and is unlikely to cause dependence
Pancreatin:
• Pancreatic enzyme supplement of porcine origin
• Must be taken with an anti-acid drug (usually a H2-receptor
antagonist) to prevent it’s destruction in the stomach
• Is inactivated by heat – caution if mixing pancreatin in with food
• Indications:
o Cystic fibrosis
o Chronic pancreatitis
o Diabetes mellitus
o Pancreatectomy
o Nausea / vomiting
o Abdominal discomfort
o Irritation of buccal / perianal mucosa
5-Aminosalicyclic acid (5-ASA) compounds:
• E.g. mesalazine, olsalazine, sulphasalazine
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• Unknown mechanism of action
• Indications:
o Induction of remission in UC (rectal preparation)
o Maintenance of remission in UC and CD:
 1 year relapse rate (73% placebo vs 21% sulphasalazine)
• Probably reduce the cancer risk associated with UC
• Drug structures:
o Olsalazine:
 Two 5-ASA molecules joined by an azo bond that is
cleaved by bacteria in the colon
o Sulphasalazine:
 5-ASA with sulphapyridine (a sulphonamide)
 The sulphapyridine carries the 5-ASA to the colon
 Most of the adverse effects are caused by sulphapyridine
o Few with the newer agents (lacking sulphapyridine)
Infliximab:
• An anti-TNFα monoclonal antibody
• Indications:
o Crohn’s disease not controlled by steroids and a
conventional immunosuppressant
o Refractory fistulating Crohn’s disease
• 65% of patients initially respond to infliximab
• 30% will go on to remission
• Of those that respond to a single treatment – 50% maintain remission
when treated for 1 year
• Infliximab closes 50% of refractory fistulas within 2 weeks and
improves healing in 65%:
o However, only 30% of those who heal remain healed at 1 year
o Local reactions
o Increased risk of infections:
 Especially tuberculosis (need to screen before therapy)
o Demyelination syndromes
o SLE-like syndrome:
 Avoid in SLE-sufferers
o Worsening of pre-existing heart failure
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Antivirals
Treatment of herpes simplex virus (HSV) and varicella zoster virus (VZV):
• Aciclovir (topical / oral / IV)
• Second-line:
o Famciclovir (good for genital herpes)
o Valaciclovir
Treatment of cytomegalovirus (CMV):
• Ganciclovir (IV) (can cause myelosuppression)
• Second-line:
o Valaciclovir
o Foscarnet
Treatment of human immunodeficiency virus (HIV):
• Highly active anti-retroviral therapy (HAART):
o Two NRTIs plus either an NNRTI or a PI
• NRTI = nucleoside reverse transcriptase inhibitor
• NNRTI = non- nucleoside reverse transcriptase inhibitor
• PI = protease inhibitor
• Treatment of opportunistic infections
Drugs treatment of chronic hepatitis B (HBV) infection:
• 40% success rate
• Interferon-α (IFN-α) given as a subcutaneous injection
• Lamivudine
• Second-line:
o Famciclovir
Drug treatment of chronic hepatitis C (HCV) infection:
• Combination therapy (most effective, up to 60% ‘cured’):
o Peginterferon-α (⇑ bioavailability – once weekly)
o Ribavirin
• Treatment depends on HCV genotype:
o Genotypes 2, 3:
 Better prognosis
 Treat for 6 months
o Genotypes 1, 4:
 Worse prognosis
 Treat for 12 months
• If HCV RNA has not decreased after 12 weeks treatment to <1% of
initial level then consider discontinuing
Drug treatment of influenza:
• Influenza A only:
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o Amantadine
• Influenza A and B:
o Neuraminidase inhibitors:
 Olseltamivir
 Zanamivir
• Only used in at-risk adults who can start treatment within 48 hours of
the onset of symptoms
• At-risk adults:
o Chronic respiratory disease
o Significant cardiovascular disease (excluding hypertension)
o Chronic renal disease
o Immunocompromised
o Diabetes mellitus
Aciclovir:
• Is a guanosine analogue and an example of a prodrug
• Aciclovir is converted to the monophosphate by thymidine kinase
• Viral thymidine kinase has a much greater affinity for aciclovir than the
human enzyme
• Aciclovir is therefore only activated in virally-infected cells, where it is
converted to the triphosphate:
o Inhibits viral DNA polymerase and terminates the nucleotide
chain
o Rash (topical preparations)
o Drip site inflammation
o Renal damage
o Bone marrow suppression (with parenteral administration
• Interactions:
o Probenicid decreases excretion of aciclovir
Adverse effects of the NRTIs:
• All of these drugs have many side-effects, only important ones for
each are listed here
• Abacavir:
o Hypersensitivity (rash, Stevens-Johnson syndrome)
o Hepatic impairment (lactic acidosis, hepatomegaly)
• Didanosine:
o Pancreatitis
• Lamivudine:
o Well tolerated
o Caution in hepatic disease
• Stavudine:
o Lipodystrophy
o Peripheral neuropathy
• Zalcitabine:
o Pancreatitis
o Peripheral neuropathy
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• Zidovudine (AZT):
o Bone marrow suppression (initially developed as an anti-
cancer agent)
Adverse effects of the NNRTIs:
• All of these drugs have many side-effects, only the important ones for
each are listed here
• Efavirenz:
o Psychiatric manifestations
• Nevirapine:
o Many drug interactions:
 E.g. methadone is metabolised much faster
Adverse effects of the PIs:
o Many side effects although an important one is lipodystrophy
• Amprenavir:
• Indinavir:
o Renal calculi
• Ritonavir:
o Peripheral and circumoral paraesthesia
• Saquinavir:
o Liver impairment
• Combination:
o Kaletra (lopinavir + ritonavir):
 The ritonavir ⇑ the concentration of the lopinavir
 Diarrhoea
Lipodystrophy:
• Also known as the fat redistribution syndrome
• A common side effect of the PIs and stavudine
• Features:
o Decreased subcutaneous fat
o Buffalo hump
o Breast enlargement
o Hyperlipidaemia
o Insulin resistance - hyperglycaemia
Amantadine:
• Indications:
o Influenza A in at-risk adults within 48 hours of symptoms
o Parkinson’s disease
• It’s anti-viral actions arise from it’s ability to inhibit a viral ion-channel
• The putative mechanism in Parkinson’s disease is an increase in
dopamine release
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Asthma / COPD
Severe asthma:
• Unable to complete sentences
• Respiratory rate >25/min
• Pulse >110/min
• PEFR <50% best or predicted
Life-threatening asthma:
• PEFR <33% best or predicted
• Bradycardia
• Hypotension
• Silent chest
• Feeble respiratory effort
• Confusion
• Blood gases:
o pCO2 > 5kPa
o pO2 <8kPa
o pH <7.35
BTS guidelines for the management of acute severe asthma in adults
• Initial management:
o 100% High flow oxygen
o Nebulised salbutamol (5mg) or terbutaline (10mg)
o Add in nebulised ipratropium bromide (0.5mg) if poor
response
o IV hydrocortisone (100mg)
• No improvement:
o Consider ITU referral
o Continue repeating nebulised salbutamol
o IV magnesium sulphate (1.2-2g over 20 mins)
o Aminophylline:
 Omit loading dose if patient is taking theophylline
o IV Salbutamol (but not with Aminophylline)
BTS 5 steps approach to the management of asthma:
• Step 1 (mild intermittent asthma):
o Inhaled short-acting β2-agonist as required
• Step 2 (regular preventer therapy):
o Step 1 + low dose inhaled steroid
• Step 3 (add-on therapy):
o Step 2 + long-acting β2-agonist (LABA)
o If partial response to LABA then:
 Continue with LABA and increase dose of inhaled steroid
o If no response to LABA then:
 Stop LABA and increase dose of inhaled steroid
 Consider adding in leukotriene antagonist or theophylline
• Step 4 (persistent poor control):
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o Step 3 + either:
 High-dose inhaled steroid
 Leukotriene antagonist (if not on one already)
 Oral theophylline
• Step 5 (continuous or frequent use of oral steroids):
o Step 4 + daily oral steroids
o Refer patient for specialist care
General principles of drug treatment of COPD:
• Discontinue drugs which may worsen COPD:
o E.g. β2-blockers for hypertension
• Maintenance therapy:
o Inhaled bronchodilators:
 β2-agonists (short-/long-acting)
 Anti-muscarinics (short-/long-acting):
• These are more important than in asthma
o Inhaled corticosteroids:
 If FEV1 <50% predicted
 Repeated exacerbations
o Theophylline
• Exacerbations:
o Oral steroids
o Antibiotics (if infection suspected)
• Vaccination:
o Influenza (definite benefit shown)
o Pneumococcal (probable benefit)
Drug treatment of COPD by stage:
• Stage 0:
o No COPD (but at risk)
• Stage 1 (mild COPD):
o FEV1 <80% predicted
o Short-acting β2-agonist
• Stage 2:
o FEV1 50-80% predicted
o Long-acting β2-agonist
• Stage 3:
o Inhaled steroids (1000 - 2000µg daily)
• Stage 4:
o Risk of cor pulmonale
o May need oxygen therapy if hypoxic at rest
Inhaled β2-agonists:
• Short-acting (last 4-6 hours):
o Salbutamol
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o Terbutaline
• Long-acting (last ~12 hours):
o Salmeterol
• Indications:
o Asthma
o COPD with reversible component
o Stimulate β2-receptors on airway smooth muscle
o Leads to ⇑ cAMP which ⇓ intracellular Ca2+
, leading to smooth
muscle relaxation
o Tachycardia
o Tremor
• Interactions (Hypokalaemia with high doses of):
o Corticosteroids
o Diuretics (loop and thiazide)
o Theophylline
Inhaled anti-muscarinics:
• Short-acting (last 3-6 hours):
o Ipratropium bromide (Atrovent)
• Long-acting (once daily):
o Tiotropium (Spiriva)
• Indications:
o Asthma
o COPD with reversible component (especially tiotropium)
o Inhibits the parasympathetic nervous supply of the bronchioles
by binding to muscarinic receptors
• Adverse effects (uncommon as poorly absorbed systemically):
o Dry mouth
o Constipation
• Cautions:
o Glaucoma
o Prostatic hypertrophy
Inhaled corticosteroids:
• E.g. beclomethasone, budesonide, fluticasone
• Indications:
o Asthma (from BTS step 2 onwards)
o Decrease formation of numerous cytokines important in asthma
o Inhibit generation of prostaglandins / leukotrienes
o Inhibit the allergen-induced influx of eosinophils into the lung
o Up-regulate β2-receptors
• Take up to 12 weeks to reach maximum efficacy
• Reduce morbidity and mortality of asthma
• Improve quality of life
• Prevent long-term decrease in airway function
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• Inhaled steroids work best at a moderate dose combined with
bronchodilators
• Adverse effects (fewer than systemic corticosteroids):
o High dose:
 Adrenal suppression (give patients steroid card)
 Cataracts
 Glaucoma
 Growth suppression (probably just initial growth
velocity)
 Osteoporosis
o Low dose:
 Candidiasis (reduced by using a spacer device)
 Hoarse voice
• Interactions:
o Very few when inhaled
• Cautions:
o Active or quiescent TB
o Oral steroids may be required during times of high stress if on
long-term high dose inhaled steroids
Methylxanthines:
• E.g. Aminophylline, theophylline
• Aminophylline is a soluble form of theophylline:
o If given IV, must be by very slow IV injection
• Indications:
o Asthma (BTS step 3 onwards) as theophylline
o Severe acute asthma (as aminophylline)
o Are phosphodiesterase inhibitors and lead to an ⇑ cAMP and
hence bronchial smooth muscle relaxation
o May also increase cGMP levels and cause smooth muscle
relaxation
o Nausea / vomiting
o Hypokalaemia
o CNS stimulation
• Interactions (many – is metabolised by liver enzymes):
o Adenosine:
 Actions of adenosine are inhibited by the methylxanthines
o Plasma concentration increased by:
 COC pill
 Erythromycin
 Cimetidine
 Verapamil
o Plasma concentration decreased by:
 Carbamazepine
 Phenytoin
 Rifampicin
• Caution:
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o Half-life is increased by:
 Cardiac failure
 Liver disease
 Viral infections
o Half-life is decreased by:
 Alcoholism
 Smoking
Leukotriene antagonists:
• E.g. montelukast
• Taken orally
• Indications:
o Asthma (BTS step 3 onwards)
o Block the effects of cysteinyl leukotrienes (e.g. LTC4, LTD4 and
LTE4) in the airways
• Advantages:
o Improved compliance (oral and don’t have the steroid stigma)
o Some patients respond well to them
o Well tolerated
• Disadvantages:
o Poor efficacy compared to inhaled steroids
o Unpredictable response
o Expensive
o GI disturbances
o Drug-induced Churg-Strauss syndrome
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Analgesics
Taxonomy of opioids:
• Opioid:
o A compound acting at an opioid receptor
• Opiate:
o An alkaloid derived from opium
Adverse effects of opioids:
• CNS:
o Respiratory depression:
 Decreased respiratory rate
 Relief of dyspnoea
o Sedation
o Euphoria
o Meiosis
o Anti-tussive
o Nausea / vomiting
• Non-CNS:
o Pruritis
o Constipation
o Urinary retention
• Opiates only:
o Histamine release:
 Not opioid receptor mediated
Mechanism of action of opioids:
• Mimic endogenous opioids by acting on µ, δ and κ receptors in the:
o Dorsal horn
o Peri-aqueductal grey matter
o Midline raphe nuclei
Contraindications to the use of strong opioids:
• Severe respiratory disease (e.g. COPD)
• Head injury / raised intracranial pressure:
o Interfere with neurological assessment
• Hepatic failure
• Acute alcohol intoxication
WHO analgesic ladder:
• Step 1:
o Non-opioid analgesics:
 Aspirin
 Paracetamol
 NSAIDs
• Step 2:
o Weak opioids /partial opioid agonists:
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 Codeine
 Tramadol
• Step 3:
o Strong opioids:
 Morphine
 Diamorphine
Paracetamol (acetaminophen):
• Indications:
o Mild to moderate pain
o Pyrexia
o Dangerous in overdose
• Overdose:
o Signs / symptoms:
 None (generally)
 Abdominal pain
 Hypoglycaemia
 Vomiting
o Investigations:
 ABG, FBC, glucose, LFTs (ALT), INR, U&Es
o Treatment:
 Remove the drug:
• If >12g and <1 hr since ingestion - gastric lavage
• If <8 hrs since ingestion - activated charcoal
 Find the time vs paracetamol concentration graph in A&E:
• If above treatment line start N-acetylcysteine
o Rule of thumb:
 If PT (secs) > time since od (hrs) then bad prognosis
o Criteria for transfer to specialist liver unit:
 Encephalopathy / ⇑ ICP
 INR > 2.0 at < 48 hrs or INR >3.5 at 72 hours:
• If INR is normal at 48 hours, patient can go home
 Renal impairment (creatinine >200µmol/L)
 Blood pH <7.3
 Systolic BP <80mmHg
• Cautions:
o Hepatic / renal impairment
o Alcohol dependence
Codeine phosphate:
• Indications:
o Cough suppression
o Diarrhoea
• Half-life of 3.5 hours
o Constipation (prominent)
o See “adverse effects of opioids”
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Tramadol:
• Synthetic analogue derived from codeine
• Indications:
o Moderate to severe pain
o µ-receptor agonist (like most opioids)
o Inhibits uptake of noradrenaline and 5-HT
• Advantages over other opioids:
o Does not depress respiration
• Disadvantage over other opioids:
o Can cause seizures
Morphine:
• Indications:
o Pain:
 Acute (e.g. myocardial infarction)
 Chronic (e.g. chronic pancreatitis)
 Terminal (e.g. malignancy)
o Acute pulmonary oedema
o Intractable cough in terminal care
• Half-life of 3 hours
• Tolerance to morphine occurs after about 2 weeks of continuous use
• Titration of morphine dose:
o Assess individual 24 hour requirement to relieve pain at rest and
on movement
o Convert to modified release morphine (MST) bd with rapid
release morphine prn for breakthrough pain
o Increase the dose of MST based on the basis of breakthrough
requirements
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The failing heart
Heart failure:
• Acute:
o Myocardial infarction (MI):
 Acute
 Post-MI
o Pulmonary oedema without MI
• Chronic:
o Chronic stable angina
o Heart failure
Drug treatment of acute myocardial infarction:
• Oxygen
• Aspirin 300mg (chewed) or clopidogrel (if aspirin contraindicated)
• Morphine 5-10mg IV + metoclopramide 10mg IV
• GTN 2 puffs or 1 tablet prn
• β-blocker (e.g. atenolol 5mg IV) unless contraindicated
• Thrombolysis:
o Indications:
 Presentation within 12 hours of chest pain and
 ST elevation >2mm in 2 or more chest leads or
 ST elevation >1mm in 2 or more limb leads or
 New left bundle branch block or
 Posterior infarction
o Contraindications:
 Bleeding
 Prolonged / traumatic CPR
 Trauma / surgery (within 2 weeks)
 Recent haemorrhagic stroke
 Severe hypertension (>200/120mmHg)
 Pregnancy
 Suspected aortic dissection
o Thrombolytic agent:
 Streptokinase (SK):
• 1.5 million units in 100mls 0.9% saline over 1 hour
• Usual first choice
• Risk of allergy / anaphylaxis
 Tissue plasminogen activator (tPA):
• Give if patient already received SK
• Alteplase  infusion
• Tenecteplase  bolus injection
• Heparin:
o DVT / PE prophylaxis
Drug treatment post-myocardial infarction:
• Aspirin 75mg od
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• β-blocker (e.g. atenolol) or verapamil if contraindicated
• ACE inhibitor (especially if evidence of heart failure)
• Statin (e.g. benefit shown even if “normal” cholesterol levels)
• Treat other risk factors:
o Diabetes mellitus
o Hypertension
• Think of the 4 A’s (Aspirin, Atenolol, ACE inhibitor and Atorvastatin)
Drug treatment of acute pulmonary oedema:
• Sit patient upright
• Oxygen
• Furosemide (40 – 80mg slow IV)
• Diamorphine (2.5 – 5mg slow IV)
• GTN 2 puffs or 2x0.3mg tablets
• If systolic BP >100mmHg start nitrate infusion (keep >90mmHg)
• If patient worsening:
o Repeat furosemide 40 – 80mg slow IV
o Consider ventilation
o Consider increasing nitrate infusion
Drug treatment of chronic stable angina:
• Aspirin
• Nitrates:
o Relief:
 GTN
o Prevention:
 Long-acting nitrates
• β-blockers (e.g. atenolol 50-100mg/24 hours po)
• Calcium-channel blockers:
 Caution with concomitant use of β-blocker
o Dihydropyridines:
 Amlodipine
o Non-dihydropyridines:
 Diltiazem
 Verapamil (caution with β-blockers)
• Potassium channel activator:
o Nicorandil
Drug treatment of chronic heart failure:
• Diuretics:
o Furosemide (symptomatic only) ±
o Spironolactone:
 Potassium-sparing
 Shown to reduce mortality
o Metolazone:
 Thiazide diuretic
 Synergistic with furosemide for refractory oedema
• ACE inhibitors:
o Shown to reduce mortality
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• β-blockers:
o Shown to reduce mortality (probably via ⇓ arrhythmias)
o Synergistic with ACEIs
o “Start low, go slow” – needs careful titration
• Digoxin:
o Can be used even if the patient is in sinus rhythm
o No reduction in mortality
o ⇓ in hospital admissions
• Angiotensin II receptor antagonists:
o Probably similar to ACEIs but little conclusive evidence
• Nitrates:
o Probably reduce mortality (but less so than ACEIs)
o Used in those in whom ACEIs are contraindicated
Nitrates:
• All function as nitric oxide (NO) donors
• Cause mainly venous dilatation (hence ⇓ preload)
• Mechanism of action of NO:
o NO stimulates guanylyl cyclase which leads to an ⇑ cGMP
o ⇑ cGMP leads to smooth muscle relaxation
• Glyceryl trinitrate (GTN):
o Onset is rapid and lasts for ~30 mins
o Usually given sublingually
• Long-acting nitrates (isosorbide mono-/dinitrate):
o More stable than GTN and last several hours
o Isosorbide mononitrate is the active metabolite of isosorbide
dinitrate:
 The mononitrate avoids the unpredictable first-pass
metabolism of the dinitrate
o Tolerance develops after as little as 24 hours – avoid by
omitting the evening dose (permits an 8 hour drug-free interval)
o Headaches (frequently dose-limiting)
o Hypotension / fainting
o Reflex tachycardia (prevented by administration of a β-blocker)
o Constrictive pericarditis
o Hypotension
o Head trauma
o Hypertrophic obstructive cardiomyopathy (HOCM)
o Valvular stenosis (aortic / mitral)
• Interactions:
o Sildenafil (Viagra):
 Profound hypotension
β-blockers:
• Non-selective:
o Propranolol:
 Is a full antagonist
o Pindolol / oxprenolol:
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 Are partial agonists
o Labetolol:
 β and α antagonist (β > α)
• “Cardio-selective” (β1-antagonists):
o Atenolol
o Metoprolol
• Indications:
o Angina
o Heart failure
o Hypertension
o Post-MI
o Prevention of variceal bleeding in liver disease (propranolol)
o Prophylaxis of migraine
o “Stress”-induced arrhythmias
o Most do not affect resting parameters (e.g. heart rate) but
prevent the exercise-induced cardiovascular changes caused by
sympathetic stimulation
o Anti-hypertensive action probably arises from an alteration in
the CNS “set-point”
o Lethargy / fatigue (usually improves with use)
o Bradycardia
o Cold hands / feet
o Hypotension
o Bronchospasm (including cardio-selective agents)
o Nightmares
o Worsened / precipitated heart failure
o Asthma / COPD
o Bradycardia / heart block
• Interactions:
o Diltiazem / verapamil:
 ⇑ risk of bradycardia / AV block
o Insulin / oral anti-diabetic agents:
 β-blockers mask the signs of hypoglycaemia
Calcium-channel blockers:
• Two classes:
o Dihydropyridines:
 Nifedipine (short-acting)
 Amlodipine (longer-acting)
 Diltiazem
 Verapamil
• Indications:
o All:
 Angina (especially vasospastic angina)
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 Hypertension
o Nifedipine:
 Raynaud’s phenomenon
o Verapamil:
 Supraventricular arrhythmias:
• Adenosine has largely replaced in acute situation
• Can be used as prophylaxis against SVTs
o Block L-type voltage-sensitive Ca2+
channels in:
 Arterial smooth muscle (vasodilatation):
• Both classes
• Can cause a reflex tachycardia
 Myocardial conduction system (negative inotropism):
• Non-dihydropyridines (as they have a high
affinity for channels in the activated state
• Amlodipine causes less tachycardia than nifedipine
• Verapamil (and to a lesser extent diltiazem) depress the sinus node:
o Mild resting bradycardia
• Verapamil slows conduction at the AVN
• Diltiazem has actions in between verapamil and nifedipine:
o Popular in treatment of angina – does not cause tachycardia
o Fluid retention (ankle oedema):
 Can be severe enough to merit withdrawal
 Is a local effect that has nothing to do with Na+
retention
o Headaches
o Hypotension
o Flushing
o Gum hypertrophy
o All:
 Cardiogenic shock
o Dihydropyridines:
 Severe aortic stenosis / HOCM
 Unstable angina
 Myocardial conduction defects (e.g. bradycardia)
 Heart failure:
• Further depression of cardiac function
o Nifedipine:
 Angina (short-acting preparation may ⇑ mortality)
o Verapamil:
 Ventricular tachycardia (potentially lethal)
 AF with Wolff-Parkinson-White syndrome
• Interactions:
o Diltiazem:
 Digoxin:
• Diltiazem ⇑ plasma concentration of digoxin
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 Carbamazepine:
• Diltiazem ⇑ plasma concentration of carbamazepine
 Phenytoin:
• Diltiazem ⇑ plasma concentration of phenytoin
o Nifedipine:
 Diltiazem:
• ⇑ plasma levels of nifedipine
 Phenytoin:
• Nifedipine ⇑ plasma levels of phenytoin
 Grapefruit juice:
• ⇑ plasma levels of nifedipine (and other
dihydropyridines but not Amlodipine)
o Verapamil:
 β-blockers (asystole, severe hypotension, heart failure)
 Digoxin:
• Verapamil ⇑ plasma concentration of digoxin
 Cyclosporin:
• Verapamil ⇑ plasma concentration of cyclosporin
Angiotensin converting enzyme inhibitors (ACEIs):
• E.g. captopril, enalapril, lisinopril
• Indications:
o Diabetic nephropathy
o Hypertension
o Heart failure
o Post-MI
• Inhibit ACE, thus reduce circulating angiotensin II
• Actions of angiotensin II (mediated via the AT1 receptor):
o Potent vasoconstrictor
o Aldosterone secretion:
 Na+
retention
 K+
excretion
• Advantages:
o Do not affect blood lipids
o May improve cardiac remodelling
o Postural hypotension:
 Usually first-dose
 More common in sodium-depleted patients
o Dry cough (Chinese are more susceptible)
o Hyperkalaemia
o Angioedema (in 1 – 2% of patients)
o Poor renal arterial perfusion pressure:
 Renal artery stenosis / coarctation of the aorta:
• Loss of renal efferent arteriole tone (caused by the
ACEI) and ⇓ afferent arteriole pressure leads to
renal ischaemia
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o Aortic stenosis
o Pregnancy
• Interactions:
o NSAIDs:
 ⇑ risk of renal impairment
o Potassium-sparing diuretics:
 ⇑ risk of hyperkalaemia
o Lithium:
 ACEIs ⇓ excretion of lithium
o Diuretics:
 ⇑ risk of hypotension
Angiotensin II (AII) receptor antagonists:
• E.g. losartan, irbesartan, candesartan
• Indications:
o Diabetic nephropathy
o Hypertension
o Heart failure (unlicensed indication)
o Block the AT1 receptor, inhibiting the actions of angiotensin II
o As they do not block ACE, they do not affect the metabolism of
bradykinin – possibly why they do not cause a cough
• Adverse effects/contraindications/interactions – as for ACE inhibitors
Digoxin:
• Indications:
o Supraventricular dysrhythmias (esp. AF) for ventricular rate
control
o Heart failure (improves symptoms not mortality)
o Is a cardiac glycoside extracted from foxglove leaves
o Inhibits cardiac membrane Na+
/K+
-ATPase:
 ⇑ intracellular Na+
 Secondary ⇑ in intracellular Ca2+
• Clinical effects:
o ⇑ force of cardiac contraction
o ⇑ cardiac vagal activity:
 ⇓ heart rate
 ⇓ AV conductance
 ⇑ AVN refractory period
• Common adverse effects:
o Anorexia
o Nausea
o Vomiting
• Toxic levels:
o Digoxin requires therapeutic drug monitoring
o Risk of toxicity increased with:
 Hypokalaemia (reduced competition for pump binding)
 Hypercalcaemia
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 Hypothyroidism
o May require digoxin specific antibody fragments (Fab)
o Features:
 Nausea (severe)
 Dysrhythmias:
• VT
• Heart block
 Xanthopsia (distortion of yellow colour vision)
o Complete heart block
o HOCM
o Wolff-Parkinson-White syndrome
• Caution in renal impairment:
 Digoxin is excreted by the kidneys
• Drugs increasing risk of digoxin toxicity:
o Anti-arrhythmics:
 Amiodarone
 Quinidine
o Calcium channel blockers (non-dihydropyridines)):
 Diltiazem
 Verapamil
o Diuretics (loop and thiazide):
 Cause hypokalaemia, thus ⇑ risk of digoxin toxicity
Nicorandil:
• Indications:
o Angina
o Potassium channel activator with a nitrate component
o Causes both arterial and venous vasodilatation
o Headache
o Flushing
o Oral ulceration (rarely)
• Interactions:
o Sildenafil:
 Profound hypotension – avoid concomitant use
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Endocrinology
Drug treatment of hyperthyroidism:
• Immediate symptom control:
o Propranolol
• Long-term treatment:
o Thionamides:
 Carbimazole or
 Propylthiouracil
o Radioiodine (131
I)
• Prior to surgery to decrease thyroid vascularity:
o Lugol’s iodine solution
Immediate management of thyrotoxic storm:
• IV fluids
• Take blood for T3, T4 (and cultures if infection suspected)
• Sedate if necessary:
o E.g. chlorpromazine
• Propranolol (oral or IV if no contraindications)
• Digoxin:
o May be needed to slow the heart
• Anti-thyroid drugs:
o Carbimazole
o Lugol’s solution
• Corticosteroids (IV hydrocortisone or oral dexamethasone)
Drug treatment of hypothyroidism:
• Hypothyroidism:
o Levothyroxine (T4)
• Myxoedema coma:
o Liothyronine (T3)
Drug treatment of Addison’s:
• Disease:
o Oral hydrocortisone:
 20mg in the morning
 10mg in the evening
 Double during febrile illness, stress or injury
o Fludrocortisone:
 Only needed if:
• Postural hypotension
• ⇓ Na+, ⇑K+ or ⇑ renin
 Give every second day
• Crisis:
o Hydrocortisone 100mg IV stat
o IV fluids (colloid to resuscitate then crystalloids)
o Glucose IV if hypoglycaemic
o Antibiotics if infection present
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Drug treatment of Cushing’s syndrome:
• Treat the underlying cause – rarely need drug therapy long-term
• Suppression of plasma cortisol level:
o Aminoglutethemide
o Ketoconazole
o Metyrapone
Drug treatment of Conn’s syndrome:
• Definitive treatment is with surgery
• Spironolactone
Drug treatment of diabetes insipidus (DI):
• Cranial DI:
o Treat the underlying cause
o Intranasal desmopressin (DDAVP)
• Nephrogenic DI:
o Treat the underlying cause
o Bendrofluazide (paradoxically, as this is a diuretic)
Drug treatment of acromegaly:
• Best treated with trans-sphenoidal surgery or irradiation
• Somatostatin analogues (first line):
o Octreotide (short-acting)
o Lanreotide (long-acting)
• Dopamine agonists:
o Bromocriptine
o Cabergoline
Drug treatment of hypopituitarism:
• Need to replace what is missing
• ACTH:
o Hydrocortisone
• GH:
o Recombinant GH is available
• FSH, LH:
o Testosterone - males
o Oestrogen (via COC pill) - females
• TSH:
o Thyroxine (if hypothyroid, but can’t use to TSH to monitor)
• No need to replace prolactin
Drug treatment of hypogonadism:
• Males:
o Testosterone
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• Females:
o COC pill
Drug treatment of hyperprolactinaemia:
• Definitive treatment is surgical
• Dopamine agonists:
o Bromocriptine
o Cabergoline
Drug treatment of hypercalcaemia:
• Treat underlying cause if possible
• IV fluids
• Bisphosphonates
• Salmon calcitonin:
o Rarely used
o Faster onset than bisphosphonates
• Steroids:
o E.g. for sarcoidosis
• Furosemide (once rehydrated)
Drug treatment of hypocalcaemia:
• Mild:
o Oral calcium supplements (e.g. sandocal)
• Severe:
o 10mls 10% calcium gluconate IVI over 30 mins
o Repeat as necessary
• Must correct magnesium levels – will never correct Ca2+
otherwise
Drug treatment of phaeochromocytoma crisis:
• Control BP with IV phentolamine (short-acting α-antagonist)
• When BP controlled, give phenoxybenzamine (irreversible α-
antagonist)
• Give β1-blocker
• Arrange for surgery within next few weeks
Thionamides:
• E.g. carbimazole, propylthiouracil
• Indications:
o Carbimazole:
 Hyperthyroidism
o Propylthiouracil:
 Usually reserved for patients intolerant to carbimazole
o All:
 Inhibition of thyroid peroxidase
 Immunosuppressive properties (controversial)
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o Carbimazole:
 Is a prodrug (converted to methimazole)
o Propylthiouracil:
 Inhibits peripheral conversion of T4  T3
• How to use:
o Aim is to render the patient euthyroid and then give a ⇓ dose for
maintenance
o It is often possible to stop treatment after 1 or 2 years (50%
relapse rate)
o GI disturbances
o Carbimazole:
 Pruritis
 Rash
o Agranulocytosis:
 Carbimazole (0.1%)
 Propylthiouracil (0.4%)
 Patients should be told to seek medical attention if they
develop symptoms of infection (e.g. sore throat):
• If neutropenia confirmed  stop treatment
• Cautions:
o Pregnancy:
 Low doses should be used as carbimazole crosses the
placenta and can cause neonatal hypothyroidism / goitre
 PTU is less problematic in pregnancy
Radioiodine (131
I):
• Treatment of choice in pts >40 years (can be used in younger pts)
• Indications:
o Hyperthyroidism
o Disseminated thyroid malignancy
o The radioactive iodine is localised to the thyroid where it
destroys thyroid tissue via β-radiation
• Treatment renders the pt euthyroid within 4-6 weeks, when thyroxine
replacement therapy can be undertaken (lifelong)
o Causes hypothyroidism
o May precipitate thyroid storm
o Children
o Pregnancy (also, pregnancy must not be allowed to occur
within 3 months)
o Mothers who are unable to leave their children in others care for
at least 10 days (to avoid exposure)
Thyroxine:
• May be either T4 (Levothyroxine) or T3 (liothyronine)
• T3 is faster acting than T4 but with a shorter half-life
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• Adverse effects (mainly in overdose):
o Angina
o Dysrhythmias (including AF)
o MI
o Tachycardia
o Hyperthyroid symptoms (even when TSH in normal range)
• Cautions:
o Thyroxine should be introduced slowly in those with IHD
• Interactions:
o Warfarin:
 Thyroxine ⇑ the effect of warfarin
Corticosteroids:
• E.g. hydrocortisone, prednisolone, dexamethasone
• Indications (many):
o Anti-inflammatory:
 Topical:
• Asthma
• Skin disorders (e.g. eczema)
 Systemic:
• Anaphylaxis
• IBD
• Rheumatoid arthritis
o Immunosuppression:
 Connective tissue diseases (e.g. temporal arteritis)
 Leukaemia
 Sarcoidosis
 Transplant rejection
o Replacement:
 Addison’s disease
 Congenital adrenal hyperplasia
o Bind to cytoplasmic receptor that diffuses into nucleus and binds
to steroid-response elements on DNA:
 Either increases or decreases transcription with numerous
effects
o Inhibits phospholipase A2 (thus ⇓ production of arachidonic acid)
o ⇓ B and T cell responses to antigens
• Adverse effects (many):
o CNS:
 Depression
 Psychosis
o Endocrine:
 Adrenal suppression
 Hirsuitism
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 Impotence
 Oligo-/amenorrhoea
 Weight gain
o Eyes:
 Cataracts
 Glaucoma
o Gastrointestinal:
 Candidiasis
 Peptic ulceration
 Pancreatitis
o Immune system:
 ⇑ susceptibility to and ⇑ severity of infections
o Metabolic:
 Hyperglycaemia
 Hypertension
o Musculoskeletal:
 Growth suppression
 Myopathy
 Osteoporosis
o Skin:
 Abdominal striae
 Buffalo hump
 Easy bruising
 Poor wound healing
 Thinning
• Differences between the different steroids:
o Hydrocortisone:
 Replacement therapy
 IV in shock / status asthmaticus
o Prednisolone:
 Orally for anti-inflammatory effects
o Dexamethasone:
 No salt-retaining properties
 Very potent
 Useful when high doses required (e.g. cerebral oedema)
o Budesonide / beclomethasone:
 Pass membranes very poorly
 Much more active topically (e.g. aerosol, gut)
• Interactions:
o Enhances activity of warfarin
o Live vaccines (impairs response)
o Reduces activity of anticonvulsants (carbamazepine,
phenytoin)
• Withdrawal of glucocorticoids – withdrawal gradually in the following:
o Course duration >3 weeks
o Received >40mg prednisolone (or equivalent) daily
o Been given repeated doses in the evening
o Taken a short course within 1 year of taking long-term therapy
• Notes:
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o “Physiological” dose of steroid is ~7.5mg prednisolone
o Patients should be given a steroid card
Metyrapone:
• Indications:
o Cushing’s syndrome:
 Especially that not amenable to surgery (e.g. lung ca)
o Resistant oedema due to aldosterone secretion in:
 Cirrhosis
 Congestive cardiac failure
o Competitive inhibitor of 11β-hydroxylase
o Inhibits endogenous production of cortisol (and to a lesser
extent aldosterone) by the adrenals
o Adrenocortical insufficiency
o Pregnancy / breast feeding
o Hypoadrenalism
Desmopressin (DDAVP):
• Synthetic vasopressin (ADH) analogue
• Indications:
o Cranial diabetes insipidus (diagnosis and treatment)
o Haemophilia
o Persistent enuresis
o Selectively agonises V2 receptors on renal tubular cells:
 Leads to increased reabsorption of water
 Thus devoid of vasoconstrictor activity (V1)
o Also increases the plasma concentration of factor VIII
o Dilutional hyponatraemia
o Fluid retention
o Heart failure
Somatostatin analogues:
• E.g. octreotide (given tds), lanreotide (given once monthly)
• Indications:
o Acromegaly
o Carcinoid syndrome
o Variceal bleeding (octreotide, unlicensed indication)
• Mechanism of action in acromegaly:
o Inhibits GH release from the pituitary gland
o 90% of patients respond and 60% have GH level normalisation
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o Gallstones
o GI disturbances
• Interactions:
o Anti-diabetic agents (oral and insulin):
 Octreotide may ⇓ requirements for these drugs
Dopamine agonists:
• E.g. bromocriptine (short-acting), cabergoline (long-acting)
• Indications:
o Acromegaly
o Idiopathic Parkinson’s disease
o Suppression of lactation
o Cyclical benign breast disease
o Directly stimulate dopamine receptors in the CNS (anti-
Parkinson’s effect)
o Inhibits release of prolactin from anterior pituitary
o Inhibits the release of GH in acromegalics:
 Increases GH levels in non-acromegalics
• Lead to a maximum ⇓ of GH of 7-60%:
o Only 10-15% of patients achieve GH normalisation
o Nausea / vomiting
o Postural hypotension
o Drowsiness / confusion
o Dyskinesia
o Fibrotic reactions (rare):
 Pericardial / pulmonary and retroperitoneal fibrosis
• Domperidone (D2 antagonist):
o Can be used to relieve the peripheral adverse effects of
bromocriptine (does not cross the BBB so has no effect on CNS
effects)
• Interactions:
o Erythromycin and sympathomimetics (e.g. dobutamine):
 Increase the plasma concentration of bromocriptine
Growth hormone:
• E.g. somatrophin
• Indications:
o Adults:
 GH deficiency
o Children:
 GH deficiency
 Chronic renal impairment
 Turner’s syndrome
Testosterone:
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• E.g. restandol (oral), sustanon (IM), andropatch (transdermal patch)
• Indications:
o Male androgen deficiency
o Androgenic effects:
 Fusion of epiphyses in prepubertal boys (stunted
growth)
 Hirsuitism
 Male pattern baldness
 Acne
o Prostate abnormalities (enlargement ± malignancy)
o Cholestatic jaundice
o Cancers:
 Male breast
 Primary liver tumour
 Prostate
• Interactions:
o Warfarin:
 Potentiates actions of warfarin
Combined oral contraceptive (COC) pill:
• E.g. cilest, microgynon
• Are preparations containing both an oestrogen and a progestogen
• Indications:
o Contraception
o Menstrual cycle control / menorrhagia
o Mild endometriosis
o Premenstrual symptoms
o Exerts a negative feedback on the pituitary and inhibits
gonadotrophin release, and thus inhibits ovulation
o Major:
 ⇑ risk of venous thromboembolism (VTE)
 ⇑ risk of hypertension
 ⇑ risk of breast carcinoma (small)
o Minor:
 Breast tenderness
 Headaches
 Nausea
 Weight gain
o Absolute:
 History of CVA / IHD / VTE
 Migraine (severe / focal)
 Blood clotting disorders
 Active breast / endometrial cancer
o Relative:
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 Age > 40 years
 Obesity
 Smokers
• Interactions:
o Drugs reducing the efficacy of the COC pill:
 Broad-spectrum antibiotics
 P450 inducers:
• Carbamazepine
• Phenytoin
• Rifampicin
o Warfarin:
 Oestrogens (including the COC pill) reduce the effect of
warfarin
• The COC pill should be stopped several weeks prior to an elective
surgical procedure to ⇓ risk of VTE
Calcitonin:
• E.g. calcitonin (porcine natural), salcatonin (synthetic salmon
calcitonin)
• Indications:
o Hypercalcaemia (rarely)
o Malignant bone pain
o Osteoporosis
o Paget’s disease of bone (especially pain relief)
o Lowers serum calcium:
 Inhibits osteoclast activity
 Increases renal Ca2+
excretion
o Facial flushing
o Nausea / vomiting
o Tingling sensation in the hands
o Unpleasant taste in the mouth
α1-antagonists:
• Non-selective (α1 and α2):
o Phentolamine (short-acting)
o Phenoxybenzamine (irreversible, long-acting)
• α1:
o Prazosin
o Doxazosin
o Tamsulosin (Flomax)
• Indications:
o Non-selective α-blockers:
 Phaeochromocytoma
o α1-blockers:
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 Hypertension
 Benign Prostatic hypertrophy (doxazosin, tamsulosin)
o Antagonism of post-synaptic α1-adrenoceptors leads to
vasodilatation
o α1 blockade also leads to relaxation of the internal urethral
sphincter, resulting in ⇑ urinary flow
o First-dose hypotension
• Interactions:
o Other hypotensive agents - ⇑ risk of hypotension
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Lipids
Which patients require lipid-lowering therapy?
• Primary prevention:
o Guidelines are frequently changing
 Total [chol] >5mmol/L and CHD risk >30% over 10yrs or
 10yr CHD risk >=15%
• Secondary prevention:
o History of CVS event (angina, MI, PVD, CVA) ±
o [chol] >=5mmol/L
• Choice of drug:
o First choice therapy:
 Statin
o Second choice therapy:
 Fibrates
 Anion exchange resins
• Note about diet:
o Diet lowers [cholesterol] only by ~10% (as we endogenously
synthesise cholesterol, not just eat it)
Drugs used to treat obesity:
• Orlistat
• Sibutramine
Statins:
• E.g. simvastatin, atorvastatin, pravastatin
• Usually taken at night
• Reduce incidence of all cardiovascular events and total mortality
o Are HMG-CoA reductase inhibitors – block the rate-limiting step
in hepatic cholesterol synthesis
o Due to the ⇓ concentration of cholesterol in the hepatocytes,
there is an ⇑ in the number of hepatic LDL receptors
o This leads to a ⇓ in plasma LDL
o Those with homozygous familial hypercholesterolaemia do not
respond to statins (as they have no LDL receptors)
• Adverse effects (all uncommon):
o Myositis:
o Patients complain of weakness / aching muscles
 If CK >5x upper limit of normal discontinue
 Can lead to rhabdomyolysis and renal failure
 If this occurs, cannot use a statin again
o Altered LFTs
o Liver disease
o Pregnancy
• Interactions:
o Drugs increasing the risk of myositis:
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 Cyclosporin
 Fibrates
o Warfarin:
 Statins potentiate the actions of warfarin
• Patients should have their LFTs monitored regularly whilst on a statin
Fibrates:
• E.g. bezafibrate, gemfibrozil
• Actions:
o Unclear mechanism – possibly stimulate lipoprotein lipase
o ⇓ TGs (~30%)
o ⇓ LDL (~10%)
o ⇑ HDL (10%)
• Are first line drugs in patients with hypertriglyceridaemia (who are at
risk of pancreatitis and retinal vein thrombosis)
o GI disturbance
o Myositis
o Gallstones
o Hepatic / renal impairment
o Pregnancy
• Interactions:
o Statins:
 ⇑ risk of myositis
o Warfarin:
 Potentiate the actions of warfarin
Anion exchange resins:
• E.g. cholestyramine, cholestipol
o Bind bile acids in the bowel
o Forces the liver to synthesise more bile acids – causes an
increase in the expression of LDL receptors and lowering of LDL
o GI disturbance:
 Bloating
 Constipation
 Nausea / vomiting
o May aggravate hypertriglyceridaemia
o Impairs the absorption of many drugs
o May impair the absorption of fat soluble vitamins:
 May require supplements of vitamins A, D and K
Omega-3-oils (fish oils):
• Can be effective in hypertriglyceridaemia
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o Fish-like odour to the patient
Orlistat:
• Indications:
o Adjunct in obesity management:
 BMI >30 if no diabetes
 BMI >27 if diabetic
o Pancreatic lipase inhibitor
o Impairs absorption of dietary fat
o GI disturbance:
 Probably why the drug works as patients reduce their fat
intake to reduce the side-effects
o May impair the absorption of fat soluble vitamins:
 May require supplements of vitamins A, D and K
o Cholestasis
o Pregnancy
• Interactions:
o Warfarin:
 Difficulty in controlling the INR
Sibutramine:
• Indications:
o As for orlistat
o Centrally acting anorectic
o Inhibits reuptake of noradrenaline and 5-HT
o Hypertension
o Many others
o Many, mainly cardiovascular
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Clotting
Antiplatelet drugs:
• Aspirin
• Dypyridamole
• Clopidogrel
• GP IIb/IIIa receptor antagonists:
o Abciximab
Anticoagulants:
• Oral:
o Warfarin
• Parenteral:
o Unfractionated heparin
o Low molecular weight heparin (LMWH)
Thrombolytic agents:
• Streptokinase
• Tissue plasminogen activator (tPA)
Indications for antiplatelet drugs:
• Acute coronary syndromes
• Primary prevention of cardiovascular events:
o If 10yr CVD risk >=20% (with a controlled blood pressure)
• Secondary prevention of cardiovascular events:
o CVA / TIA
o IHD
o PVD
• Heart valve replacements
• AF (in those who cannot be anti-coagulated)
Indications for oral anti-coagulants:
• AF
• Prophylaxis / treatment of VTE:
o DVT
o PE
• Mechanical heart valve replacements
• Dilated cardiomyopathy / left ventricular aneurysm
• ? TIAs
Indications for parenteral anti-coagulants:
• Acute coronary syndromes
• Acute arterial obstruction
• Treatment of VTE:
o DVT
o PE
Indications for thrombolytic agents:
• Acute myocardial infarction
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• Arterial thrombus
• Life-threatening PE
• Occluded lines / shunts
Aspirin:
• Indications:
o Pyrexia
o Anti-platelet:
 Acute myocardial infarction
 History of:
• Angina
• Intermittent claudication
• Myocardial infarction
• Stroke
• TIA
 AF (in patients where warfarin is contraindicated)
 Kawasaki syndrome (only childhood indication)
o Irreversibly inactivates platelet COX
o Platelets cannot synthesise new COX:
 Takes 4 – 7 days for new platelets to be synthesised
following a single dose (300mg)
 Reduction in production of the platelet aggregating
compound thromboxane A2
o Bleeding
o Bronchospasm
o GI irritation / bleeding
o Dangerous in overdose
• Overdose:
o Signs / symptoms:
 Coma
 Dehydration
 Hyperventilation
 Tinnitus
 Seizures
 Sweating
 Vertigo
 Vomiting
o Investigations:
 Levels (salicylate and paracetamol, may have taken
both):
• Levels >700mg/L are potentially fatal
 ABG, FBC, Glucose, LFTs, INR, U&Es
o Treatment:
 Remove drug:
• Gastric lavage if od <1 hour ago
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 Correct acidosis with 1.26% HCO3
-
 >500mg/L:
• Consider alkalinization of the urine
 Consider dialysis when:
• Levels >700mg/L
• Cardiac / renal failure
• Seizures
• Cautions:
o Asthma
o Uncontrolled hypertension
o Children <16 years (unless Kawasaki’s syndrome):
 Risk of Reye’s syndrome
o Active peptic ulceration
o Bleeding disorders (e.g. haemophilia)
• Interactions:
o Warfarin:
 Increased risk of bleeding
o Methotrexate:
 Aspirin ⇑ risk of toxic effects of methotrexate
Dipyridamole:
• Indications:
o Secondary prevention of CVA / TIA:
 Some synergistic benefit with aspirin
 Used in those patients who have had a CVA on aspirin
o Prevention of thromboembolism from prosthetic heart valves:
 Adjunct to oral anti-coagulation
o Phosphodiesterase inhibitor
o Leads to an ⇑ in cAMP and potentiation of prostacyclin
• No increased risk of bleeding (cf aspirin)
o Headache
o Myasthenia gravis (risk of exacerbation)
• Interactions:
o Adenosine:
 Dipyridamole prolong / enhances the effects of adenosine
Clopidogrel:
• Indications:
o Secondary prevention of CVD:
 Within 35 days of MI
 Within 6 months of CVA
o Acute coronary syndrome (without ST elevation):
 Given with aspirin
 Not for >12 months
o Coronary artery stents
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• Mechanisms of action:
o Irreversibly blocks the action of ADP on platelets – leading to a
reduction of platelet aggregation
o Bleeding
o Bone marrow suppression (rare)
• Cautions:
o First few days following MI / CVA
• Interactions:
o Warfarin:
 Increased risk of bleeding
Abciximab:
• Indications:
o Patients awaiting PTCA:
 Short-term prevention of MI in those with ACS
o Patients undergoing PTCA:
 Adjunct to aspirin and heparin
o Monoclonal antibody to GP IIb/IIIa
o Inhibit platelet aggregation
o Bleeding
o Thrombocytopenia
Warfarin:
• Indications:
o Prevention / treatment of VTE:
 DVT
 PE
o Prevention of thromboembolism:
 AF
 Prosthetic heart valves
o Vitamin K antagonist
o Inhibits the vitamin K-dependent synthesis of clotting factors II,
VII, IX and X
o Also inhibits formation of protein C and S:
 Has an initial procoagulant effect
o Takes at least 2–3 days to work (due to the half-life of pre-
existing clotting factors in the circulation)
o Prolongs the prothrombin time (PT)
• Pharmacokinetics:
o Long half-life (40 hours)
o Takes ~5 days after stopping treatment for INR to normalise
o Highly protein-bound (albumin)
• Dosage:
o Loading:
 Warfarin therapy begins with a loading dose, usually:
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• Day 1 - 10mg
• Day 2 – 10mg  measure INR and adjust dose
• Day 3 – 5mg (if still not target INR)
o Daily dose:
 Daily maintenance is usually 3-9mg daily (taken at same
time each day)
• INR (International Normalised Ratio):
o Prothrombin results can vary depending on the thromboplastin
reagent used
o The INR is a conversion unit that takes into account the different
sensitivities of thromboplastins
o Target INRs:
 2 – 2.5:
• Prophylaxis of DVT
 2.5:
• AF
• Treatment of DVT / PE
• Rheumatic mitral valve disease
 3.5:
• Recurrent DVT / PE
• Mechanical prosthetic heart valves
o Monitoring the INR:
 The INR should be determined daily (or alternate days) in
the early days of therapy, then at longer intervals
(depending on response) then up to every 12 weeks
o Bleeding / bruising
o Skin necrosis
o Alopecia
o Liver damage
o Pancreatitis
• Management of warfarin-induced haemorrhage:
o Major bleeding:
 Stop warfarin
 Give vitamin K (phytomenadione) by slow IV injection
 FFP
o INR >8 (no bleeding or minor bleeding):
 Stop warfarin and restart when INR <5
 Vitamin K (either IV or oral)
o INR 6-8: (no bleeding or minor bleeding):
 Stop warfarin and restart when INR <5
o INR <6 but >0.5 units above target value:
 Reduce or stop warfarin and restart when INR <5
o Pregnancy:
 Teratogenic (1st
trimester)
 Foetal haemorrhage (3rd
trimester)
o Peptic ulcer
o Severe hypertension
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• Interactions (many!):
o Drugs that ⇑ the efficacy of warfarin:
 Alcohol
 Cimetidine
 Omeprazole
 Simvastatin
o Drugs that ⇓ the efficacy of warfarin:
 Carbamazepine
 COC pill
 Rifampicin
o Drugs increasing risk of haemorrhage:
 Aspirin
Heparin:
• Low molecular weight heparins (LMWHs) include:
o Enoxaparin
o Tinzaparin
• Indications:
o Treatment of VTE
o Unstable angina
o Acute peripheral arterial occlusion
o Prophylaxis in surgery
o Extracorporeal circuits (e.g. cardiac bypass surgery)
o Heparin potentiates the actions of antithrombin III
o Antithrombin III inactivates factor IIa (thrombin)
o Prolongs the APTT
• Structure:
o Both types of heparin are extracted from bovine lung or hog
intestine
o Unfractionated heparin:
 Mixture of sulphated glycosaminoglycans with a range of
molecular weights up to 40,000
o LMWH:
 Fragments of heparin with weights 4000 – 15,000
• Unfractionated or LMWH?
o Unfractionated heparins are best used when there is a high risk
of bleeding as their effect can be terminated rapidly by stopping
the infusion
o LMWHs do not require monitoring of the APTT and only need to
be given once-daily
o LMWHs have a more predictable subcutaneous absorption
o Thrombocytopenia:
 Immune-mediated
 Develops ~6 days after starting treatment
o Hyperkalaemia:
 Heparin inhibits aldosterone activity
o Haemorrhage
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o Osteoporosis
o Skin necrosis
o Hypersensitivity
o Alopecia
o Bleeding disorders (e.g. haemophilia)
o Thrombocytopenia
o Peptic ulcer
o Recent cerebral haemorrhage
o Severe hypertension
o Severe liver disease (especially variceal disease)
o Hypersensitivity
• The effects of heparin can be reversed by IV protamine sulphate:
o A strongly basic protein that forms an inactive complex with
heparin
Streptokinase (SK):
• Indications:
o Acute MI
o Thromboembolic events:
 PE
 Thrombosed arteriovenous shunts
o Binds circulating plasminogen and converts it to plasmin
o Plasmin then lyses fibrin within the thrombus and dissolves it
o Allergic reactions:
 Rash (common)
 Anaphylaxis
o Hypotension
o Guillain-Barre syndrome
o Bleeding
o Prolonged / traumatic CPR
o Trauma / surgery (within 2 weeks)
o Recent haemorrhagic stroke
o Severe hypertension (>200/120mmHg)
o Pregnancy
o Suspected aortic dissection
• Interactions:
o Warfarin (increased risk of haemorrhage)
• Patients develop antibodies to streptokinase:
o If a patient requires thrombolysis and has received SK in the
past – they should be given recombinant tPA
Tissue plasminogen activator (tPA):
• E.g. alteplase (requires infusion), tenecteplase (bolus)
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• Indications:
o As for SK but in those patients who cannot receive SK
• In contrast to SK, co-administration of tPA and heparin produces
added benefit (but increases the risk of stroke)
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Mood disorders
Which antidepressant?
• No hard and fast rules, although TCAs and SSRIs are generally first
choice
• All antidepressants take 2-6 weeks to work
• Antidepressants should be continued for 4-6 months after resolution
of symptoms
• When to use a TCA:
o Severe depression
o When insomnia is prominent symptom
• When to use a SSRI:
o Suicidal patient (safer in overdose)
o Intolerance to TCAs:
 Prostatism
 Dementia (TCAs can cause confusion)
 Cardiac illness
• When to use a MAOI:
o “Atypical” depression
o Depression refractory to first-line drugs
• When to use venlafaxine:
o Severe depression with hypersomnia
Drugs used as mood stabilisers:
• Lithium carbonate
• Anticonvulsants:
o Carbamazepine
o Valproate
Tri-Cyclic Antidepressants (TCAs):
• More sedating:
o Amitriptylline
o Clomipramine
o Dothiepin
• Less sedating:
o Imipramine
• Indications:
o Moderate to severe depression
o Neuropathic pain (amitriptylline – unlicensed indication)
o Nocturnal enuresis (children)
o Inhibit noradrenaline (NA) and serotonin (5-HT) uptake in
central nerve terminals
o Most TCAs act on several other neurotransmitter receptors and
this is the reason for their large side-effect profile:
 Anti-muscarinic  most TCAs
 Histamine receptor blockade
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o Sedation (some more than others)
o Confusion
o Seizures (⇓ seizure threshold)
o Blurred vision (loss of accommodation)
o Dry mouth (can lead to ⇓ dental hygiene)
o Heart block
o Constipation
o Impotence
o Dysrhythmias (especially heart block)
o Epilepsy
o Severe coronary heart disease
o Suicidal patient (danger in overdose)
• TCA overdose:
o Clinical features:
 Tachycardia
 Mydriasis
 Convulsions
 Arrhythmias
 Hypotension
o Management:
 Treat convulsions with diazepam
 Treat SVT / VT with sodium bicarbonate (even in absence
of acidosis)
• Interactions:
o MAOIs:
 Danger of potentially fatal hyperthermia syndrome
o Anti-arrhythmics:
 Increased risk of ventricular dysrhythmias
o Anticonvulsants:
 TCAs lower the seizure threshold and thus antagonise the
effect of anticonvulsants
o Antipsychotics:
 Increased risk of ventricular dysrhythmias
Selective Serotonin Reuptake Inhibitors (SSRIs):
• E.g. fluoxetine (prozac), paroxetine (seroxat), citalopram
• Indications:
o Depression:
 High suicide risk
 Those intolerant to TCAs (e.g. Prostatism)
o Obsessive compulsive disorder (OCD)
o Eating disorders
o “Selectively” block the uptake of 5-HT by central nerve terminal,
thus increasing it’s concentration
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o Fewer side-effects than the TCAs:
 Less anti-muscarinic effects
 Safer in overdose
o Nausea / anorexia
o Insomnia
o Sexual dysfunction:
 Loss of libido
 Failure of orgasm
o Children <18 years of age:
 ⇑ risk of self-harm / suicidal behaviour
o Mania
• Interactions:
o MAOIs:
 Do not start an SSRI until at least 2 weeks after stopping
a MAOI
 Risk of hyperthermia syndrome:
• Hyperthermia
• Tremor
• Collapse
o Anticonvulsants (e.g. carbamazepine, phenytoin):
 SSRIs ⇑ plasma levels of these drugs
o Haloperidol:
 SSRIs ⇑ plasma levels of haloperidol
Monoamine Oxidase Inhibitors (MAOIs):
• Non-selective (inhibit MAO-A and MAO-B):
o Phenelzine
• MAO-AIs (reversible):
o Moclobemide
• MAO-BIs:
o Selegiline
• Indications:
o “Atypical” depression (especially in young patients):
 Weight gain
 Hypersomnia
o Second-line use in depression (after TCA / SSRI)
o MAO is found throughout body tissues (including the gut)
o There are 2 isoforms of MAO - A and B
o MAO-A has a preference for 5-HT (this is seen to be beneficial in
depression)
o MAO-B has a preference for dopamine (hence an anti-Parkinson
effect with selegiline)
o MAO regulates intra-neuronal concentration of it’s substrates (it
is not involved in the inactivation of released transmitter)
o Hypotension
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o Weight gain
o Sedation
o Anti-muscarinic effects
o Phaeochromocytoma
o Non-compliant patients (unable to monitor diet)
• Interactions:
o Main hazard is with foods – the “cheese reaction”:
 Caused by foods containing high levels of tyramine:
• Hard cheeses
• Yeast extracts (e.g. marmite)
• Red wine / beer
 MAO in the gut wall usually metabolises tyramine, thus
preventing it reaching the systemic circulation
 In the presence of a MAOI, tyramine reaches the
circulation and acts as a sympathomimetic (triggers the
release of NA) and can lead to severe hypertension
 Treat with:
• α1-antagonist (e.g. phentolamine) or
• Nifedipine
o Antidepressants (TCAs, SSRIs):
 Avoid concomitant use (allow washout period in between)
 Potentiation of all side-effects and risk of hyperthermia
syndrome
o Pethidine:
 Hyperthermia
 CNS depression or excitement
o Carbamazepine:
 MAOIs can ⇓ the plasma levels of carbamazepine
• The selective MAO-AIs have a much smaller risk of the “cheese
reaction”
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs):
• E.g. venlafaxine
• Indications:
o Severe / refractory depression
o Anxiety disorders
o Nausea
o Insomnia
o Hypertension (at high doses)
o Withdrawal problems common
• Interactions:
o MAOIs:
 Risk of hyperthermia syndrome
• Fewer side-effects than the TCAs but no more efficacious
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Noradrenaline and Specific Serotenergic Antidepressants (NaSSAs):
• E.g. mirtazapine
• Indications:
o Depression (especially with insomnia)
o Drowsiness (even at low doses)
o ⇑ appetite / weight gain
o Blood dyscrasias (rarely)
• Interactions:
o Other sedatives (including alcohol)
o MAOIs
• Safe in overdose
• Minimal effects on sexual function
Lithium carbonate:
• Indications:
o Acute mania
o Prophylaxis of bipolar disorder
o Recurrent depression
o Aggressive / self-mutilating behaviour
• Toxicity:
o Lithium requires therapeutic drug monitoring:
 Normal range is 0.4 – 1.0mmol/L
o 0.4 – 1.0mmol/L:
 Nausea
 Diarrhoea
 Polyuria / polydipsia (nephrogenic DI)
 Weight gain
o 1.0 – 2.0mmol/L:
 Blurred vision
 Anorexia / vomiting
 Ataxia / dysarthria / tremor
 Drowsiness
o >2.0mmol/L:
 Convulsions
 Hyperreflexia
 Oliguria
 Circulatory failure - death
• Long-term effects:
o Can cause renal tubular damage and hypothyroidism
o Pregnancy (although consider relative risks of drug cessation)
o Renal impairment
o Thyroid disease
o Sick sinus syndrome
o Poor compliance
• Interactions:
o Lithium levels increased by:
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 Diuretics (thiazides > loop)
 ACEIs
 NSAIDs
 Alcohol
o Lithium levels decreased by:
 Xanthines (e.g. theophylline)
 Antacids
 Acetazolamide
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Anti-arrhythmic drugs
Vaughan-Williams classification:
• Class I:
o Are all Na+
channel blockers (local anaesthetics)
o Ib only works in the ventricles
o Ia (A, SAN, AVN, V):
 E.g. quinidine, disopyramide, procainamide
 ⇑ AP duration
 Hardly ever used in the UK (but used in the USA)
o Ib (V only):
 E.g. lidocaine (lignocaine)
 AP duration unaffected or slightly ⇓
o Ic (A, SAN, AVN, V):
 E.g. flecainide
 AP duration slightly ⇑
 Primarily act by slowing conduction
• Class II (A, SAN, AVN, V):
o β-blockers (e.g. propranolol)
o ⇓ automaticity
o ⇓ AP duration acutely (may prolong it with prolonged use)
o ⇓ refractory period
• Class III (A, SAN, AVN, V):
o E.g. amiodarone, sotalol (a β-blocker)
o All have effects on various K+
channels
o ⇑ AP duration
o ⇑ refractory period
• Class IV (SAN, AVN):
o Ca2+
channel blockers (e.g. verapamil)
o Dihydropyridines (e.g. amlodipine) have no role in arrhythmias
• Unclassified:
o Digoxin (AVN)
o Adenosine (AVN)
Supraventricular arrhythmias:
• Supraventricular tachycardias (SVTs) are often due to re-entry:
o SNRT (sinus node re-entry tachycardia)
o AVNRT (atrioventricular node re-entry tachycardia)
o AVRT (atrioventricular re-entry tachycardia):
 Caused by an accessory pathway
• Atrial arrhythmias:
o Atrial tachycardia
o Atrial flutter
o Atrial fibrillation (AF):
 Paroxysmal
 Persistent
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 Permanent
Treatment of SVTs:
• Vagal manoeuvres
• Adenosine:
o 6mg  12mg  12mg
• If adenosine fails:
o Cardiovascular instability:
 Synchronised cardioversion
o No cardiovascular instability:
 Verapamil or
 Digoxin or
 Amiodarone
• Prophylaxis:
o β-blockers
o Flecainide (AVRT)
o Verapamil (AVNRT)
• Wolff-Parkinson-White (WPW) syndrome:
o If pt with WPW has AF and fast ventricular rate:
 Adenosine, digoxin and verapamil are absolutely
contraindicated
 Use Flecainide
Treatment of atrial tachycardia:
• Treat underlying coronary / structural heart disease if present
• Exclude digoxin toxicity
• β-blockers
• Verapamil
• Often refractory to drug treatment – treat with radiofrequency
ablation (RFA)
Treatment of atrial flutter:
• Drugs are generally ineffective, but can try:
o Amiodarone:
 Drug most likely to work
o Digoxin:
 Rate control only
o β-blockers:
 Rate control
 Chance of return to sinus rhythm (SR)
o Verapamil:
 Rate control
 Chance of return to SR
• DC cardioversion ± anticoagulation can work
• RFA is the treatment of choice
Treatment of atrial fibrillation (AF):
• Acute:
o Treat underlying cause (e.g. pneumonia)
o DC cardioversion (first-line choice):
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 Anticoagulation is not essential if AF is of recent onset
(<48 hours) with a structurally normal heart (but most
people do)
 If required, give warfarin for at least 3 weeks before and
at least 4 weeks after
o Control ventricular rate:
 Digoxin
 If ventricular rate still too fast:
• β-blocker (can return patient to sinus rhythm)
o Chemical cardioversion:
 Amiodarone or
 Flecainide (if haemodynamically stable) or
 β-blocker
• Chronic:
o Control ventricular rate:
 Digoxin
 If rate still too fast consider:
• (Cautiously) ⇑ digoxin dose
• β-blocker
• Amiodarone
o Anticoagulation:
 > 65 years:
• Warfarin (INR 2.5 – 3.5)
 <65 years with no risk factors or > 65 years and unable
to be warfarinised:
• Aspirin
Treatment of ventricular tachycardia (VT):
• Acute:
o Haemodynamically stable:
 Amiodarone or
 Lidocaine
o Not haemodynamically stable:
 Synchronised DC cardioversion
 Amiodarone
• Recurrent / paroxysmal:
o Drugs:
 Amiodarone
 β-blocker (works synergistically with amiodarone)
 Sotalol
o Implantable defibrillator:
 ⇓ mortality
Drug treatment of Torsade de Pointes:
• Often associated with prolongation of the QT interval
• Causes of QT prolongation:
o Electrolyte disturbances:
 Hypokalaemia
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 Hypocalcaemia
o Congenital long QT syndromes
o Drugs:
 Class Ic and III anti-arrhythmics
 TCAs
o Ischaemia
• Treatment:
o IV MgSO4
Treatment of bradyarrhythmias:
• Haemodynamically compromised:
o Drugs:
 Atropine ±
 Isoprenaline / adrenaline
o Pacing:
 External
 Temporary transvenous
• Stable:
o Withdraw any negatively chronotropic drugs (e.g. β-blockers)
o Exclude secondary causes:
 ACS
 Hypothyroidism
o Assess need for permanent pacemaker
Adenosine:
• Indications:
o Paroxysmal SVT
o To aid diagnosis of broad complex SVTs
o Binds to adenosine (A1) receptors in the cardiac conduction
system:
 Opens ACh-sensitive K+ channels
o Slows conduction in the heart by prolonging the refractory
period in the AVN / bundle of His
o All are short-lived (half-life of 8 – 10secs)
o Bronchospasm
o Chest pain
o Flushing
o Severe bradycardia (rare)
o Asthma
o 2nd
or 3rd
degree heart block (unless pacemaker in-situ)
• Interactions:
o Dipyridamole:
 Prolongs / enhances action of adenosine
o Theophylline:
 Inhibits adenosine
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Amiodarone:
• Indications:
o Paroxysmal:
 SVT
 Nodal tachycardia
 VT
o Atrial flutter
o AF
o VF
• Amiodarone is generally used when other drugs have been
ineffective or are contraindicated
o Not fully understood
o Blocks several channels:
 α-adrenoceptors, β-adrenoceptors, Na+
and Ca2+
o Generally slows conduction through the heart
o Very long half-life:
 10 – 100 days (average 36 days)
o Requires a loading dose in life-threatening arrhythmias:
 Central vein (causes phlebitis in peripheral veins)
o This means that drug interactions can occur long after
amiodarone has been stopped
o Common:
 Corneal microdeposits (reversible):
• Can cause driver headlight dazzling at night
 Photosensitive rash
o Less common:
 Thyroid dysfunction (hyper- or hypo-)
 Pulmonary fibrosis
 Grey skin colour
 Peripheral neuropathy
 Ataxia
• Special notes:
o Thyroid function must be checked before treatment and every 6
months:
 If hyperthyroidism develops, this can be very refractory
and may require cessation of amiodarone
o Shortness of breath suggests development of pulmonary fibrosis
o Thyroid disease
o Pregnancy
o Iodine allergy (as amiodarone contains iodine)
• Interactions:
o β-blockers / non-dihydropyridines (e.g. diltiazem, verapamil):
 ⇑ risk bradycardia, AV block and myocardial depression
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o Digoxin:
 Amiodarone ⇑ plasma levels of digoxin
o Class Ia drugs:
 ⇑ QT interval
o Phenytoin:
 Amiodarone ⇑ plasma levels of phenytoin
o Warfarin:
 Amiodarone ⇑ plasma levels of warfarin
Lidocaine (lignocaine):
• Indications:
o Ventricular arrhythmias (especially after MI):
 Stops VT and ⇓ risk of VF
 Does not ⇓ mortality when used prophylactically
o Local anaesthesia
o Class Ib anti-arrhythmic agent
o Not active orally (massive 1st
-pass metabolism)
o Blocks fast Na+ channels:
 Slows conduction in the heart (only ventricles)
 Inhibits AP propagation in nerve axons
o Uncommon:
 Convulsions
 Drowsiness
 Bradycardia
 Cardiac arrest
o AV node block (all degrees)
o Severe heart failure
o Hypovolaemia
• Interactions:
o Cimetidine:
 ⇑ plasma levels of lidocaine
Flecainide:
• Indications:
o AVRT
o WPW syndrome associated arrhythmias
o Paroxysmal AF (chemical cardioversion)
o Class Ic anti-arrhythmic agent
o Na+
channel blocker
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o Previous MI
o Haemodynamically significant valvular disease
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Hypertension
British hypertension society (BHS) classification of BP levels:
• Optimal:
o <120 / <80 mmHg
• Normal:
o <130 / <85 mmHg
• High normal:
o 130-139 / 85-89 mmHg
• Hypertension:
o Grade 1 (mild):
 140-159 / 90-99 mmHg
o Grade 2 (moderate):
 >160 – 179 / 100-109 mmHg
o Grade 3 (severe):
 >=180 / >=110 mmHg
o Isolated systolic:
 Systolic BP is more important than diastolic
 Grade 1:
• 140-159 / <90 mmHg
 Grade 2:
• >=160 / <90 mmHg
Complications of hypertension:
• Cerebral:
o Encephalopathy
o Haemorrhage
o Thromboembolism
o TIA
• Other:
o MI (hypertension accounts for 25% of MIs)
o Heart failure
o Dissecting aneurysm
o Renovascular disease
o Peripheral vascular disease
When to treat patients with anti-hypertensive agents:
• Definitely treat:
o >=160 / >=100 mmHg (i.e. grade II hypertension)
• Treat if
o >=140 / >=90 mmHg and (i.e. grade I hypertension)
o Target organ damage or
o CVS complications or
o Diabetes or
o CV event risk >=2%/year (>=20% at 10 years)
Target blood pressure for patients on anti-hypertensive medication:
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• There is evidence for these systolic values but the diastolic is arbitrary
• Patients with diabetes, renal impairment or CVS disease:
o <=130 / <=80 mmHg
• Other patients:
o <=140 / <=85 mmHg
The BHS ABCD approach to the treatment of hypertension:
• Key:
o ACE inhibitor
o Beta blocker
o Calcium channel blocker
o Diuretic (thiazide)
• Step 1:
o Young (<55 yrs) and non-black:
 A (or B*)
o Older (>55 yrs) or black:
 C or D
• Step 2:
o A (or B*) + C or D
• Step 3:
o A (or B*) + C + D
• Step 4 (resistant hypertension):
o Add either:
 α-blocker
 Spironolactone
• *β-blockers will probably be removed from this algorithm as they may
induce new onset diabetes mellitus
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Antibiotic therapy
Below are empirical treatments only – the correct antibiotic will depend upon
sensitivities determined by bacteriological culture
Treating pneumonia:
• Community acquired:
o Mild (streptococcus, haemophilus, mycoplasma):
 Amoxicillin po ±
 Erythromycin po (if penicillin sensitive or atypicals)
o Severe (same bugs as for mild):
 Co-amoxiclav IV or
 Cefuroxime IV and
 Erythromycin IV
o Atypical:
 Legionella:
• Clarithromycin ± rifampicin
 Chlamydia:
• Tetracycline
 Pneumocystis carinii:
• Co-trimoxazole
• Hospital acquired (Gram (–ve), pseudomonas, anaerobes):
o Aminoglycoside IV and
o 3rd
generation cephalosporin IV ±
o Anti-pseudomonal penicillin IV
• Aspiration:
o Cefuroxime IV and
o Metronidazole IV
Treating meningitis:
• Immediate treatment:
o Outside hospital:
 Benzylpenicillin 1.2g IV/IM
o Inside hospital:
 Cefotaxime 2g IV
• Subsequent treatment:
o Depends on sensitivities
o Generally cefotaxime
o Benzylpenicillin and rifampicin for meningococcal meningitis
• Contacts – eradicate carriage:
o Rifampicin (2 days)
o Ciprofloxacin (single dose)
Treating tuberculosis:
• Initial phase (8 weeks on 3–4 drugs):
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o Rifampicin
o Isoniazid
o Pyrazinamide
o Ethambutol (if isoniazid resistance is possible)
• Continuation phase (4–10 months on 2–3 drugs, depends on site):
o Rifampicin
o Isoniazid ±
o Ethambutol
• Give pyridoxine throughout treatment (prevents isoniazid neuropathy)
Treating septicaemia – source unknown:
• Take blood cultures first!
• Anti-pseudomonal penicillin (e.g. ticarcillin) and
• Cefuroxime IV or
• Gentamicin IV
Treating Neutropenic sepsis:
• Take blood cultures first!
• First-line:
o Piperacillin + Gentamicin
• Second-line:
o Ceftazidime + vancomycin
• Third-line:
o Add amphotericin B
Treating a UTI:
• Depends on sensitivities
• Cystitis:
o Mild:
 Trimethoprim
o More severe:
 Co-amoxiclav
 Ciprofloxacin
• Acute pyelonephritis:
o Cefuroxime
Treating MRSA infection:
• Vancomycin or
• Teicoplanin
Treating clostridium difficile:
• Metronidazole po or
• Vancomycin po
Treating cellulitis:
• Depends on the organism, but a good start would be:
o Benzylpenicillin and
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o Flucloxacillin
Prophylactic antibiotics and surgery:
• Single bolus as good as prolonged therapy:
o Metronidazole IV and
o Cefuroxime IV
Helicobacter pylori eradication therapy:
• One PPI and two antibiotics for two weeks
• Usual combination (but there are many):
o Omeprazole
o Clarithromycin
o Amoxicillin (or metronidazole)
• Resistance to metronidazole is common
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Antibiotics
Antibiotics that inhibit cell wall synthesis:
• β-lactams:
o Penicillins
o Cephalosporins
• Glycopeptides:
o Vancomycin
o Teicoplanin
• Carbapenems:
o Imipenem
• Monobactams:
o Aztreonam
Antibiotics that inhibit protein synthesis:
• 30S ribosome:
o Aminoglycosides:
 Gentamicin
 Amikacin
o Tetracyclines:
 Tetracycline
 Doxycycline
• 50S ribosome:
o Macrolides:
 Erythromycin
 Clarithromycin
o Chloramphenicol
o Fusidic acid
Antibiotics that inhibit nucleic acid synthesis:
• Quinolones:
o Ciprofloxacin
• Metronidazole
• Trimethoprim
• Rifampicin
• Sulphonamides
Antibiotics that do not accumulate in renal impairment:
• Chloramphenicol
• Co-trimoxazole
• Doxycycline
• Isoniazid
• Macrolides
• Quinolones
• Rifampicin
Penicillins:
• Are all active against Gram +ve bugs (some against Gram –ve bugs)
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• A common mechanism of resistance is the production of an enzyme (β-
lactamase) that degrades the drug
• Penicillin:
o Benzylpenicillin (penicillin G):
 Parenteral (is destroyed by gastric acids)
o Phenoxymethylpenicillin (penicillin V):
 Oral (but poor bioavailability)
 Used for prophylaxis in:
• Splenectomy patients
• Sickle cell anaemia patients
o Indications:
 Pneumococcus
 Streptococcus
 Meningococcus
 Leptospiral infections
• Broad-spectrum (activity against some Gram –ve bugs as well):
o Amoxicillin (oral or parenteral)
o Indications:
 (As for penicillin)
 Escherichia coli
 Haemophilus influenzae (resistance is increasing ~15%)
 Salmonella
• β-lactamase resistant:
o Flucloxacillin:
 Indications:
• β-lactamase-producing staphylococci
o Co-amoxiclav (Augmentin):
 Amoxicillin +
 Clavulanic acid (β-lactamase inhibitor)
 Indications:
• Amoxicillin resistant URTIs and UTIs
• Anti-pseudomonal:
o Ticarcillin
o Pipericillin:
 Combined with Tazobactam (a β-lactamase inhibitor) as
Tazocin
o Rash:
 Common to all penicillins
 Maculopapular rash in glandular fever if given amoxicillin
o Nausea / vomiting
o Uncommon:
 Anaphylactic shock
 Convulsions
o Penicillin hypersensitivity
• Interactions:
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o COC pill:
 Penicillins reduce the efficacy of the pill
o Probenicid:
 Probenicid ⇓ excretion of the penicillins
 Allows for a ⇓ dose of penicillin to be used or for
prolonged high plasma levels to be attained
Cephalosporins:
• Have a similar range of activity to amoxicillin but are more β-
lactamase stable
• Are 3 “generations” of parenteral cephalosporins:
o As the generations progress, the cephalosporins become more
effective against Gram –ve bugs
o First generation have pretty much been superseded
o Second:
 Cefuroxime:
• Similar spectrum to amoxicillin
o Third:
 All are a common cause of C. difficile diarrhoea
 Cefotaxime:
• Important drug in the treatment of meningitis
 Ceftazidime:
• Pseudomonas and others
 Ceftriaxone:
• Long-half life (once daily administration)
• Effective in serious infections:
o Pneumonia
o Septicaemia
• Are 2 “generations” of orally active cephalosporins:
o Both have similar spectrums of action:
 URTIs
 Refractory cystitis
 Otitis media
o First (e.g. cefalexin)
o Second (e.g. cefaclor)
o Bleeding
o Diarrhoea
o Nausea / vomiting
o Thrombophlebitis (parental cephalosporins)
o Hypersensitivity:
 There is also a 10% cross-reactivity with penicillins
• Interactions:
o Probenicid:
 Probenicid ⇓ excretion of the cephalosporins
 Allows for a ⇓ dose of cephalosporin to be used
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Glycopeptides:
• E.g. vancomycin, teicoplanin
• Active against aerobic and anaerobic Gram +ve bacteria
• Vancomycin (oral or IV):
o Indications:
 IV:
• Infective endocarditis
• MRSA
 Oral:
• Clostridium difficile (pseudomembranous colitis)
• Teicoplanin:
o Indications (IV or IM):
 Used for serious Gram +ve infections
• IV Vancomycin requires therapeutic drug monitoring
o Ototoxicity (tinnitus and deafness)
o Nephrotoxicity (less so with teicoplanin)
o Neutropenia
• Interactions:
o Increased risk of ototoxicity with:
 Loop diuretics
o Increased risk of nephrotoxicity with:
 Aminoglycosides
 Cyclosporin
Carbapenems:
• E.g. imipenem, meropenem
• Incredibly broad spectrum:
o Active against both Gram +ve and –ve bacteria
o β-lactamase stable
o Is effective against MRSA and anaerobes
o Best single agent choice for nosocomial infection
• Imipenem:
o Rapidly degraded by renal dipeptidase
o Must be given in conjunction with cilastatin (a dipeptidase
inhibitor)
• Meropenem:
o Similar to imipenem but is stable to renal dipeptidase, does not
need to be given with cilastatin
o Nausea / vomiting / diarrhoea (3–4% of patients)
o Cross-reactivity with β-lactam antibiotics
o Seizures (imipenem >> meropenem)
Aminoglycosides:
• E.g. Gentamicin, amikacin, streptomycin
• Active against many Gram –ve and some Gram +ve bacteria
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• Indications:
o Second line treatment for severe Gram –ve infection:
 Infective endocarditis
 Septicaemia
 Acute pyelonephritis
o Topical:
 Eye
 Ear
o Streptomycin is reserved for resistant tuberculosis
o Bactericidal
o Inhibit bacterial protein synthesis by binding to the 30S
ribosome
o Inactive orally (must be given IV / topically)
o Excreted unchanged by the kidneys:
 Use with caution in renal impairment (adjust dose)
o Therapeutic drug monitoring is required:
 Peak plasma levels should be measured (~1 hour after
administration)
o Nephrotoxicity (renal tubular damage)
o Ototoxicity (damage to CN VIII):
 “Deaf and dizzy”
 Can be irreversible
o Myasthenia gravis:
 Aminoglycosides can impair neuromuscular transmission
by inhibiting Ca2+
-influx into nerve terminal and
preventing release of ACh
o Pregnancy
• Interactions:
o Drugs potentiating the nephrotoxicity of aminoglycosides:
 Cyclosporin
 Loop diuretics:
• Also potentiate ototoxicity
o Anticholinesterases (e.g. neostigmine):
 Aminoglycosides antagonise the effects of these drugs
• Notes:
o Neomycin is very poorly absorbed:
 Often used dermatologically or as part of bowel prep
o Tobramycin:
 Can be inhaled (good in CF patients)
 Can precipitate acute airway obstruction
Tetracyclines:
• E.g. tetracycline, doxycycline
• Indications:
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o Good for some intracellular organisms (as they penetrate
macrophages):
 Chlamydia (STD)  doxycycline
 Rickettsia (Q-fever)
 Borrelia burgdorferi (Lyme disease)
o Acne
o Anthrax (doxycycline)
o Were the first orally-active broad-spectrum antibiotics (can be
given IV)
o Bacteriostatic
o Absorption from gut is variable - ⇓ by:
 Ca2+
(milk)
 Mg2+
(antacids)
 Iron preparations
o Excreted unchanged in the urine (except doxycycline)
o Deposited in growing bones / teeth:
 Causes staining and (occasionally) dental hypoplasia
 Do not use in children <12 years or in pregnancy
o Renal impairment (except doxycycline)
o Renal impairment (except doxycycline)
Fusidic acid:
• Potent narrow-spectrum anti-staphylococcal antibiotic
• Always used in combination to prevent resistance
• Indications:
o Infections caused by penicillin-resistant staphylococci
o Especially:
 Osteomyelitis (well concentrated in bone)
 Staphylococcal endocarditis
o Can be used topically
o Reversible jaundice
o Acute renal failure (monitor renal function)
o Liver impairment (monitor LFTs)
Macrolides:
• E.g. erythromycin, clarithromycin
• Indications:
o Erythromycin:
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 Active against Gram +ve bacteria (e.g. staphylococci,
streptococci) and the atypicals (e.g. mycoplasma,
chlamydia, legionella)
 A good “respiratory” antibiotic
 A substitute for penicillin in those with hypersensitivity
o Clarithromycin:
 More potent than erythromycin (except H. influenzae)
 Part of helicobacter pylori eradication therapy
• Do not cross the blood-brain-barrier (no good for meningitis)
o Erythromycin causes nausea / vomiting / diarrhoea:
 Is an agonist at the motilin receptor in the gut
o Phlebitis
• Interactions:
o Inhibit cytochrome P450:
 ⇑ levels of warfarin, theophylline, cyclosporin A (and
many others)
o Digoxin:
 ⇑ plasma levels of digoxin
o Terfenadine (non-sedating antihistamine):
 ⇑ risk of arrhythmias
Quinolones:
• E.g. ciprofloxacin, ofloxacin
• Active against many Gram –ve and some Gram +ve bacteria:
o Campylobacter
o Escherichia coli
o Pseudomonas
o Salmonella
• Indications:
o UTI
o Salmonella infection
o Cystic fibrosis lung infections
o Gonorrhoea
o Tuberculosis (3rd
-line drug)
o Anthrax
o Ciprofloxacin has a near 100% bioavailability when taken
orally
o GI disturbance
o Tendon damage (including rupture)
o Seizures (lowers seizure threshold)
• Cautions:
o Epilepsy
o Myasthenia gravis
o History of tendon damage
• Interactions:
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o Inhibits cytochrome P450 (many interactions):
 ⇑ levels of warfarin, theophylline, cyclosporin A
Metronidazole:
• Indications:
o Anaerobes
o Protozoal infections:
 Entamoeba histolytica
 Giardia lamblia
 Trichomonas vaginalis
o Part of helicobacter eradication therapy
o Pseudomembranous colitis (C. difficile)
o Oral, IV or rectal
o Clinical / laboratory monitoring if treatment > 10 days
o GI disturbances (uncommon and well tolerated)
• Cautions:
• Interactions:
o Disulfiram (Antabuse)-like reaction with alcohol:
 Flushing
 Hypotension
 Abdominal pain
o Phenytoin:
 ⇑ plasma levels of phenytoin
o Warfarin:
 ⇑ plasma levels of warfarin
Rifampicin:
• Indications:
o Tuberculosis
o Leprosy
o Meningitis contact prophylaxis
o MRSA
o Deranged LFTs (usually mild but can be serious)
o Stains secretions pink / orange:
 Saliva
 Tears
 Urine
o Jaundice
• Interactions:
o Potent cytochrome P450 inducer (many reactions):
 ⇓ efficacy of:
• Carbamazepine
• COC pill
• Corticosteroids
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• Phenytoin
• Warfarin
Isoniazid:
• Indications:
o Tuberculosis
o Peripheral neuropathy (more likely in):
 Alcoholism
 Chronic renal failure
 Diabetics
 HIV
 Malnutrition
 Can be prevented by pyridoxine (vitamin B6)
o Hepatitis
o Psychosis
• Interactions:
o Anticonvulsants (carbamazepine, phenytoin):
 Isoniazid ⇑ plasma levels of these drugs
Pyrazinamide:
• Indications:
o Tuberculosis
o Good CSF penetration (good in TB meningitis)
o Hepatocellular toxicity
o Gout (avoid in acute attack)
o Porphyria
Ethambutol:
• Indications:
o Tuberculosis (if isoniazid resistance is suspected)
o Visual disturbances (reversible if drug stopped early):
 Caused by a retorbulbar neuritis
 Not too much of a problem with only 8 weeks of therapy
o Renal impairment (⇑ risk of visual damage)
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Diabetes
Treatment of diabetes:
• Both types:
o Diet:
 ⇓ weight (as this ⇓ insulin resistance)
 ⇓ simple sugars
 ⇑ complex carbohydrates
 ⇑ fibre intake
o Address associated risk factors:
 Hyperlipidaemia
 Hypertension (<=130 / <=80 mmHg)
 Smoking
• Type I:
o All require insulin
• Type II:
o BMI < 25:
 Sulphonyurea
o BMI > 25:
 Meformin (a biguanide)
o If not controlled on a sulphonylurea, add metformin
o If not controlled on metformin, add a sulphonylurea
o If not controlled on 2 drugs or intolerant consider adding:
 A glitazone
 Acarbose
o Insulin if poor glycaemic control with oral agents:
 50% of pts will require insulin within 6 years of diagnosis
What to check at a diabetic’s annual review:
• Blood glucose record
• BP
• HbA1c
• Lipids
• Renal function
• Urine (protein / glucose)
Treatment of diabetic ketoacidosis (DKA):
• Only occurs in type I diabetes
• IV fluids:
o Patients may be 5–10L fluid deplete
o Use 0.9% saline (first bag usually ran in stat)
• Monitor (initially hourly):
o Creatinine (to look for pre-renal failure)
o Glucose
o HCO3
-
/ pH
o K+
(Initially plasma levels ⇑ - masks body wide K+
depletion)
• Insulin:
o Aim for a glucose fall of 5mmol/h
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o Initial bolus of soluble insulin then insulin infusion
• Potassium replacement (monitor plasma levels):
o Has been lost due to the diuresis
o Don’t give more than 20mmols/L in each bag
• If acidosis severe (pH <7.0) consider bicarbonate:
o Severe acidosis can impair insulin binding to its receptor
o Comes in 50ml bottles (8.4% = 1mg / ml)
• Identify the cause of the DKA (e.g. infection)
• LMWH (to prevent thrombosis) until mobile
Treatment of hyperglycaemic hyper-osmotic non-ketotic (HHONK) coma
• Only occurs in type II diabetes
• No acidosis (as ketosis is suppressed by endogenous insulin)
• IV fluids
• Insulin (small doses):
o Wait until 1 hour after fluids (may not be needed)
• Full heparin anticoagulation
Treatment of hypoglycaemia:
• If able to take oral treatment:
o Lucozade (or other high sugar drink / sweet)
• Else:
o 20–30mg dextrose IV (e.g. 200–300mls 10% dextrose):
 high concentrations (e.g. 50%) can be irritative and can
even cause stroke!)
o Glucagon 1mg IV/IM:
 Almost as fast as IV dextrose
 Doesn’t work when given repeatedly or if given to
patients with no or poor glycogen reserves (e.g.
alcoholics)
• Once conscious:
o Give the patient a meal
• When to admit:
o If patient is hypoglycaemia following oral anti-diabetics (as
they can be very long-acting)
Sulphonylureas:
• E.g. tolbutamide (very short-acting), glicazide (short-acting),
glibenclamide (once daily)
o Are insulin secretagogues (thus require some functional β-
cells)
o Reduce the K+
permeability of β-cells by blocking ATP-sensitive
K+
channels:
 Causes depolarisation and Ca2+
entry
 Thus causing insulin secretion
o All bind strongly to albumin (several drug interactions)
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o Weight gain (largely due to ⇑ appetite)
o Hypoglycaemia (can be severe / fatal):
 Admit (as the hypoglycaemia can persist for up to 24 hrs)
 Much greater risk than with metformin
o GI disturbances (~3% of patients)
o Bone marrow suppression (rare)
• Cautions:
o Elderly ± renal impairment:
 ⇑⇑ risk of hypoglycaemia (mainly glibenclamide)
o Breast-feeding
• Interactions:
o Drugs potentiating the hypoglycaemic effect:
 Sulphonamides (including co-trimoxazole)
 Chloramphenicol
Metformin:
• Usually given twice daily
• A biguanide (the only available one!)
o Is an insulin-sensitizer
o ⇓ gluconeogenesis
o ⇑ peripheral utilization of insulin
o ⇓ LDL / VLDL
• Does not cause hypoglycaemia
o GI disturbances:
 Start at ~1g / daily
 Nausea / anorexia / vomiting / diarrhoea
o Lactic acidosis (uncommon):
 Caused by a build-up of pyruvate
o ⇓ absorption of vitamin B12
o Conditions predisposing to metformin-induced lactic acidosis:
 Mild renal impairment
 Severe hepatic impairment
 Severe heart failure
o Pregnancy / breast-feeding
• Interactions:
o Alcohol:
 ⇑ risk of lactic acidosis
Glitazones (thiazolidinediones):
• E.g. pioglitazone, rosiglitazone
• Indications:
o Type II diabetes:
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 P a t i e n t s w h o c a n n o t t o l e r a t e ( o r t h e r e a r e
contraindications to) combination therapy with metformin
and a sulphonylurea
 In such cases, the glitazone should replace whichever
drug in the combination is poorly tolerated /
contraindicated
o Interact with a nuclear receptor (peroxisome proliferator-
activator receptor gamma  PPAR-γ)
o PPAR-γ regulates genes involved in lipid metabolism and insulin
action
o Reduce insulin resistance
o ⇓ circulating insulin relative to plasma glucose but do not ⇓
glucose levels to normal
o Hepatotoxicity:
 Monitor LFTs before and during treatment
o Weight gain
o Anaemia (uncommon)
o Combination with insulin (risk of heart failure)
Acarbose:
o Intestinal α-glucosidase inhibitor
o Delays the digestion of starch and sucrose
o Is taken with meals and lowers the post-prandial increase in
blood glucose (~1-2mmol/L)
o Abdominal pain / bloating
o Flatulence
o IBD
o History of abdominal surgery
o Pregnancy
Insulin:
• N.B. normal individuals require ~60U of endogenous insulin daily
• Indications:
o All T1DM
o T2DM where control / symptoms / complications poor
o Hyperkalaemia (with glucose)
o Physical state:
 Short-acting soluble insulins (rapid onset):
• E.g. Actrapid, insulin lispro, insulin asparte
• Inject 15–30 mins before meals
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• Onset in 30–60 mins
• Maximum effect 2–4 hours
• Duration up to 8 hours
 Intermediate-acting (isophane insulins):
• Are insulin with protamine preparations
• E.g. insulatard
 Long-acting:
• Either insulin zinc suspensions (e.g. ultratard) or
synthetics (e.g. insulin glargine)
 Mixed-insulins:
• E.g. mixtard
o Human insulin absorbed faster than porcine / bovine insulin
o Porcine / bovine insulin may cause less hypoglycaemia
o Factors affecting absorption:
 Temperature
 Exercise
• Insulin effects:
o Adipose tissue:
 ⇑ lipoprotein lipase activity:
• ⇓ TGs
 ⇑ GLUT-4 activity:
• ⇑ glucose storage as fat
 ⇓ lipolysis:
o Liver:
 ⇓ glycogenolysis
 ⇓ gluconeogenesis
 Inhibition of ketogenesis
o Muscle:
 ⇓ proteolysis
 ⇑ GLUT-4 activity:
• ⇓ plasma glucose levels
• Insulin regimes:
o Twice daily mixed insulins:
 Possibly better for children or older T2DM
o Basal bolus (qds) regime:
 More “physiological”
 Involves more injections
 Best regimen for ⇓ diabetic complications
• Problems with Actrapid (short-acting human insulin):
o Needs to be given 15 minutes before meals
o Can cause a late post-prandial hypoglycaemia:
 Leads to post-prandial hyperglycaemia (as patients don’t
give enough as they fear the hypoglycaemia)
• Problems with insulin glargine (long-acting human insulin analogue):
o Nocturnal hypoglycaemia (can be dangerous)
o Uniform action (not physiological)
o Hypoglycaemia:
 30% of T1DM ever (10%/year, 3% frequent episodes)
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 Sweating
 Tachycardia
 Tremor
 Aggression
 Confusion
 Coma
o Fat hypertrophy / atrophy at injection site (rotate site to avoid
this)
o Weight gain:
 As blood [glucose] is ⇓ you get hungry!
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Epilepsy
Classification of epilepsy:
• Generalised:
o Implies bilateral abnormal electrical activity in the brain with
bilateral motor manifestations
o Consciousness is impaired
o Types:
 Tonic-clonic (grand-mal)
 Absence (petit-mal)
 Myoclonic
• Partial:
o A localised seizure that may be either:
 Simple (without loss of consciousness):
• Jacksonian seizure
 Complex (with loss of awareness)
o May progress to a generalised seizure
Management of status epilepticus:
• Remember 25% of status turns out to be pseudostatus
• ABC (need to maintain airway)
• Oxygen
• If alcoholism / malnutrition give thiamine
• If hypoglycaemic give glucose
• Stop the seizure:
o Lorazapam (slow IV bolus) if fails
o Phenytoin (IV infusion) if fails
o Phenobarbital IV if fails
o Anaesthetise with thiopentone / propofol
Drug treatment of epilepsy (NICE recommendations):
• Generalised seizures:
o First-line (all):
 Valproate
o Second-line (tonic-clonic):
 Carbamazepine
 Phenytoin
o Second-line (absence):
 Ethosuximide
o Second-line (myoclonic):
 Ethosuximide
 Lamotrigine
• Partial seizures:
o First-line:
 Carbamazepine
 Valproate
o Second-line:
 Lamotrigine
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 Gabapentin
 Vigabatrin
o Third-line:
 Phenytoin
Carbamazepine:
• Indications:
o Partial seizures (first-line)
o Tonic-clonic seizures (second-line)
o Trigeminal neuralgia
o Bipolar disorder
o Related to the tri-cyclic antidepressants
o Induces a use-dependent block of neuronal Na+
channels
o Has an active metabolite (produced in the liver)
o t½ of 10–20 hours
o Is an enzyme inducer (even of it’s own metabolism)
o Requires therapeutic drug monitoring
o Ataxia
o Nausea
o Neutropenia
o Sedation
o SIADH
o Teratogenic:
 Foetal neural tube defects
o AV conduction abnormalities (unless paced)
o History of bone marrow depression
o Porphyria
• Interactions (many as is an enzyme inducer):
o Carbamazepine ⇓ the efficacy of:
 COC pill
 Corticosteroids
 Cyclosporin
 Phenytoin
 Warfarin
o Drugs that ⇑ the level of carbamazepine:
 Cimetidine
 Erythromycin
Phenytoin:
• Indications:
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o All types of epilepsy (except absence seizures) but not
first-line
o Status epilepticus
o Trigeminal neuralgia
o Related to the barbiturates
o Induces a use-dependent block of neuronal Na+
channels
o Has a saturable metabolism (zero-order kinetics):
 This means that over the therapeutic plasma
concentration range, the rate of inactivation does not ⇑ in
proportion to the plasma concentration
 This means that the t½ ⇑ as the dose is ⇑
o ~90% protein bound:
 Some drugs (e.g. valproate, salicyclates) inhibit this
binding competitively
 This ⇑ the free [phenytoin] but also ⇑ the hepatic
clearance of phenytoin
 The net result is unpredictable
o Is a potent enzyme inducer
o Once daily dosage (should be nocte)
o Requires therapeutic drug monitoring
o Ataxia
o Sedation
o Acne
o Folate deficiency
o Gum hypertrophy
o Hirsuitism
o Lymphadenopathy
o Osteomalacia (vitamin D resistance)
o Photosensitivity
• Cautions:
o Hepatic impairment (⇓ dose)  common
o Pregnancy:
 Cleft palate
• Interactions (many):
o Phenytoin ⇓ the efficacy of:
 COC pill
 Rifampicin
 Warfarin
o Drugs that ⇑ the level of phenytoin:
 Aspirin
 Cimetidine
Sodium valproate:
• Indications:
o All types of epilepsy (first-line)
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o Not fully understood
o Causes a significant ⇑ in brain [GABA]
o Metabolised by the liver but not an enzyme inducer (may be an
enzyme inhibitor)
• Adverse effects (fewer severe effects than most anticonvulsants):
o Hepatotoxicity:
 Need to monitor LFTs
o Teratogenicity:
 Neural tube defects
 Probably the safest anticonvulsant to use in pregnancy
o Thinning / curling of the hair
o Thrombocytopenia
o Tremor
o Sedation
o Weight gain
o Severe liver disease
• Interactions:
o Drugs that ⇓ the efficacy of valproate:
 Neuroleptics
 Tri-cyclic antidepressants
Phenobarbital:
• Indications:
o All types of epilepsy (except absence seizures) but not first-line
o Status epilepticus
o Is a barbiturate
o Binds to the GABA receptor and enhances actions of GABA
o Well absorbed
o 50% protein bound
o t½ 36–120 hours
o Enzyme inducer
o Sedation with impairment of intellectual and motor
performance
o Ataxia
o Osteomalacia
o Folate deficiency
• Cautions:
o Elderly
o Respiratory depression
o Impaired hepatic / renal function
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• Interactions (many more than shown below):
o Phenobarbital ⇓ the efficacy of:
 COC pill
 Warfarin
Vigabatrin:
• Indications:
o Epilepsy (usually second- or third-line)
o Was the first “designer” drug in the field of epilepsy
o Is a irreversible GABA-transaminase inhibitor:
 ⇑ [GABA] in the CSF
o t½ 5 hours (although duration of action is long)
o Is not an enzyme inducer
o Depression
o Psychotic disturbances
o Visual field defects (~30% of patients)
o Those with visual field defects
Lamotrigine:
• Indications:
o Can be used as monotherapy of:
 Generalised seizures (especially absence seizures)
 Partial seizures
o t½ 15–70 hours
o Rashes (very common):
 Can be as severe as Stevens-Johnson syndrome
o Drowsiness
o Tremor
• Interactions:
o Valproate:
 Valproate ⇑ the plasma levels of lamotrigine
Primidone:
• Is a pro-drug of phenobarbital
• ? an anticonvulsant in it’s own right
o As for phenobarbital
Ethosuximide:
• Indications:
o Absence seizures (second-line)
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o Is not an enzyme inducer
o Nausea / anorexia
o Sedation
o Ataxia
o Hypersensitivity (rare)
Gabapentin:
• Indications:
o Adjunctive treatment of partial seizures
o Neuropathic pain
o It’s role is likely to increase in the future
o Not metabolised
o Few (if any) interactions
o Ataxia
o Drowsiness
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Migraine
Prophylaxis against migraine:
• Avoid precipitating factors (if possible):
o Foods (mainly tyramine containing food)
o Irregular meals / sleeping patterns
o Alcohol
o “Weekend” migraines are probably caused by caffeine
withdrawal
• 5-HT antagonists:
o E.g. pizotifen
o Methysergide:
 Only prescribed by those experience in its use
 Good for cluster headaches
 Fibrotic side effects:
• Cardiac fibrosis
• Pulmonary fibrosis
• Retroperitoneal fibrosis
• β-blockers:
o E.g. propranolol, atenolol, metoprolol
o High doses often needed
• Amitriptylline:
o Unrelated to it’s antidepressant effect
• Sodium valproate:
o Refractory migraines
Treatment of migraine:
• Simple analgesics:
o E.g. paracetamol / aspirin / NSAIDs
o Give with metoclopramide:
 Anti-emetic and ⇑ gastric emptying (thus ⇑ absorption of
the analgesic)
o Must be given early in an attack
• 5-HT1D agonists:
o E.g. sumatriptan
o Can be given oral / sc / intranasally
o Is a (relatively) selective vasoconstrictor
o ~70% efficacy:
 Best if taken at onset to abort the migraine
o Adverse effects:
 Dizziness
 Flushing
o Avoid:
 In patients with IHD or uncontrolled hypertension:
• Can cause angina-like pain (discontinue)
 With SSRIs and MAOIs
• Ergotamine:
o Rarely used now
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o Primarily a vasoconstrictor
o Adverse effects:
 Nausea / vomiting
 Peripheral /coronary vasoconstriction
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Multiple sclerosis
Drug treatment of an acute relapse of MS:
• IV methylprednisolone:
o High dose
o Short course (3–5 days)
o Does not alter the long-term prognosis
• No other approaches have shown any benefit
Prevention of relapse in MS:
• Interferon-β1 (IFN-β1a and IFN-β1b):
o Given SC / IM
o Trials have shown a 30%⇓ in relapses (only in relapsing /
remitting disease)
o Probably does not alter the natural history
o Expensive:
 ~£10,000/person/year
o Adverse effects:
 ‘Flu-like symptoms
 Depression
• Glatiramer:
o May prevent relapsing as for IFN-β but does not alter the long-
term prognosis
Symptomatic treatment of MS:
• Spasticity / painful spasms:
o Baclofen:
 Inhibits nerve transmission at the spinal level
 Adverse effects:
• Sedation
• Hypotonia
• Urinary disturbance
 Serious side effects can occur on abrupt withdrawal:
• Convulsions
• Hyperthermia
• Psychiatric reactions
o Dantrolene:
 Inhibits muscle contraction:
• Prevents Ca2+
release from sarcoplasmic reticulum
 Adverse effects:
• Aggravates weakness
• Hepatotoxic
• Detrusor instability:
o Anticholinergics (e.g. oxybutynin, TCAs)
• Paroxysmal pain:
o Anticonvulsants / TCAs
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Parkinson’s disease
Features of Parkinson’s disease:
• Bradykinesia
• Rigidity (“lead-pipe”)
• Tremor (4–7 Hz, “pill-rolling”)
• Festinant gait
• Loss of arm swinging
• Monotonous speech
• Loss of facial expression
• Micrographia
Drug treatment of Parkinson’s disease (PD):
• Treatment should not be started before it is necessary because of
delayed unwanted effects
• Levodopa (L-dopa):
o First-line therapy
• Direct dopamine agonists:
o E.g. apomorphine, bromocriptine, lisuride, pergolide
o Used as an alternative or adjunct to L-dopa
• Amantadine:
o Useful in mild / moderate PD
o May have a use in late disease with marked dyskinesia
• Anticholinergics:
o E.g. benzhexol
o Most useful in mild PD with tremor in younger patients
o Also good for controlling dribbling
• Monoamine oxidase B inhibitors (MAO-BIs):
o E.g. selegiline
o Used as an adjunct to L-dopa to allow a ⇓ in dose:
 Can also ⇓ dose-related response fluctuations
• Catechol – O – methyl transferase (COMT) inhibitors:
o E.g. entacapone
o May be useful in ⇓ end-of-dose fluctuations with L-dopa
Levodopa:
• An example of a prodrug
• Must be combined with a peripheral dopa-decarboxylase inhibitor:
o E.g. carbidopa, benserazide
o Prevents L-dopa metabolism in the periphery
o Do not cross the blood-brain barrier (BBB)
o Thus ⇓ dose (by about 10 fold)
o ⇓ adverse effects
o t½ of 2 hours
o There is a large individual variation in kinetics, thus slow
titration is essential
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o Is a pro-drug of dopamine
o (Dopamine is not used as it cannot cross the BBB)
o L-dopa crosses the BBB and is rapidly converted to dopamine
by dopa-decarboxylase in the brain
o This dopamine replaces the deficiency in the basal ganglia
• With L-dopa, ~80% show improvement in rigidity and hypokinesia and
~20% are restored to near-normal function (for a period)
o Short-term:
 Nausea / vomiting:
• Treat with domperidone (dopamine antagonist)
 GI disturbances
 Postural hypotension
 Cardiac dysrhythmias
 Haemolytic anaemia (rarely)
o Long-term:
 Neuropsychiatric syndromes:
• Delirium
• Hallucinations (patient maintains insight)
• Psychosis
• Treatment:
o Dose ⇓
o Atypical neuroleptics (e.g. clozapine)
 Response fluctuations:
• Akinesia:
o End-of-dose
• Dyskinesia:
o Peak dose
o Onset / end-of-dose
• Unpredictable on-off responses (“yo-yo”-ing)
• Treatment:
o Careful regulation of plasma L-dopa levels
o Use modified-release preparations
o Try:
 COMT inhibitor
 MAO-BI
 Dopamine agonist
 Loss of response:
• Usually within 2–5 years
• ~50% are back to pre-treatment status after 5 yrs
• Treatment:
o Try dopamine agonist
o Closed angle glaucoma
• Interactions:
o Non-selective MAOIs:
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 Risk of hyperthermia syndrome with concomitant use
 Withdraw MAOIs 2 weeks before starting L-dopa
o Anti-hypertensives:
 Enhanced hypotensive effect
o Neuroleptics:
 Neuroleptics antagonise the action of L-dopa (and vice-
versa)
Apomorphine:
• PD indications:
o Advanced disease with “on-off” periods with L-dopa
o Must be given parenterally (SC)
o Very potent dopamine D1 and D2 agonist
o Profound nausea / vomiting
o As for L-dopa
o Respiratory / CNS depression
o Neuropsychiatric problems / dementia
Dopamine agonists:
• Older compounds (ergot derivatives):
o Bromocriptine, cabergoline, lisuride, pergolide
• Recent compounds (synthetic):
o Pramipexole, ropinirole
o Side-effects are less than the older agents
• Indications:
o Can be used as an alternative to L-dopa but are usually used as
adjuncts
• Pharmacology:
o Duration of action:
 Pergolide = cabergoline > bromocriptine > lisuride
o Potency:
 Pergolide = lisuride > cabergoline > bromocriptine
• Are less effective than L-dopa but are associated with fewer late
unwanted dyskinetic effects
o Nausea / vomiting
o Hypotension
Amantadine:
o Unknown
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o May cause release of dopamine
o May be a weak anticholinergic
• Is less effective than L-dopa or even bromocriptine but it’s use may be
revived for late onset dyskinesia
o Dizziness
o Insomnia
o Livedo reticularis
o Peripheral oedema
Anticholinergics:
• E.g. benzhexol, procyclidine
• Until L-dopa was discovered, anti-muscarinic agents were the only
available treatment for PD
o As the nigrostriatal neurones progressively degenerate in PD,
the release of (inhibitory) dopamine ⇓ and the excitatory
cholinergic interneurones in the striatum become relatively
overactive
o Blocking these mACh receptors “resets” this balance
o Only really reduce the tremor of PD (little effect on rigidity
and Bradykinesia)
• Use is declining rapidly (especially in the elderly) largely due to
their unwanted effects on memory
o CNS:
 Confusion
 Hallucinations
 Memory impairment
o Other:
 Blurred vision
 Dry mouth
 Constipation
Monoamine oxidase B inhibitors (MAO-BIs):
• E.g. selegiline
• Indications:
o May allow L-dopa dose ⇓
o ⇓ end-of-dose deteriorations in advanced PD
o Can be used alone to delay need for L-dopa for a few months
• Adverse effects (reasonably well tolerated):
o No “cheese reaction” (does not affect MAO-A)
o Potentiates L-dopa related symptoms
o Insomnia
Catechol-O-methyl transferase (COMT) inhibitors:
• E.g. entacapone
o Prolongs the action of a single dose of L-dopa
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o Has no anti-PD activity when used alone but ⇓ the “off” time in
late disease when used with L-dopa
o GI disturbances
o Dyskinesias
o Urine may be coloured reddish-brown
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Drug-induced movement disorders
The most commonly implicated drugs in this section are the antipsychotics
(but also more common drugs such as metoclopramide)
To be covered:
• Acute dystonias
• Akathisia
• Parkinsonism
• Tardive dyskinesia
• Neuroleptic malignant syndrome
Acute dystonias:
• Dystonia is a syndrome of sustained muscle contractions that produce
twisting and repetitive movements or abnormal postures
• Presentation:
o Most common in young males
o Occurs within hours / days of starting the implicated drug
o Usually oculogyric:
 Spasm of the extra-ocular muscles, forcing the eyes into
upward or lateral gaze
• Treatment:
o IV anticholinergics (e.g. procyclidine)
o ? continue oral anticholinergics for ~48 hours
Akathisia:
• This is a restless, repetitive and irresistible need to move
• Can culminate in suicide
• Occurs within days or months of starting the implicated drug
• Equal sex incidence
• May persist even after drug is stopped
• Treatment:
o Often ineffective
o May respond to:
 Amantadine
 Anticholinergics
 β-blockers
Parkinsonism:
• Bradykinesia and rigidity but little tremor
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• Affects up to 20% of patients on antipsychotics
• Presentation:
o Usually in first few months of starting the drug
o More common in the elderly
• Treatment:
o Withdraw / ⇓ dose of drug if possible
o Anticholinergics / Amantadine may be effective:
 Do not use L-dopa
o May persist even after drug is stopped
Tardive dyskinesia (TD):
• Are involuntary movements of the tongue, lips, face, trunk and
extremities
• Presentation:
o Occurs after many months / years of using the drug
o Affects up to ~20% of patients
o More common in women and the elderly
• Treatment:
o Some neuroleptics are less likely to cause TD:
 Clozapine, risperidone, sulpiride
o A change of neuroleptic may help
Malignant hyperthermia syndrome:
• Is a rare idiosyncratic drug reaction that is unpredictable
• Commonly implicated drugs:
o Antipsychotics
o Suxamethonium
• Presentation:
o Often a young male
o Extreme rigidity
o Hyperthermia
o Fluctuating conscious level
• There is a very high mortality if the syndrome goes unrecognised
• Treatment:
o Stop the causative drug
o Dantrolene:
 Stops Ca2+
release in muscle
 Thus stopping the excessive muscle contractions
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Myasthenia gravis
The Tensilon (edrophonium) test:
• Give edrophonium IV as a bolus dose
• Positive test:
o Improvement of weakness occurs within seconds and the
response lasts for 2–3 minutes
• To be certain, the test should be preceded by a bolus of saline to act
as a control
Drug treatment of myasthenia gravis (MG):
• Oral anticholinesterases:
o Provide symptomatic improvement (complete relief is rare)
• Corticosteroids:
o Lead to a rapid improvement in most patients
o Can produce total remission
o High doses are usually needed (60mg on alternate days)
• Immunosuppressants:
o E.g. azathioprine, cyclophosphamide, cyclosporin
o Lead to an improvement in most patients
o Are steroid-sparing agents
o More effective in older patients
• Thymectomy:
o Improves prognosis (especially in women <40 years with
positive AChR antibodies and a history of <10 years)
o Must always remove a thymoma if present
o Complete remission is rare
• Plasmapheresis:
o Useful during exacerbations
o Effects may last up to 3 months
Anticholinesterases:
• E.g. neostigmine, pyridostigmine
• Indications:
o Myasthenia gravis (oral)
o Reversal of non-depolarising muscle relaxants (IV)
o Inhibit acetylcholinesterase, thus ⇑ the concentration of ACh
in the synaptic cleft
o Myasthenia gravis:
 The ⇑ concentration of ACh has an ⇑ probability of binding
to a receptor at the neuromuscular junction
o Reversal of muscle relaxants:
 The ⇑ concentration of ACh overcomes the competitive
blockade of the muscle relaxant
o Abdominal cramps
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o Bradycardia
o Hypersalivation
o Nausea / vomiting
o Sweating
• Interactions:
o Aminoglycosides:
 ⇓ the action of anticholinesterases
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Diuretics
Loop diuretics:
• E.g. furosemide
• Indications:
o Acute pulmonary oedema
o Chronic heart failure
o Oliguria secondary to acute renal failure
o Inhibit NaCl reabsorption in the thick segment of the
ascending loop of Henle:
 Inhibit the Na+
/K+
/2Cl-
pump
o This section has a high capacity for absorbing NaCl and so loop
diuretics produce the most profound diuresis
o The ⇑ Na+ that reaches the distal tubule also leads to an
osmotic effect, drawing yet more water into the lumen
o Also possess venodilator properties that are independent of
their diuretic effect
o Hypokalaemia
o Hypocalcaemia
o Hypomagnesaemia
o Hyperuricaemia (can cause gout)
o Deafness (high doses – effects on the endolymph)
o Renal failure with anuria
• Interactions:
o Aminoglycosides:
 ⇑ risk of ototoxicity and nephrotoxicity
o Digoxin:
 Hypokalaemia caused by furosemide ⇑ risk of digoxin
toxicity
o Lithium:
 ⇓ excretion of lithium - ⇑ plasma levels
Thiazide diuretics:
• E.g. bendrofluazide, metolazone
• Indications:
o Hypertension
o Heart failure
o Moderately powerful diuretics (metolazone > bendrofluazide)
o ⇓ reabsorption of Na+
in the distal tubule
o The ⇑ Na+ load in the distal tubule stimulates Na+ exchange
with K+ and H+ ions thus ⇑ their excretion and tending towards
hypokalaemia and a metabolic alkalosis
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o Hypokalaemia
o Hyponatraemia
o Hyperglycaemia
o Hypercalcaemia
o Hyperlipidaemia
o Hyperuricaemia
o Impotence
o Severe hepatic / renal impairment
o Gout
• Interactions:
o Digoxin:
 Hypokalaemia caused by thiazides ⇑ risk of digoxin
toxicity
o Lithium:
Spironolactone (a potassium-sparing diuretic):
• Indications:
o Chronic heart failure (shown to ⇓ mortality)
o Refractory hypertension (BHS step 4)
o Ascites / oedema caused by cirrhosis
o Conn’s syndrome (primary hyperaldosteronism)
o Potassium conservation with thiazide and loop diuretics
o Is a competitive aldosterone antagonist
o Aldosterone causes Na+
reabsorption and K+
excretion in the
distal tubule
o Inhibition of this action leads to a mild diuresis and retention of
K+
o It is a weak diuretic because only 2% of the total Na+
reabsorption is under aldosterone control
o Hyperkalaemia
o Gynaecomastia
o Impotence
o Hyperkalaemia
o Addison’s disease
• Interactions:
o ⇑ risk of hyperkalaemia:
 ACE inhibitors / AII receptor antagonists
 NSAIDs
o Lithium:
o Potassium salts (⇑ risk of hyperkalaemia)
Other potassium-sparing diuretics:
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• E.g. amiloride, triamterene
• Indications:
o Potassium conservation with thiazide and loop diuretics
o Block Na+
channels in the distal tubule
o ⇑ Na+
excretion (thus causing a diuresis) and ⇓ K+
excretion
o Hyperkalaemia
o Renal impairment
• Interactions:
o ⇑ risk of hyperkalaemia:
 ACE inhibitors / AII receptor antagonists
 NSAIDs
o Lithium:
o Potassium salts (⇑ risk of hyperkalaemia)
Osmotic diuretics:
• E.g. mannitol
• Indications:
o Cerebral oedema
o Mannitol is a compound that is filtered by the kidneys but is not
reabsorbed
o Is given in amount such that it significantly contributes to
plasma osmolarity
o The ⇑ plasma osmolarity (by compounds which cannot cross
the blood-brain barrier) leads to extraction of water from
the brain
o Chills
o Fever
o Congestive cardiac failure
o Pulmonary oedema
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Muscle relaxants
Types of muscle relaxants:
• Depolarizing:
o Suxamethonium
• Non-depolarizing (competitive):
o Can be reversed with an anticholinesterase (unlike
suxamethonium)
o Pancuronium:
 Long-duration of action
 Atropine-like effects
o Vecuronium:
 No cardiovascular effects
 Short duration of action
o Atracurium:
 Decomposes spontaneously in plasma:
 Does not depend on liver / kidneys for excretion
o Rocuronium:
 Rapid onset (almost as fast as Suxamethonium)
Suxamethonium:
o Is 2 ACh molecules linked by their acetyl groups
o Rapid onset (1–1.5 minutes)
o Very short duration of action (3–7 minutes):
 Metabolised by plasma pseudocholinesterase
o Suxamethonium diffuses slowly to the motor endplate and
persist for long enough to cause loss of electrical excitability
o Before paralysis occurs, the muscle fibres are activated causing
twitching (fasciculation)
o Muscle aches (caused by the fasciculation)
o Prolonged block:
 ~1 in 2000 people have a deficiency of plasma
pseudocholinesterase and paralysis may last several
hours
o Bradycardia
o K+
release (from muscle)
o Malignant hyperthermia:
 Very high mortality (~65%)
 Treated with dantrolene
o Family history of malignant hyperthermia
o Hyperkalaemia
• Interactions:
o Drugs ⇑ action of Suxamethonium (many):
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 Aminoglycosides
 Metoclopramide
 Verapamil
Non-depolarizing muscle relaxants:
• E.g. pancuronium, vecuronium, atracurium, rocuronium
o Do not cross the BBB or the placenta
o Block the nicotinic ACh receptor at the motor endplate,
thus inhibiting muscle contraction
o These vary between the various drugs (see above)
o Hypotension
o Anaphylactoid reactions
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Anti-emetics
Causes of nausea and vomiting:
• Drugs:
o Antibiotics (e.g. erythromycin)
o Cytotoxic agents
o Digoxin
o Opioids
• Vestibular disease (e.g. labyrinthitis)
• Provocative movement (e.g. seasickness)
• Migraine
• Abdominal disease
• Pregnancy
Physiology of nausea:
• Emesis is coordinated by the vomiting centre (medulla oblongata)
• An important input to the vomiting centre is the chemoreceptor
trigger zone (CTZ) in the area postrema:
o The CTZ is not protected by the BBB, therefore circulating
toxins/drugs can stimulate it
o Possesses the following receptors:
 Dopamine (D2)
 Serotonin (5HT3)
• The vomiting centre also receives cholinergic (muscarinic) and
histamine input
• Thus the following drug classes are helpful anti-emetics:
o D2 receptor antagonists
o 5-HT3 receptor antagonists
o Anti-muscarinic agents
o Antihistamines (H1)
• Dexamethasone is a useful anti-emetic following cancer
chemotherapy
• Vomiting is easier to prevent than it is to stop
D2 receptor antagonist anti-emetics:
• E.g. metoclopramide, domperidone
• Indications:
o Nausea and vomiting due to:
 Abdominal disease
 Drugs (especially opioids)
 Migraine
 Post-operative nausea / vomiting
o Blocks D2 receptors in the CTZ
o Prokinetic actions on the gut (⇑ absorption of many drugs):
 Can be an advantage (e.g. analgesics in migraine with
vomiting)
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o Acute dystonia (especially if age <20 years and female)
• Domperidone does not readily cross the BBB and is much less
likely to cause central reactions (e.g. dystonic reactions)
o GI obstruction / perforation / haemorrhage
o Recent (3–4 days) GI surgery
• Interactions:
o NSAIDs:
 ⇑ absorption of NSAIDs ⇑ their beneficial (and toxic)
effects
5-HT3 antagonist anti-emetics:
• E.g. ondansetron, granisetron
• Indications:
 Cytotoxic agents
 Radiotherapy
 Post-operative nausea / vomiting
o Headache
o Constipation
Anti-muscarinic anti-emetics:
• E.g. hyoscine
• Indications:
o Prophylaxis against motion sickness
o Blurred vision
o Dry mouth
o Drowsiness
o Prostatic enlargement
o Glaucoma
o Myasthenia gravis
o Paralytic ileus
• Interactions:
o Alcohol:
 Sedative effects of hyoscine are enhanced by alcohol
Antihistamine anti-emetics:
• E.g. cinnarizine, cyclizine
• Indications:
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 Vestibular disease
 Drugs
o Drowsiness
o Anti-muscarinic effects, e.g.:
 Blurred vision
 Dry mouth
o Prostatic enlargement
o Glaucoma
o Urinary retention
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The eye
Maintenance of intraocular pressure (IOP):
• The IOP is determined by aqueous humour volume
• Production:
o Aqueous humour is produced by the highly vascularised
processes of the ciliary body
o The ciliary epithelial cells (which contain ATPase and carbonic
anhydrase) absorb Na+
from the stroma and transport it to the
intercellular clefts (which open on the aqueous humour side)
o The hyperosmolality in the clefts leads to water flow from the
stroma, producing a continuous flow of aqueous
o The ciliary epithelium is also leaky and ~30% of aqueous is
formed by ultrafiltration
• Drainage:
o Pupil  trabecular meshwork  canal of Schlemm  episcleral
veins
Treatment of acute narrow-angle glaucoma:
• This must be treated quickly to prevent permanent retinal damage
• ⇓ aqueous production:
o Acetazolamide IV stat
• ⇑ aqueous outflow:
o Pilocarpine eye drops stats
o Mannitol IV stat:
 To draw water out of the eye
• Prevent recurrence:
o Surgery (Peripheral iridotomy)
Drug treatment of chronic open-angle glaucoma:
• All of the following treatments are given topically (eye drops)
• ⇓ aqueous production:
o β-blockers
o α-agonists
o Carbonic anhydrase inhibitors
• ⇑ aqueous outflow:
o Muscarinic agonists
Age-related macular degeneration (AMD):
• Most common cause of blindness in the UK
• New blood vessels form under the retina and leakage of fluid and blood
from the vascular complexes causes severe loss of vision within a few
years
• Treatment (relatively new):
o Verteporfin (photodynamic therapy):
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 Is a light-sensitive dye that is given IV and is taken up by
vascular endothelium
 A laser is then applied to the eye and this activates the
dye, which releases free radicals that destroy the new
vessels
Mydriatic drugs:
• Muscarinic antagonists:
o Also cause cycloplegia (paralysis of the ciliary muscle)
o Tropicamide
o Cyclopentolate
• α-agonists:
o Do not affect the pupillary light reflex or accommodation
o Phenylephrine
β-blockers and glaucoma:
• E.g. timolol
• Drugs of choice in chronic open-angle glaucoma
o Block β2 receptors on the ciliary processes and ⇓ aqueous
secretion
o May also block β-receptors on afferent blood vessels to the
ciliary processes (this vasoconstriction ⇓ ultrafiltration)
• Adverse effects (may be absorbed systemically):
o Bradycardia
o Bronchospasm
o Asthma
o Heart block
o Heart failure
α-agonists in glaucoma:
• E.g. adrenaline, phenylephrine
• ⇓ IOP by vasoconstriction of the ciliary body afferent blood vessels
• Interestingly, α-antagonists and β-agonists also ⇓ IOP:
o ⇑ aqueous outflow rather than ⇓production
o Dilatation of the aqueous / episcleral veins
Carbonic anhydrase inhibitors:
• E.g. Acetazolamide (IV / IM / oral), dorzolamide (topical)
• Inhibition of carbonic anhydrase prevents HCO3
-
formation
• Since HCO3
-
and Na+
transport are linked, this leads to a ⇓ in aqueous
formation
• Dorzolamide can be used alone in those in whom β-blockers are
contraindicated
• Dorzolamide is a sulphonamide and systemic side effects can occur:
o Rashes
o Bronchospasm
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Muscarinic agonists:
• E.g. pilocarpine
• ⇓ IOP by contracting the ciliary muscle
• This pulls the scleral spur and results in the trabecular meshwork
being stretched and separated
• The fluid pathways are opened up and aqueous outflow is increased
o Miosis:
 Causes near-sightedness (blurred distance vision)
 Brow ache
 Headache
 Poor night vision
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Antipsychotics (neuroleptics)
The dopamine hypothesis of psychosis:
• Psychotic symptoms result from ⇑ dopamine neurotransmission
• Dopamine receptors:
o D1-like:
 D1 and D5
 Are post-synaptic
 Stimulate adenylate cyclase and ⇑ cAMP
o D2-like:
 D2, D3 and D4
 Are both pre- and post-synaptic
 Inhibit adenylate cyclase and ⇓ cAMP
• Dopaminergic pathways:
o Mesolimbic / mesocortical:
 Concerned with mood and emotional stability
 Ventral tegmental area:
• Ventral striatum and the frontal cortex
o Nigrostriatal:
 Concerned with movement
 Substantia nigra and the dorsal striatum
• Neuroleptics block D2 receptors:
o Explains why they cause movement disorders as a side effect
Clinical classification of neuroleptics:
• Typical:
o Produce extrapyramidal symptoms (EPS)
• Atypical:
o So-called because they have a low incidence of EPS
o However, all apart from clozapine can cause EPS at high doses
Chemical classification of neuroleptics:
• Typical:
o Phenothiazines:
 Propylamines (chlorpromazine):
• Sedation ++
• Anticholinergic ++
• EPS ++
 Piperidines (thioridazine):
• Sedation ++
• Anticholinergic ++
• EPS +
• Can cause torsade de pointes
 Piperazines (fluphenazine):
• Sedation +
• Anticholinergic +
• EPS +++
o Thioxanthines (flupenthixole):
 Sedation +
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 Anticholinergic +
 EPS ++
o Butyrophenones (haloperidol):
 Sedation -
 Anticholinergic -
 EPS +++
• Atypical:
o “True”:
 Clozapine:
• Sedation ++
• EPS -
o “Apparent”:
 Sulpiride:
• Sedation +
• Anticholinergic –
• EPS +
 Risperidone:
• Sedation ++
• EPS +
General effects of the neuroleptics:
• Early (hours):
o Desired:
 Sedation (histamine / α-receptor blockade)
 Tranquilisation (dopamine blockade)
o Unwanted:
 Acute dystonic reactions
• Medium (days–weeks):
o Desired:
 Suppression of:
• Delusions
• Disordered thinking
• Hallucinations
o Unwanted:
 Akathisia
 Parkinsonism
• Late (months–years):
o Desired:
 Prevention of relapse
o Unwanted:
 Tardive dyskinesia
• Any time:
o Neuroleptic malignant syndrome
Chlorpromazine:
• Indications:
o Psychotic disorders (e.g. schizophrenia / mania)
o Labyrinthine disorders / vertigo
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o Nausea / vomiting
o Chronic hiccups
o Common:
 Sedation
 Anticholinergic effects:
• Blurred vision
• Dry mouth
• Postural hypotension
• Constipation
• Urinary retention
 Extrapyramidal effects:
• Acute dystonia
• Akathisia
• Parkinsonism
• Tardive dyskinesia
 Hyperprolactinaemia:
• Amenorrhoea
• Galactorrhoea
• Impotence
o Uncommon:
 Neuroleptic malignant syndrome
 Agranulocytosis
 Cholestatic jaundice
• Interactions:
o ACE inhibitors:
 Can cause severe hypotension
Haloperidol:
• Indications:
o Psychosis
o Motor tics
o Common:
 Extrapyramidal effects:
• Acute dystonia
• Akathisia
• Parkinsonism
o Uncommon:
 Convulsions
 Neuroleptic malignant syndrome
 Tardive dyskinesia
 Weight loss
• Interactions:
o Amiodarone:
 ⇑ risk of ventricular arrhythmias
o Carbamazepine:
 ⇓ plasma levels of haloperidol (metabolism accelerated)
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o Fluoxetine:
 ⇑ plasma levels of haloperidol
Clozapine:
• Regarded by many as the only “true” atypical neuroleptic:
o EPS is not evident even at high doses
o Effective in patients refractory to other neuroleptics
o Can treat the negative symptoms of schizophrenia
o Blocks D4 and 5-HT2 receptors
o Weak blockade of striatal D2 receptors
o Agranulocytosis (requires regular blood monitoring)
o Myocarditis / cardiomyopathy
o Ileus
o Severe cardiac disorders
o History of neutropenia / agranulocytosis
• Interactions:
o Avoid concomitant use with drugs that have a high risk of
causing agranulocytosis (e.g. carbimazole)
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Drugs in the elderly, young or pregnant
Pharmacokinetics in the elderly:
• Distribution:
o ⇓ body water:
 Thus water soluble drugs have a ⇓ volume of distribution
(Vd)
 Thus ⇑ [water soluble drugs]
o ⇑ body fat:
 Lipid soluble drugs have an ⇑ Vd
 Thus ⇓ [fat soluble drugs]
o ⇓ plasma albumin:
 ⇓ drug protein binding
 Thus ⇑ levels of drugs that usually bind to protein
o ⇓ weight (no longer a 70kg man!):
 Thus standard dose will lead to ⇑ [drug]
• Metabolism:
o ⇓ oxidation
o ⇓ first-pass metabolism
o ⇓ induction of liver enzymes
o Warfarin is more effective
• Excretion:
o ⇓ GFR
o ⇓ tubular secretion
Altered end-organ sensitivity in the elderly:
• Autonomic nervous system:
o Defective compensatory mechanisms:
 E.g. antihypertensives  postural hypotension
o β-receptors (⇓ density)
• Brain:
o ⇑ sensitivity to anxiolytics and hypnotics (may lead to confusion)
• Heart (failing):
o ⇓ perfusion of liver / kidneys  ⇓ function of these organs
Two groups of drugs in the elderly cause 2/3 of all adverse drug reactions:
• Drugs acting on the:
• Brain:
o Antidepressants
o Anti-Parkinson’s drugs
o Hypnotics
• Circulation:
o Antihypertensives
o Digoxin
o Diuretics
Compliance issues in the elderly:
• Living alone / unsupervised
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• Confusion because of change in tablet shape / colour
• Impaired vision
• Arthritic hands
Pharmacokinetics in neonates:
• Absorption:
o ⇓ gastric motility
o Variable peripheral perfusion (care with IM injections)
• Distribution:
o Blood brain barrier is immature
o ⇑ body water:
 Thus ⇓ [water soluble drugs]
o ⇓ body fat:
 Thus ⇑ [fat soluble drugs]
o Protein binding low (adult levels at 1 year of age)
• Metabolism:
o ⇓ P450 activity
o ⇓ conjugation:
 E.g. chloramphenicol  grey baby syndrome
• Excretion:
o ⇓ GFR:
 The neonate has 30% of adult GFR and 20% of adult
tubular secretion
 This ⇑ to 50% at 1 week of age
 ⇑ to 100% at 6 months of age
Drugs with adverse effects on foetal development:
• ACE inhibitors
• Alcohol
• Androgens
• Anticonvulsants
• Folate antagonists (e.g. methotrexate)
• Tetracyclines
• Thalidomide
• Warfarin
Drugs to avoid in later pregnancy:
• Aspirin:
o Haemorrhage
o Kernicterus
• Aminoglycosides:
o CN VIII damage
• Anti-thyroid drugs (e.g. carbimazole):
o Goitre
o Hypothyroidism
• Benzodiazepines:
o “Floppy baby” syndrome
• Chloramphenicol:
o Grey baby syndrome
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• Warfarin:
o Haemorrhage
• Sulphonylureas:
o Kernicterus
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Cytotoxic chemotherapy
Classification of anti-cancer drugs:
• Alkylating agents:
o Cyclophosphamide
o Chlorambucil
o Cisplatin
o Dacarbazine
o Ifosfamide
o Mitomycin C
• Anti-metabolites:
o Folate antagonists:
 Methotrexate
o Pyrimidine analogues:
 5-Fluorouracil (5-FU)
 Cytarabine (cytosine arabinoside)
 Gemcitabine
o Purine analogues:
 Azathioprine
• Cytotoxic antibiotics:
o Anthracyclines:
 Doxorubicin (adriamycin)
o Bleomycin
• Plant derivatives:
o Taxanes:
 Paclitaxel
o Vinca alkaloids:
 Vincristine
 Vinblastine
• Epipodophyllotoxins:
o Etoposide
• Hormonal:
o Antagonists:
 Anti-androgens:
• Cyproterone
 Anti-oestrogens:
• Tamoxifen
o Corticosteroids
o GnRH analogues:
 Goserelin
o Somatostatin analogues:
 Octreotide
• Miscellaneous compounds:
o Hydroxyurea
Some example chemotherapy regimens:
• BEP:
o Bleomycin
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o Etoposide
o Cisplatinum
o Testicular teratoma
• CHOP:
o Cyclophosphamide
o Hydroxydaunomycin (doxorubicin)
o Oncovin (vincristine)
o Prednisolone
o Radical treatment of non-Hodgkin’s lymphoma (NHL)
• ABVD:
o Adriamycin (doxorubicin)
o Bleomycin
o Vinblastine
o Dacarbazine
o Hodgkin’s lymphoma
• FEC:
o 5-Fluorouracil
o Etoposide
o Cyclophosphamide
o Breast cancer
General adverse effects of cytotoxic agents:
• Nausea / vomiting
• Alopecia
• Oral / intestinal ulceration
• Diarrhoea
• Bone marrow suppression:
o Anaemia
o Leucopenia
o Thrombocytopenia
• Teratogenicity
• Carcinogenesis
Emesis-risk:
• High risk:
o Treat with granisetron + dexamethasone + domperidone)
o Cisplatinum (high dose)
o Etoposide (high dose)
o Dacarbazine
o Ifosfamide
• Moderate risk:
o Cisplatinum (low dose)
o Cyclophosphamide
o Doxorubicin
o Methotrexate (high dose)
• Low risk:
o Treat with domperidone ± dexamethasone
o Bleomycin
o Methotrexate (low dose)
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patient’s biggest concern
physician’s biggest concern

o Mitomycin
o Vincristine
Prevention of nausea / vomiting:
• Acute:
o 5-HT3 antagonist (e.g. granisetron) +
o Dexamethasone
• Delayed:
o Domperidone / metoclopramide
o Dexamethasone
Alkylating agents:
• E.g. cyclophosphamide, chlorambucil, cisplatin, dacarbazine,
ifosfamide, mitomycin
o Readily form covalent bonds with the bases in DNA
o Prevent cell division by cross-linking the two strands of the
double helix
o Their main action occurs during replication (i.e. during S phase
with a block at G2)
o Results in apoptotic cell death
• Cyclophosphamide:
o Indications:
 Malignancy
 Autoimmune disease (e.g. SLE, rheumatoid arthritis)
 Nephritic syndrome
 Vasculitis
o Adverse effects (in addition to the general ones above):
 Haemorrhagic cystitis:
• Due to the metabolite acrolein
• Can be ameliorated by:
o ⇑ fluid intake
o Mesna (a sulphydryl donor)
 Infertility in men:
• Long-term use
• May be irreversible
• Cisplatin:
o A platinum containing alkylating agent
o Revolutionised the treatment of tumours of the testes / ovary
o Adverse effects:
 Nephrotoxicity
 Very severe nausea / vomiting
 Peripheral neuropathy
 Ototoxicity
 Anaphylactoid reactions
Pyrimidine analogues:
• E.g. 5-FU, cytarabine, gemcitabine
• 5-FU:
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o Mechanism of action:
 Interferes with thymidylate synthetase (essential for
the production of thymidylic acid)
 Impairs DNA synthesis (but not RNA or protein
synthesis)
• Cytarabine:
o Mechanism of action:
 Incorporated into DNA and RNA
 Inhibits DNA replication and (to a lesser extent) DNA
repair
• Gemcitabine:
o An analogue of cytarabine
o Has fewer unwanted effects:
 ‘Flu-like symptoms
 Mild myelotoxicity
Purine analogues:
• E.g. 6-mercaptopurine (6-MP), azathioprine (a pro-drug of 6-MP)
• Indications:
o Autoimmune diseases (e.g. rheumatoid arthritis, SLE)
o Prevention of transplant rejection
o Steroid-sparing agent
o 6-MP is converted to a “fraudulent” nucleotide
o Is incorporated into and interferes with replicating DNA
o Also impairs the de novo pathway of purine synthesis
o Nausea / vomiting
o Bone marrow suppression
o Alopecia
o Jaundice
• Interactions:
o Allopurinol:
 Allopurinol inhibits the metabolism of azathioprine, thus ⇑
it’s toxicity
Cytotoxic antibiotics:
• E.g. doxorubicin
o Inserts itself between base pairs (intercalation):
 Alters the topography of DNA
 Causes unwinding of DNA
o Causes topoisomerase II-associated DNA strand breaks
o Causes free-radical formation:
 Responsible for cardiac toxicity (as the heart cannot
inactivate them due to a lack of catalase activity)
o Cardiac toxicity:
 Acute Myocarditis / pericarditis
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 Late onset cardiac failure:
• 5% of patients after high dose therapy
Taxanes:
• E.g. paclitaxel (taxol)
• Derived from Yew tree bark
o Stabilise cell microtubules (in effect “freezing” them)
o Prevents spindle formation in mitotic cells and causing cell cycle
arrest in metaphase
o Bone marrow suppression
o Hypersensitivity:
 Must pre-treat the patient with:
• Antihistamines
• Corticosteroids
o Neurotoxicity
Vinca alkaloids:
• E.g. vincristine, vinblastine
• Extracts of the periwinkle plant
o Bind to tubulin and inhibit it’s polymerisation into
microtubules
o This prevents spindle formation
o Leads to cell cycle arrest in metaphase
o Relatively non-toxic
o Neurotoxicity:
 Paraesthesia
 Neuromuscular abnormalities
o Fatal if given intrathecally
Hydroxyurea:
• Indications:
o Malignancy
o Sickle cell anaemia (⇑ production of fetal Hb)
o A urea analogue
o Inhibits ribonucleotide reductase
o Interferes with the conversion of ribonucleotides to
deoxyribonucleotides
Anti-malarials
Main signs / symptoms of malaria:
• ‘Flu-like symptoms:
o Headache
o Malaise
o Myalgia
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• Fever ± chills
• Anaemia
• Jaundice
• Hepatosplenomegaly
• No lymphadenopathy / rash
Poor prognostic signs:
• Young (< 3 years)
• Pregnant
• Hyperparisitaemia (> 5% of RBCs)
• CNS:
o Fits
o Coma
• Renal:
o Blackwater fever (haemoglobinuria)
o Oliguria
o Acure renal failure
• Hypoglycaemia (< 2.2 mmol/L)
• Acidosis (⇑ [lactate])
Treatment of malaria:
• If species unknown or mixed infection then treat as for falciparum
• P. Falciparum:
o Quinine and
o Tetracycline or doxycycline or clindamycin
o Alternatives:
 Malarone or
 Fansidar
• Non-falciparum:
o Chloroquine ±
o Primaquine (if P.ovale / P.vivax):
 Improves liver clearance of the parasite
Prophylaxis against malaria:
• Avoid getting bitten if possible
• High risk of P.falciparum:
o Mefloquine
o Malarone
o Doxycycline
• No / low risk of P.falciparum:
o Chloroquine and proguanil
Quinine:
o Tinnitus
o Nausea
Chloroquine:
o Retinopathy
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o Psychosis
Fansidar:
o Stevens-Johnson syndrome
o Blood dyscrasias
o Deranged LFTs
Primaquine:
o Haemolytic anaemia (G6PD-deficiency)
o Methaemoglobinaemia
Mefloquine:
o Severe psychiatric reactions:
 More common in young women with a previous history of
psychiatric illness
• Has a long t½ (needs to be started 2–3 weeks before travelling)
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