Advanced Clinical

Pharmacology for Masters

Nursing Students

By

Solomon M Abay (PhD)

 Introduction to pharmacology

• Pharmacology: study of substances that interact

with living systems through chemical process,
especially by binding to regulatory molecules &
activating or inhibiting normal body process

• Basic areas of pharmacology:

– Pharmacokinetics
– Pharmacodynamics
• Pharmacokinetics: deals with absorption,
distribution, biotransformation & excretion of drugs

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 Introduction cont’d

• Pharmacodynamics: study of biochemical & physiological

effects of drugs & their mechanisms of action
• Pharmacotherapeutics: use of drugs in prevention &
treatment of disease
• Toxicology: branch of pharmacology which deals with the
undesirable effects of chemicals on living systems
• Drug: any substance that brings about a change in biologic
function through its chemical action
• Chemotherapy: effect of drugs upon microorganisms,
parasites and neoplastic cells living & multiplying in living
organism
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 History of pharmacology
• Prehistoric people recognized beneficial & toxic effects of
many plant & animal materials
• Preceding the modern era, there were attempts to introduce
rational methods into medicine. But none were successful
owing to the dominance of systems of thought [without
experimentation & observation]
• Around end of 17th century, reliance on observation &
experimentation began
• About 50yrs ago, controlled clinical trial reintroduced;
Expansion of research efforts
– Drug action & receptor
• Now, the molecular mechanism of action of many drugs is
known 4
 Drugs

• Drugs mostly interact with a specific molecule in a

biologic system that plays a regulatory role
[receptor]

• To interact chemically with its receptor, a drug

molecule must have the appropriate :
• Size,
• Electrical charge,
• Shape &
• Atomic composition

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 Source of drugs

• Mineral: liquid paraffin, mg trisilicate

• Animals: insulin, heparin
• Plants: morphine
• Synthetic: aspirin
• Microorganism: penicillin
• Genetic engineering: human insulin

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 Drug nomenclature

• Existence of many names for each drug causes

lamentable & confusing situation
– Chemical names
– Code names
– Nonproprietary/generic name
– Proprietary/trademark/trade name

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 Pharmacokinetics

• Pharmacokinetics:
– Pharmaco: drug
– Kinetics: motion
• Action of body on drug/ how body handles drugs
• Pharmacokinetics: ADME

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 Absorption
• It is a process by which the drug leaves the site of
administration to circulatory system

How drugs transfer from site of administration

1. Filtration [aqueous diffusion]
• Size should be less than size of pore
• Has to be water soluble
• Na+, glucose, caffeine

2. Lipid diffusion
• Drugs supposed to pass through the membrane
• Drugs must be lipid soluble
• High partition coefficient  high absorption
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 Absorption cont’d

3. Carrier mediated absorption

a. facilitated diffusion
- passive diffusion but facilitated
e.g. Levo-dopa & amino acid into brain
b. Active transport
- use ATP & carrier proteins
- against the concentration gradient
e.g. penicillin secretion

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 Absorption cont’d

4. Phagocytosis & pinocytosis

- Process by which large molecules are engulfed by
the cell membrane & releases them intracellulary
- E.g. protein, toxin

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 Routes of administration

• Enteral
– Oral, rectal, sublingual, buccal
• Parenteral
– Intramuscular, subcutaneous, intravenous,
intraarterial
• Inhalation
• topical

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Factors affecting absorption from GI
• pH of media & pKa of the drug
• Area of absorbing surface
• Particle size of the drug
• Formulation
• Gut motility
• Splanchic blood flow
• Gastric secretion
• Drug interaction

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 Bioavailability
• Bioavialability: fraction of administered drug that
reaches the systemic circulation
– Amount of drug available in the circulation/site of
action
– Bioavailability is expressed in percentage

Factors affecting bioavailability

– Extent of absorption
– First pass effect

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• Bioequivalence: Cmax and AUC

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 Drug distribution

• Process by which a drug reversibly leaves the blood

stream & enters the interstitium and/or cells of the
tissues

Factors affecting drug distribution

1. Plasma protein binding
– Albumin [acidic drugs]
– -glycoprotein [basic drugs]
– Plasma protein binding is not selective
– E.g. sulphonamide displaces bilirubin
Kernicterus
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 Drug distribution cont’d

2. Tissue uptake of drugs

adipose tissue [DDT]
bone [TTC]
liver [chloroquine]
thyroid gland [iodine]
3. Barriers
Blood brain barrier & Placental barrier
4. Rate of blood flow
brain, kidney, liver & lung- highly perfused

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 Drug distribution cont’d

• Volume of distribution (defn):

– the volume of fluid required to contain the total amount of
drug as the same concentration with that of plasma.

• Actual volume of distribution

• Polar & large molecules: contained in the plasma
• Nonpolar: distribute to the total body fluid
– Actual Vd is not suitable for calculation of Vd
for nonpolar

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 Drug distribution cont’d
• Apparent volume of distribution
– Apparent Vd=Dose/Co
– Where:
• Co- initial concentration, Dose- to be administered

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Biotransformation/metabolism
• Alteration of drug structure
• Main site of biotransformation
– Liver, intestine, plasma

Phase I biotransformation
• Consists of reactions:
– Oxidation [ethanol]
– Reduction [estrone]
– Hydrolysis [procaine]
• The products are more reactive than parent drug
• Purpose of phase I reaction is to introduce
functional groups; [NH2, thiol, hydroxyl] 20
 Biotransformation cont’d

Phase II reaction [conjugation]

• Conjugating compounds include:

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 Biotransformation cont’d

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Acetaminophen (AC) paracetamol
 Biotransformation cont’d
• Enzyme inducer
– Phenobarbitone: nonselective
– DDT: induces cyp1A1
• Enzyme inhibitor
– Cimetidine
– Ketoconazole
– Erythromycin
– chloramphenicol

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Liver enzyme inhibitor

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 Biotransformation cont’d

Consequences of drug biotransformation

• Activation [L-dopa dopamine]
• Maintenance of activity [Diazepam  oxazepam]
• Inactivation [Phenobarbital  hydroxypentobarbital]
• Alteration of activity [Progesterone  Pregnanediol]

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 Excretion of drugs

• Minor route of excretion

– Eye, breast, skin
• Intermediate route
– Lung [Volatile]
– Bile [Digoxin, rifampin]
• Renal excretion

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Pharmacodynamics

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 Factors that modify drug effect &
drug dosage
• Sex: m/f
• Body weight: lean/obese
• Age: child (ppb, incomplete dev’t of BBB, Underdeveloped renal &
enzyme system)
• Environment: hypnotic in daytime
• Food
• Route of administration
• Physiological variables: fluid & electrolyte
• Pathological factor (kidney & liver)
• Genetic makeup: pseudocholinesterase; & acetylation
• Tolerance to drug
• Drug interaction

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 Drug interaction: classification

• Pharmaceutical
– Diazepamin infusion fluid: precipitation
• Pharmacokinetic
– Absorption (TTC & milk)
– Distribution (phenoxybenzamine & warfarin)
– Biotransformation
• Induction (phenobarbitone & warfarin)
• Inhibition (cimetidine & warfarin)
– Excretion (probenecid & penicillin)
• Pharmacodynamic (phenoxybenzamine & adrenaline)

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 Types of drug interaction
• Additive [1+1= 2]
• Synergism [1+ 1> 2]
• Potentiation [0+1 > 1]
• Antagonism [0+1< 1]
– Chemical antagonism
– Physiological antagonism
– Pharmacological antagonism
• Competitive
• noncompetitive

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 Adverse drug reaction
• ADR: defined as any response to a drug that is noxious
and unintended and that occurs at doses used in man for
prophylaxis, diagnosis or therapy.
• Types of ADR:
– Predictable:- side effect & toxic effect
– Non predictable:- allergy & idiosyncrasy
1. Side effects: Pharmacological effects produced with therapeutic
dose of the drug
E.g. dryness of mouth with atropine and useful when used as pre-
anesthetic medication.
2. Toxic effect: Excessive pharmacological action of the drug due to
overdosage or prolonged use.
Overdosage may be absolute [accident, homicidal, suicidal] or
relative [usual dose of gentamicin in presence of renal failure]

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 Adverse drug reaction cont’d
3. Untoward/ Secondary effects: indirect consequences of primary
action of drug,
– suppression of bacterial flora by tetracycline paves the way for superinfection;
corticosteroids weaken host defense mechanisms and latent tuberculosis gets
activated.

4. Idiosyncratic reaction: genetically determined ADR,

– Neuropathy by INH
– Hemolytic anemia by primaquine

5. Hypersensivity reaction/ allergy:

– Type I(Anaphylactic reaction): antigen + IgE on basaphil/mast cell
 Anaphylaxis, asthma, hay fever or urticaria
6. Teratogenic effect: the effect of drug to cause foetal
abnormalities when administered to the pregnant mother.
– E.g. thalidomide cause phocomelia [absent or grossly abnormal limbs]
7. Carcinogenicity and mutagenicity: a drug to cause cancer and
genetic defects respectively

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Development and evaluation of new drugs

• Drug development comprises

1. Preclinical development
2. Clinical development

Preclinical development:
– Used to explore drug’s safety & efficacy
– Drugs tested on animals or in vitro
– Pharmacodynamic, pharmacokinetic and toxicity
will be studied

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 Development and evaluation cont’d

2. Clinical development
a. Pharmaceutical study: formulation study
b. Pharmacological study: toxicological study in human
being
c. Clinical trial: safety and efficacy of a compound is
studied in human
Phase I
Phase II
Phase III
Phase IV

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 Clinical Trials

• Phase I: Drug is tested on healthy volunteers

to determine toxicity relative to dose and to
screen for unexpected side effects
 Clinical Trials
• Phase II: Drug is tested on small group of
patients to see if drug has any beneficial effect and to
determine the dose level needed for this effect.
 Clinical Trials
• Phase III: Drug is tested on many larger
group of patients and compared with existing
treatments and/or with a placebo (??)
 Clinical Trials
• Phase IV: Drug is placed on the market and patients
are monitored for side effects
Summary: drug discovery & development
Thank you

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