CLINICAL PHARMACOLOGY SERIES
ADVERSE DRUG EFFECTS AND DRUG SAFETY
BY: PATSON KALUNGA (DR KALUSON)
BSc.HB
MBcHB (UNZA)
CLINICAL SENSE
A 24-year-old woman presents to the clinic with
complaints of painful urination and lower pelvic pain.
After evaluation, she is diagnosed with a urinary tract
infection (UTI) and is prescribed nitrofurantoin for
treatment. A few days later, she develops pallor,
fatigue, jaundice, and dark urine. What is the most
likely cause of these symptoms?
A) Nitrofurantoin-induced hypersplenism in susceptible
individuals
B) Drug-induced hemolysis in a patient with G6PD
deficiency
C) Hemolysis secondary to the UTI itself
D) Sickle cell crisis induced by nitrofurantoin exposure
INTRODUCTION
● Adverse effect is any undesirable or unintended
consequence of drug administration.
● This definition includes trivial, serious and even fetal
noxious effects of drug administration.
● Adverse drug reaction: any noxious change which
is suspected to be due to a drug, occurs at doses
normally used in man, requires treatment or
decrease in dose or indicates caution in the future
use of the same drug.
● This excludes trivial effects, poisonings or overdose.
● Another terms, adverse drug event: ‘any untoward
medical occurrence that may present during treatment
with a medicine, but which does not necessarily have a
causal relationship with the treatment
CATEGORIES OF ADRs
1. Predictable (Type A or Augmented)
reactions:
● Based on pharmacological properties
of the drugs and is dose dependent.
They include side effects, withdrawal
Nausea symptoms and toxic effects.
2. Unpredictable (Type B or Bizarre)
reactions:
● Based on patient perculairites. May include
allergies and idiosyncratic reactions.
● They can be also based on the metabolites
obtained from drugs.
● For example the turning of body fluids red
orange on taking rifampicin
Red, orange urine from taking
rifampicin
CATEGORIES
1. Type C (Chronic): occurs due to
prolonged used of the drug. E.g.
cushing syndrome in patients taking
glucocorticoids
2. Type D (delayed): delayed reaction
occurring long after drug exposure
and even after the drug has been
discontinued E.g. secondary cancers after
taking chemotherapy drugs.
SEVERITY OF ADRs
1. Minor: no therapy required.
2. Moderate: requires change in drug therapy,
hospitalization by at least one day.
3. Severe: potentially life threatening, causing permanent
damage or requiring ICU care.
4. Lethal: directly or indirectly contributors to the death of
the patient.
SIDE EFFECTS
● These are unwanted but often unavoidable
pharmacodynamic effects that occur at therapeutic
dose
● Side effects are usually predictable in a population
and occur due to the mechanism of action of a drug.
● For example estrogen is one of the active ingredient in
contraceptive pills.
● It’s mechanism of action includes inhibiting the follicle
stimulating hormone and reducing the likelihood of
ovulation.
● At the same time, estrogen binds to the
chemoreceptor trigger zone in the brain causing
nausea.
● In one context, a side effect can be a therapeutic
benefit. E.g. codeine used for cough suppression causes
constipation (side effect) can be used to treat diarrhoea in
some patients.
SECONDARY EFFECTS
● These includes consequences of
a primary action of a drug.
● For example, taking an antibiotic
can suppress vaginal normal
bacterial flora which causes
bacterial vaginosis and in some
cases candidiasis.
● Taking corticosteroids can weaken
the immune system that later
causes activation of latent TB in
the patient.
TOXIC EFFECTS
● Direct effects of prolonged drug
use or overdosage.
● Overdosage can be:
○ Absolute: accidental, homicidal or
suicidal.
○ Relative: usual dose in the presence of
another drug, or an important organ
involved in metabolism or excretion
fails.
● These toxic effects are usually
predictable and dose related.
● Toxicity can also be an extension of
therapeutic effects of a drug. E.g.
morphine causing respiratory
depression.
CLINICAL SENSE
1. Mrs Simate has a history of chronic liver disease. She has been taking drug X,
which is metabolised and excreted by the liver. The drug has a very narrow
therapeutic index/window. The latest lab results show a 50% decline in liver
and normal kidney function. Which of the following actions would be the best
option for the clinician to take?
A. Reduce the dose of drug X by 50%
B. Maintain the dose of drug X
C. Increase the dose of drug X by 50%
D. Prescribe a different drug that is metabolised by the kidney
INTOLERANCE
● Includes the appearance of
characteristic toxic effects of a
drug in an individual at
therapeutic doses.
● This is due to low threshold for
toxicity in these individuals.
● For example in some patients, a
few doses of carbamazepine well
tolerated by other individuals can
cause ataxia.
IDIOSYNCRASY
● Genetically or immunologically determined
abnormal reactivity to a chemical.
● These drug reactions are restricted to people
who posses a specific phenotype and is a
common cause of bizarre reactions seen in some
patients.
● They are not dose-dependent and are
unpredictable.
● An example is drug induced hemolysis seen
in patients with glucose-6-phosphate
dehydrogenase deficiency.
● Another example is malignant hyperthermia
that occurs in some patients taking
Anesthetic Agents like Dantrolene
CORE QUESTION
DRUG ALLERGY
● Also known as drug
hypersensitivity:
Immunologically mediated
reaction which is unrelated to
the pharmacodynamic profile of
the drug.
● These reactions occur even at low
doses and have different onset of
actions duration.
● A common allergy is seen with
penicillin
CLINICAL SENSE
Mr Banda has a history of chronic kidney and liver disease. He has been taking
drug A, which is metabolized and excreted in the lungs. The latest lab results show
a 50% decline in liver and kidney function. Which of the following actions best
indicates what the clinician would do?
A. Reduce the dose of drug A by 50%
B. Increase the dose of drug A by 50%
C. Prescribe a different drug that is metabolised by the liver or kidney
D. Maintain the dose of drug A
PHOTOSENSITIVITY
● Has two types:
1. Phototoxic: Accumulation of metabolite or
durg under the skin which absorbs light and
undergoes a photobiological reaction that
causes local tissue damage.
● Seen with tetracyclines
2. Photoallergic: Drug or its metabolite induces
a cell mediated immune response which
on exposure to light of longer
wavelengths
● Seen with sulfonamides, sulfonylureas
DRUG WITHDRAWAL REACTIONS
● Abrupt interruptions of certain drugs can
lead to adverse reactions especially those
involved in worsening of the clinical
condition.
● These occur because of the adaptive changes
that the body undergoes after the drug has
being introduced.
● For example;
○ Worsening of angina pectoris after stoppage of
ß-blockers.
● It helps to gradually withdraw drugs to
prevent these reactions.
MATCH THE FOLLOWING
1. Anaphylactic shock after taking penicillin for strep throat A. Secondary effects
2. A TB patient noticing his urine is orange after starting B. Intolerance
rifampicin C. Allergy
3. A person who formerly abused morphine experiencing D. Idiosyncratic
anxiety, sweating, stomach cramps and increased respiratory E. Type A reaction
rate F. Withdrawal symptoms
4. Liver failure after taking paracetamol in large amounts G. Type C reaction
5. A patient with rheumatoid arthritis treated with H. Type D reaction
glucocorticoids develops bone weakness and increased risk
I. Drug side effect
of fractures.
6. Malignant Hyperthermia after administration of Dantrolene
7. Nausea and vomiting after taking iron tablets
8. Clostridium difficile (C. difficile) infection in a patient treated
with broad spectrum antibiotics
9. A patient prescribed codeine at standard dose for pain
management may experience excessive sedation, nausea, and
dizziness.
10. Dizziness and sedation after taking an antihistamine.
TERATOGENICITY
● Teratogenesis signifies the production of
gross structural malformations during
fetal development.
● This is different from the effect of
drug-induced fetal damage such as growth
retardation, dysplasia or asymmetrical limb
reduction.
● The placenta acts as a barrier for many
substances but some characteristic properties
of some drugs allow them to cross the
placenta and affect the dynamic biology of
a developing fetus.
● That is why is important that before any
female in the child bearing age is
pregnancy unless proven otherwise.
MECHANISMS
● Teratogenesis occurs at three main stages:
1. Fertilization and implantation
(blastocyst formation):
● Occurs from day conception to day
17
● Most drugs affecting the embryo at
this stage affect cell division and are
cytotoxic.
● Sometimes pregnancy loss at this
stage goes unnoticed.
MECHANISM
2. Organogenesis: Day 18 to 60
● At this stage, the organ
structural organisation
occurs.
● This leads to predictable
malformations depending on the
day of exposure.
● Mechanism is usually due to
DNA damage or disruption of
DNA synthesis (e.g.
methotrexate, phenytoin)
MECHANISM
3. Histogenesis and maturation of function:
● Occurs from day 60 to term.
● Malformation usually occur with drugs that
affect supply of nutrients, alter
endogenous metabolites, hormones,
substances in the fetus.
● This leads to deleterious effects on
growth and development.
● Malformations at this stage are usually not as
dramatic as in the other stages.
● For example, administration of ACE
inhibitors can lead to hypoplasia of organs
such as the lungs and kidneys and
oligohydramnios.
● NSAIDs can cause premature closure of the
ductus arteriosus
● Androgens can masculaise a female fetus.
US-FDA CATEGORIES
● The US-FDA has categories drugs depending on their risk
to cause birth defects.
● It is important that clinicians are able to identify and weigh the
risk vs benefit of administered drugs to pregnant women.
1. Category A: no risk.
2. Category B: no adequate evidence of harm in humans but
animal studies have shown ADRs in developing fetuses.
3. Category C: Potential risk. No adequate studies in
pregnant women
US-FDA CATEGORIES
4. Category D: Evidence of risk in human fetus but
benefit may outweigh the risks. Caution needed to
administer the drug.
5. Category X: contraindicated in pregnant women. E.g.
Warfarin, isotretinoin, misoprostol.
● A new system is more used by clinicians today called the The
Pregnancy and Lactation Labeling Rule.
● This system gives more detailed studies on a drug rather
than an oversimplified letter.
CLINICAL SENSE
A 35-year-old woman with a history of atrial
fibrillation is currently on propranolol and warfarin
for management of her condition. She is planning to
conceive and consults you regarding the safety of
her medication regimen during pregnancy. What
would be the most appropriate course of action?
A) Continue her current drug regimen throughout
pregnancy
B) Discontinue her medications during the first and
second trimesters and resume them in the third trimester
C) Switch her anticoagulant from warfarin to heparin or
low molecular weight heparin (LMWH) during pregnancy
D) Switch her beta blocker from propranolol to an ACE
inhibitor, as propranolol is unsafe during pregnancy
E) Discontinue the anticoagulant throughout the
pregnancy
