Adverse Effects
and
Toxic Effects
of Drugs
All things are poison, and nothing is without
poison.
Solely the dose determines that a thing is not a
poison.
Paracelsus
Specific, desired effects of drug
administration
Therapeutic
Effect
Drug toxicity is critically important in drug
development.
Drug Early in drug development, preclinical and
Development clinical studies are used to evaluate compound
potency, selectivity, pharmacokinetic and
metabolic profiles, and toxicity
Drug
Development
Preclinical Studies
In Vitro Animal Testing
Lethal Dose 50 (LD50): the amount of a material, given all at once, which
causes the death of 50% (one half) of a group of test animals.
Effective Dose 50 (ED50) is the dose of a medication that produces a specific
effect in 50% of the population that has been administered that dose.
Toxic Dose 50 (TD50): is the dose of a substance that causes a toxic effect in 50% of
the tested population
Phase I Normal volunteers (20-50)
Phase II Selected patients (100-
500)
Clinical
Studies
Phase III Large sample (1000-5000)
Phase IV
Any untoward medical occurrence that
may present during treatment with a
Adverse pharmaceutical product but that does
Event (AE) not necessarily have causal relationship
with this treatment
Any response that is
noxious, unintended and
which occurs at doses
Adverse normally used in humans for
Drug prophylaxis, diagnosis or
therapy of disease, or for
Reaction modification of
(ADR) physiological function
Adverse drug reaction has a direct
causal relationship with the drug
Adverse drug reactions can be classified
according to
Adverse drug
reaction Their onset Degree Predictability
(ADR) - Acute - Mild - Predictable and dose relate
- Subacute - Moderate - Unpredictable and not necessarily
- Delayed - Severe dose related
- Lethal - Idiosyncratic
- Immunologic reactions
Adverse effect is defined as any
undesirable or unwanted effect due to
drug administration.
Adverse
Effects As a general matter, adverse effects range
from those that are common and
relatively benign to those that pose
serious risk of organ damage or death.
Adverse • Predictable (Type A or augmented) reactions
Effects • Unpredictable (Type B or Bizarre) reactions
These reactions are based on pharmacological
Predictable properties of the drug, i.e. they are augmented
but qualitatively normal response to the drug.
(Type A or
This type of adverse effects include
augmented)
- Side effects
Reactions - Toxic effects
- Consequences of drug withdrawal
(mechanism based
adverse reactions)
They are more common, dose related and are
mostly preventable and reversible
These reactions are based on peculiarities of the
patient and not on the drug’s known actions.
Such reactions include
- Allergy
Unpredictable - Idiosyncrasy.
(Type B or
They are less common, often non-dose related,
Bizarre) generally more serious and require withdrawal of
the drug.
Reactions
Some of these reactions can be predicted and
prevented if their genetic basis is known and
suitable tests to characterize the individual’s
phenotype is performed.
Adverse Effects
The adverse drug effects may be categorized into:
1. Side effects 7. Photosensitivity
2. Secondary effects 8. Drug dependence
3. Toxic effects 9. Drug withdrawal reactions
4. Intolerance 10. Teratogenicity
5. Idiosyncrasy 11. Carcinogenicity and mutagenicity
6. Drug allergy (hypersensitivity) 12. Drug-induced diseases
(Iatrogenic diseases)
Predictable, dose-dependent reactions
unrelated to the goal of therapy, and often at
therapeutic doses
Side Effects
Secondary Indirect consequences of a primary action of the
Effects drug
These are the result of excessive
pharmacological action of the drug due to
overdosage or prolonged use.
Toxic Effects • Hepatotoxicity
• Nephrotoxicity
• Ototoxicity
• Ocular Toxicity
Wheatfield with Crows
Café Terrace at Night
Van Gogh
Sun Flowers
Starry Night
Xanthopsia
Dr. Paul Gachet
Intolerance a low threshold of the individual to the action of
a drug.
Idiosyncratic a genetically determined abnormal reaction to
Reactions drugs
Drug Allergy (Hypersensitivity)
A drug allergy is an immunologic response to a drug resulting in
a reaction such as a rash or anaphylaxis.
Unlike other adverse reactions, allergic reactions are neither
predictable nor dose related.
A) HUMORAL
1. Type I hypersensitivity (immediate type,
anaphylactic shock)
Types of 2. Type-II hypersensitivity (cytotoxic reaction)
Allergic 3. Type-Ill hypersensitivity (immune complex–
Reactions mediated, Arthus reaction)
B) CELL MEDIATED
Type-IV hypersensitivity (delayed
hypersensitivity) reactions
Type I
Hypersensitivity
(immediate type,
anaphylactic
shock)
It is a medical emergency and should
be treated promptly with:
1. Inj. adrenaline (1:1000) 0.3–0.5 mL
intramuscularly.
2. Inj. hydrocortisone 100–200 mg
intravenously.
3. Inj. pheniramine 45 mg
intramuscularly/intravenously.
4. Intravenous fluids.
Type II
Hypersensitivity
(cytotoxic reaction)
AG:AB complexes are formed
Type III
Fix complement
Hypersensitivity
(immune complex– Deposition of complexes on vascular
endothelium
mediated,
Arthus reaction)
Destructive inflammatory response
Tissue Damage
It is mediated by sensitized T lymphocytes.
Re-exposure to the antigen leads to a local
Type IV inflammatory response.
Hypersensitivity The manifestations usually occur 1–2 days after
exposure to the sensitizing antigen,
(cell-mediated or
e.g. contact dermatitis due to local anaesthetic
delayed creams, topical antibiotics and antifungal
hypersensitivity) agents.
Type II, type III and type IV reactions are
treated with glucocorticoids.
It is a cutaneous reaction resulting from drug
Photosensitivity induced sensitization of the skin to UV radiation.
(a) Phototoxic
(b) Photoallergic
Drug or its metabolite accumulates in the skin,
absorbs light and undergoes a photochemical
reaction followed by a photobiological reaction
resulting in local tissue damage (sunburn like),i.e.
erythema, edema, blistering followed by
hyperpigmentation and desquamation.
Phototoxic
The shorter wavelengths
(290– 320 nm,UV-B) are responsible
Drug or its metabolite induces a cell-mediated
immune response which on exposure to light of
longer wavelengths (320–400 nm, UV-A) produces a
papular or eczematous contact dermatitis like
picture.
Occasionally, antibodies may also mediate
photoallergy, and the reaction takes the form of
immediate flare and wheal on exposure to sun.
Photoallergic Drugs involved are sulfonamides, sulfonylureas,
griseofulvin, chloroquine,
chlorpromazine.
World Health Organization (WHO) defines drug
dependence as
‘a state—psychic and sometimes also
Drug physical—resulting from the interaction between
a living organism and a drug, characterized by
Dependence behavioural and other response that always
includes a compulsion to take the drug on a
continuous or periodic basis in order to
experience its psychic effects and sometimes to
avoid the discomfort of its absence’
The dependence could be psychological or physical.
1. Psychological dependence: There is an intense desire
to continue taking the drug as the patients feel that their
Drug well-being depends upon the drug.
Dependence 2. Physical dependence: Repeated drug use produces
physiological changes in the body that makes continuous
presence of the drug in the body necessary to maintain
normal function.
.
Principles of treatment of drug dependence are:
1. Hospitalization.
Treatment of 2. Substitution therapy: e.g.
Methadone/buprenorphine substitution for
Drug morphine addiction.
Dependence 3. Aversion therapy: Disulfi ram for alcohol
addiction.
4. Psychotherapy.
5. General measures: Maintain nutrition, family
support and rehabilitation.
Abrupt stoppage of the drug results in an
imbalance wherein the body has to readjust to
the absence of the drug resulting in the
Withdrawal development of signs and symptoms known as
Syndrome withdrawal syndrome.
The withdrawal signs and symptoms are
generally opposite to the effects produced by
the drug.
Apart from drugs that are usually recognised as
producing dependence, sudden interruption of
therapy with certain other drugs also results in
adverse consequences, mostly in the form of
worsening of the clinical condition for which the
drug was being used.
Drug
withdrawal Worsening of angina pectoris, precipitation of
myocardial infarction may result from stoppage
reactions of b blockers.
Frequency of seizures may increase on sudden
withdrawal of an antiepileptic.
These manifestations are also due to adaptive
changes and can be minimized by gradual
withdrawal.
• The ability of a drug to cause cancer is
Carcinogenicity carcinogenicity and the agent is known
as carcinogen.
and
• The abnormalities of genetic material in
Mutagenicity a cell produced by a drug are known as
mutagenicity, e.g. Anticancer drugs and
oestrogens.
These are also called iatrogenic (physician
induced) diseases, and are functional
disturbances (disease) caused by drugs
which persist even after the offending drug
Drug-induced has been withdrawn and largely eliminated
Diseases • Peptic ulcer by NSAIDs and corticosteroids.
• Parkinsonism by phenothiazines and other
antipsychotics.
• Hepatitis by isoniazid.
It refers to the capacity of a drug to cause fetal
abnormalities when administered to the pregnant mother.
The placenta does not constitute a strict barrier, and any
drug can cross it to a greater or lesser extent.
Teratogenicity The embryo is one of the most dynamic biological systems
and in contrast to adults, drug effects are often
irreversible.
Teratogenicity
Fetal Alcohol Syndrome
Teratogenicity
Fetal hydantoin
syndrome caused by
Phenytoin
Thalidomide Disaster
Teratogenicity
