Importance of understanding the drug effects in pharmacology

1. LS 1.3.3 - Drug Antagonism, Additive Effects &
Loss of Drug Effects

2. DRUG ANTAGONISM, LOSS OF DRUG EFFECTS &
ADDITIVE DRUG EFFECTS …. CONT’D
LEARNING OBJECTIVES:
• To describe the additive, synergistic and antagonistic
effects of administering drugs concurrently
• To explain the loss of drug effect observed with
continuous or repeated drug administration

3. INTRODUCTION:
When two or more drugs are given concurrently,
the effect may be additive, synergistic or
antagonistic
With additive and synergistic effects, the effect
observed when the drugs are give concurrently is
more that the effect of giving one drug
With antagonism, one drug opposes or inhibits the
effects of another drug
DRUG ANTAGONISM, LOSS OF DRUG
EFFECTS & ADDITIVE DRUG EFFECTS

4. INTRODUCTION …. CONT’D:
With repeated or continuous administration of a
drug, the effects may diminish or be completely lost
due to a number of pharmacodynamics or
pharmacokinetic factors
DRUG ANTAGONISM, LOSS OF DRUG
EFFECTS & ADDITIVE DRUG EFFECTS

5. MECHANISMS OF DRUG ANTAGONISM
• Chemical antagonism
• Pharmacokinetic antagonism
• Competitive antagonism
• Non-competitive antagonism
• Physiological antagonism
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6. CHEMICAL ANTAGONISM
Two substances interact chemically to result in
inactivation of the effects
Examples
• Chelating agents bind to heavy metals like lead and
mercury to form inactive complexes
• Antacids like aluminium hydroxide neutralize gastric
acid
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7. PHARMACOKINETIC ANTAGONISM
A situation in which the antagonist reduces the
concentration of the drug at its site of action
This occurs through reduction in absorption, interference
with distribution, and acceleration of elimination
(metabolism and excretion)
Examples
• Tetracyclines bind to iron in the GIT resulting in
reduced absorption
• Phenobarbitone increases the hepatic metabolism of
warfarin thereby reducing its anticoagulant effect
• Sodium bicarbonate accelerates the renal excretion of
aspirin
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8. ANTAGONISM THROUGH RECEPTOR
BLOCKADE (COMPETITIVE ANTAGONISM)
The antagonist binds on the same receptor site as the
agonist and prevents it from binding. This blocks the action
of the agonist. Competitive antagonists may be reversible or
irreversible.
Reversible: The binding on the antagonist on the receptor is
non-covalent and the antagonist dissociates from the
receptor. The antagonism can be overcome by increasing the
concentration of the agonist (i.e. is surmountable).
Irreversible: The antagonist forms a covalent bond with the
receptor and does not dissociate from the receptor. The
antagonism is non-surmountable, i.e. increasing agonist
concentration does not overcome the antagonism.
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9. NON-COMPETITIVE ANTAGONISM
A non-competitive antagonist binds to an allosteric site on
the receptor (a different site from where the agonist binds) to
prevent activation of the receptor.
The antagonism can be reversible or irreversible.
• Reversible: The antagonist forms a non-covalent bond with
the receptor and dissociates from the receptor
• Irreversible: The antagonist forms a covalent bond with
the receptor and does not dissociate from the receptor
Non-competitive antagonism is insurmountable regardless of
whether it is reversible or irreversible because the agonist
and antagonist bind on different sites
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10. PHYSIOLOGICAL ANTAGONISM
Two drugs act at different sites to produce opposing
effects
Examples
• Insulin and glucagon: have opposite effects on the
blood glucose level, with each one acting on its own
specific receptors
• Histamine and adrenaline: histamine produces
bronchospasm and hypotension through an action on
histamine H1 receptors, while adrenaline reverses these
effects by acting on adrenergic receptors
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11. LOSS OF DRUG EFFECT
The effect of a drug often gradually diminishes when it is
given continuously or repeatedly:
• Tachyphylaxis (desensitization) – when the loss of drug
effect develops within minutes
• Tolerance – when the decrease in responsiveness occurs
over days or weeks
• Refractoriness – loss of therapeutic efficacy
• Drug resistance – loss of effectiveness of anti-microbial or
anti-cancer drugs
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12. MECHANISMS CAUSING LOSS OF DRUG EFFECT
• Change in receptors: A conformational change occurs
in the receptor. The receptor may still be able to bind
the agonist but no effect occurs.
• Loss of receptors: Gradual decrease in number of
receptors occurs with prolonged exposure. Recovery
to normal takes several days.
• Exhaustion of mediators: Desensitisation occurs due
to depletion of an essential intermediate substance
involved in producing drug effect
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13. MECHANISMS CAUSING LOSS OF DRUG
EFFECT …. CONT’D
• Increased metabolic degradation: E.g. the tolerance
that occurs with ethanol is due to increased
metabolism of ethanol
• Physiological adaptation: Homeostatic responses
reduce the drug’s effects e.g. with use of thiazide
diuretics there is gradual activation of the renin-
angiotensin system
• Active removal of the drug from cells: E.g. drug
resistance that occurs in chemotherapy
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14. COMBINING DRUGS WITH SIMILAR
EFFECTS
When drugs with similar effects are combined, one of
the following effects may occur:
Additive effect: Occurs when two or more drugs with
similar effect are combined. The combined effect of the
drugs when given concurrently equals the sum of the
individual drugs’ effects i.e. 1+1=2
Potentiation: Occurs when two drugs are taken
together and one of them increases the potency of the
other drug, i.e. ½ + 1 = 2
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15. COMBINING DRUGS WITH SIMILAR EFFECTS ….
CONT’D
Synergism: Occurs when the total response obtained by
giving two or more drugs concurrently is significantly
higher than the total effects of each individual drug
effects, i.e. 1+1=3.
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