General Principles of Pharmacology

Pharmacodynamics
Lecture Learning outcomes:

By the end of the lecture, learners will be able to:

1. Explain the basic concepts regarding drug effect & safety
2. Relate the basic concepts to therapeutic application
3. Drug dose; factors influencing drug dose & response

Dr. P. Sabitha
25,27-9 -2017
 Drug administered

Pharmacokinetics

Metabolism
Absorption Systemic Circulation Elimination
Excretion

Drug distribution tissues

Pharmacodynamics

Pharmacological action (Mechanism)

Pharmacological action

Adverse effect Therapeutic / beneficial effect

 Pharmacodynamics (PD)
 The actions of drug on the body are termed “Pharmacodynamic” processes

 Pharmacological actions / effects of drugs on the body ( beneficial / adverse)

 Mechanism of action of the drug at cellular / molecular levels

o What any drug can finally do to the body function?

 A drug can only accelerate or depress a normal physiological / biochemical

function
 A drug can’t confer an entirely new activity on the organ

o Drug effect, action, mechanism of action?

 The type of response produced by a drug – therapeutic effect / response

 How this effect is produced – action
 How this action is produced – mechanism
 Drug Mechanism Action Effect

Epinephrine β1 receptor activation ↑ force of ↑ Cardiac output

on myocardium contraction
Pilocarpine M receptor activation Contraction of Miosis
on pupillary constrictor pupillary constrictor
Amlodipine Blocks ‘L’ Calcium Vascular smooth Vasodilation &
channels muscle relaxation ↓ Blood Pressure

o What are the different sites drugs can act?

 Extracellular
 Cell surface
 Intracellular

o What are the different mechanisms by which drugs can bring about
Therapeutic effect / response ?

 Non-Receptor mediated
 Receptor mediated
 Non-receptor mediated mechanisms of drug action

1. By Physical action

Physical property of the drug contributes to its action & therapeutic response
 Bulk laxatives ( Ispaghula) → form Bulk in intestinal lumen → retain water
→ ↑ Bulk → ↑ peristaltic activity → useful to treat constipation

 Osmotic diuretics (Mannitol)→ Osmotic action → draws water from brain

& CSF → useful to treat cerebral edema

 Demulcents (Glycerin) → Viscous in nature → form a thick coating over

inflamed mucus membrane → soothing effect → useful to treat pharyngitis

 Astringents (Tannic acid) → Denature superficial protein → firms up the

mucosal surface → useful to treat gingivitis
 Activated charcoal → Adsorbs drug molecules in GIT lumen (Physical
antagonism) → less drug absorbed into blood → drug + charcoal excreted
in fecal matter → useful in treatment of drug poisoning
 2. By Chemical action ( Chemical antagonism )
Some drugs ( Chemical antagonist ) bind and interact with body molecules
or with another drug → inactivate / sequester them → render them unavailable
for carrying out their physiological functions / pharmacological actions

Neutralization: Basic drugs neutralize acid / acidic drugs

 Antacids (Mag.hydroxide) neutralize stomach acid→ relief from gastritis pain
 Protamine sulfate (basic) neutralizes heparin (acidic) → used to treat
heparin toxicity
Conjugation: Mesna forms a conjugate with acrolein, a bladder toxic
metabolite of cyclophosphamide → acrolein inactivated → Mesna is used to
prevent / treat cyclophosphamide induced hemorrhagic cystitis
Conjugation: N acetylcysteine (NAC) forms a conjugate with NAPQI, a
hepatotoxic metabolite of paracetamol → NAPQI inactivated → NAC is used to
treat paracetamol poisoning

3. By False incorporation of nucleotides ( anticancer drugs)

4. By Formation of antibodies ( vaccines)
5. Irritation of nerve endings ( irritant laxative)
 6. By Interacting with Ion channels

 Ion selective channels participate in trans-membrane signaling → regulate

intracellular ionic composition

 Drugs → physically obstruct channels / modulate ion channels → ions can

not move across the channel
 Amlodipine blocks ‘L’ type voltage operated Calcium channels → inhibits
calcium inward movement → vasodilation → used to treat hypertension
 Lignocaine inhibits Sodium channels → used to treat ventricular tachycardia

Ion Ion channel Ion Ion channel Ion

modulator blocker

Cell membrane
 7. By Interacting with Substrate transporters

 Several substrates (5HT, NE, Dopamine)→ bind to specific transporters →

transported across cell membranes

 Drugs → interact with these transporters → inhibit the transport of these

substrates
 Fluoxetine → interacts with 5HT transporter in brain neurons→ inhibits
neuronal uptake of 5HT→ used to treat mental depression
 Amitriptyline → interacts with Norepinephrine (NE) transporter in brain
neurons→ inhibits neuronal uptake of NE→ used to treat neuralgia pain

Transporter Substrate
Substrate Drug

Cell membrane

Inside cell
Substrate
 Enzyme
8. By Enzyme inhibition inhibitor substrate
drug
Almost all biological reactions are carried out under enzyme
the catalytic influence of enzymes
 Some drugs having structural resemblance with the
Biological
natural substrate → compete with the substrate for product
enzyme binding → substrate can’t bind to enzyme → substrate not metabolized

Reversible (Equilibrium type) enzyme inhibition by drugs:

• Drug Enzyme Substrate
Drug binding to enzyme is neither permanent (non-covalent) nor does it bring
permanent structural alteration in the enzyme. Drug associates & dissociates
from enzyme (at equilibrium). When drug dissociates, substrate can bind to the
enzyme to carry out normal function. Hence → If drug administration is
stopped → drug eliminated completely → enzyme available free to carry out
its normal functions → Duration of drug effect is dependent on the rate of
elimination of drug
Ex: ACE catalyzes conversion of A I ( substrate) to AII. Enalapril (structurally
similar to AI) → binds to ACE → AI can’t bind to ACE → AII is not formed→ No
vasoconstriction → Enalapril used to treat HTN
Irreversible (Non-Equilibrium type) enzyme inhibition by drugs:
• Drug Enzyme ⁄ Substrate
Drug forms either a covalent bond with the enzyme (drug never dissociates from the
enzyme) or brings about permanent structural alteration in the enzyme → substrate
can never bind to the enzyme → enzyme inhibition by drug is permanent → Even
if the drug administration is stopped → enzyme is not available to carry out
its normal functions → Duration of drug action is independent of the rate of
elimination of drug
 Fresh enzymes need to be synthesized (7-10 days) to carry out normal
body functions → drug effect lasts for 7-10 days → Duration of drug effect
depends on the rate of turn over of enzymes
Ex: Cyclooxygenase (COX) metabolizes arachidonic acid (substrate) to TXA2.
Aspirin (drug) binds to COX irreversibly → TXA2 not formed from arachidonic acid
(Fresh COX has to be synthesized by platelets to form TXA2 but platelets can’t
synthesize new enzyme) → most efficacious antiplatelet drug → prophylaxis of MI
Ex: H+K+ ATPase enzyme necessary for final step involved in the synthesis of HCl in
the stomach. Omeprazole binds to this enzyme irreversibly → inhibits acid secretion
most efficaciously → used to treat peptic ulcer
 Receptor mediated mechanism of drug action
o What is a receptor?
 It is a specific, regulatory, macromolecule (protein); membrane bound /
intracellular; that serves to recognize the endogenous signal molecule / drug
( ligand) to initiate the response to it.
 Receptor- ligand resembles Lock-key three dimensional structure

o Features of Drug (D) – Receptor (R) interaction

 Drug exhibits Specificity to the receptor
 D + R ↔ DR complex →-----→ Response (↑ or ↓ physiological function)
 DR binding usually reversible – hydrogen / vanderwaals / eletrostatic bonds
 DR binding can be irreversible – covalent bond

 Affinity of a drug to the receptor = Ability / strength of the drug to bind

to the receptor & form DR complex
 Intrinsic activity of the drug (IA) = Ability of the drug to trigger a response
after forming a DR complex
Based on Affinity & IA, drugs acting at receptors can be classified as :

1]. Full Agonist 3]. Pharmacological (receptor) Antagonist

2]. Partial Agonist 4]. Physiological (functional) Antagonist

(Full) Agonist: Has both affinity & maximal IA → can trigger maximal biological
response after binding to the receptor
 Agonist drugs can be endogenous substances: Epinephrine ↔ β1 receptor
 Agonist drugs with structural similarity with endogenous substances:
Dobutamine ↔ β 1 receptor
Agonist + R ↔ DR complex →----→↑ Physiological response
Ex: Epinephrine / Dobutamine (agonist drugs) ↔ β 1 receptor → ↑cardiac out→
used to treat shock

Affinity Intrinsic activity

Full Agonist + Maximal

Partial agonist + Submaximal

Receptor Antagonist + No
Agonist (endogenous substance & drug ) &
Antagonist interaction with receptors

Antagonist
drug
Natural Natural
agonist agonist Natural
agonist

Agonist
drug
Antagonist
drug
 Agonist ↔ Receptor →Transducer ( Effector) interaction

Agonist
Receptor
Intracellular signaling
Transducer /
Action /
Effect
 Receptor types based on Transducer mechanisms
Ion channel receptor Enzyme linked receptor

Onset of response:
milliseconds

Onset of response:
minutes

G protein coupled receptor

Receptor regulating gene expression
Onset of response
: seconds

Onset of response:
minutes - hours
Partial Agonist (PA) : Binds to receptor ( affinity )
Activates receptor with sub maximal intrinsic activity
Therapeutic relevance: In presence of a full agonist or if there is endogenous
agonist over activity, PA can compete with a full agonist for binding to the
receptor → acts as an antagonist → ↓ efficacy of full agonist
• Buprenorphine – PA at µ receptor → less efficacy analgesic
Morphine – full agonist at µ receptor → more efficacy analgesic
But if both are used together → buprenorphine prevents morphine binding to µ
receptor → ↓ analgesic efficacy of morphine
• Aripiprazole is a PA at Dopamine receptor.
In Schizophrenia, there is ↑ activity of Dopamine in limbic system → ↑ full agonist
→ aripiprazole acts as antagonist → used to treat Schizophrenia
But in Nigrostriatal tract, there is normal Dopamine activity → agonist activity
normal → aripiprazole acts as PA → ↓ extra pyramidal adverse effects
• As such, there are few PA drugs

Full agonist Full agonist +Partial agonist Full agonist + Antagonist

Receptor ( Pharmacological ) Antagonist: Has only affinity; NO IA
 An antagonist binds to the receptor ( affinity )
 Does not activate the receptor → NO action of its own
 By occupying the receptor, it prevents an agonist ( endogenous ligand /
drug) from binding to the receptor → agonist efficacy ↓

 Antagonist + R ↔ AR complex → ↓ Physiological response to an

endogenous agonist
Ex: Epinephrine → endogenous agonist at β1 receptor on SA node → Normal
or ↑ Heart rate
Metoprolol → antagonist drug at β1 receptor → prevents endogenous
epinephrine from binding to β1 receptor → ↓ heart rate
Note: Metoprolol did not decrease the heart rate on its own; it only prevented the action
of endogenous epinephrine on SA node → unopposed cholinergic activity → ↓ heart rate

 Antagonist + R ↔ AR complex → ↓ response to an agonist drug

Ex: Morphine → agonist drug at μ receptor → respiratory depression
Naloxone → antagonist drug at μ receptor → prevents drug morphine from
binding to μ receptor → corrects respiratory depression caused by morphine
Synonymous terms for receptor antagonist:
 Receptor blocker
 Pharmacological antagonist : (Physiologically, there is no receptor
antagonist; only drugs act as receptor antagonists; drug= pharmacology)
Reversible ( Equilibrium type) Receptor Antagonist:
Reversible Antagonist binds to the receptor with non-covalent bonds →
associates & dissociates (at equilibrium) from receptor → when antagonist
dissociates → agonist binds to receptor → high concentration of agonist can
overcome the effect of a given concentration of antagonist → Efficacy of
agonist remains unchanged for any fixed concentration of antagonist
Therapeutic relevance:
Duration of effect of antagonist is dependent on its rate of elimination
 Increase in concentration of agonist will overcome antagonism
Ex: Acetylcholine ( agonist) ↔ M receptor ↔ ( antagonist) Atropine
In case of Atropine toxicity, increasing the concentration of Ach by using drugs
will help to correct the symptoms of Atropine toxicity
 Most of the receptor antagonists used in therapy are reversible antagonists
Irreversible (Non-Equilibrium type) Receptor Antagonist:
Irreversible Antagonist binds to the receptor with covalent bonds → will NOT
dissociate ( non-equilibrium) from receptor / brings about permanent changes in
receptor structure → agonist can never bind to the receptor→ high concentration
of agonist can NOT overcome the effect of a given concentration of antagonist→
Efficacy of agonist is decreased for any fixed concentration of antagonist
Therapeutic relevance:
 The antagonist-bound receptor is no more functional
 Increasing the concentration of agonist will NOT help overcome
antagonism
 Duration of effect of antagonist is independent of its rate of elimination but
depends on the rate of turn-over of receptor molecules ( 7- 10 days)
Ex : Epinephrine ( agonist) ↔ α receptor ← (antagonist) Phenoxybenzamine

Note: Irreversible inhibition concept is more clinically relevant with Enzyme

inhibition as discussed earlier (One can consider enzyme as receptor also.)
Physiological / Functional Antagonist:
 There are NO receptor antagonists in normal physiology
 If so, how the physiological functions are regulated ?
 Regulated through Physiologic ( functional ) antagonism =
Two ligands / drugs act on different sites / receptors or by different mechanisms,
but have opposite effects on the same physiological function
o Acetylcholine ↔ agonist at M receptor on SAN → ↓ heart rate
Epinephrine / Isoproterenol ↔ agonist at β1 receptor on SAN→ ↑ heart rate
o Glutamate ↔ agonist at NMDA receptor brain → ↑ CNS
GABA ↔ agonist at GABA receptor brain → ↓ CNS (used to treat convulsions)
o Glucocorticoid ↔ GC receptor liver → hyperglycemia
Insulin ↔ Insulin receptor liver → hypoglycemia
o Leukotriene ↔ agonist at LT receptor → Bronchospasm
Salbutamol ↔ agonist at β2 receptor → Bronchodilation (used to treat asthma)

Leukotriene Salbutamol
Bronchial smooth muscle
LT receptor Β2 receptor
 Regulation of receptors
 Desensitization & Down-regulation of receptors
 Super-sensitivity & Up-regulation of receptors

 Desensitization & Down regulation of receptors

Repeated stimulation of receptor by an agonist can result in →
1] Receptor Desensitization: ↓ efficiency of coupling of receptors to distal
effector ( transducer) mechanism OR
2] Receptor Down-regulation: ↓ number of receptor sites due to
internalization and sequestration of receptors
→ ↓ therapeutic efficacy of agonist → ↑ doses are needed to produce the
same magnitude of therapeutic effect as before → Tolerance
Ex: Salbutamol (β2 agonist) for bronchial asthma; Opioid for cancer pain
Nitrates for prophylaxis of chronic stable angina : ↓ therapeutic efficacy
on repeated use
 How to prevent / minimise the development of drug tolerance
 give ‘drug holiday’ period → allow drug free interval in the plasma or
 switch to other drugs acting by different mechanism
 Super-sensitivity & Up-regulation of receptors

In tonically active systems, continued deprivation of agonist by using an

antagonist can result in →
1] Receptor Super-sensitivity: ↑ efficiency of coupling of receptors to distal
effector mechanisms
2] Receptor Up-regulation: ↑ number of receptor sites

Therapeutic relevance:
 Metoprolol, (β1 antagonist) on prolonged use to treat angina → β1 receptor
super sensitivity & up-regulation. If Metoprolol is stopped abruptly, circulating
epinephrine will act at up-regulated β1 receptors → Rebound hypertension/
arrhythmia / angina
So Metoprolol should not be stopped abruptly; if it has to be stopped, dose
should be gradually reduced to give enough time for reversal of up-regulation
of receptors. Similarly,
 Clonidine & Methyl dopa are central sympatholytic drugs used to treat HTN.
→ continued deprivation of sympathetic activity. If stopped abruptly →
Rebound HTN ( for above reason). So shouldn’t be stopped abruptly
 Drug Dose
Dose = appropriate amount of the drug needed to produce a certain degree of
response in an individual
Expressed as – weight (mg / gm); volume; units; moles
Dosage = Preparation (tablet, capsule, injection) + Drug name + Drug quantity+
Frequency & route of drug administration + Duration of drug administration
Ex: Capsule Amoxicillin, 500 mg, take orally at 8 hourly intervals, for 5 days (to
treat bronchitis)

 Therapeutic dose: Dose used to TREAT an established disease condition

 Prophylactic dose: Dose used to PREVENT the onset of disease ( usually
smaller / less frequent doses than the therapeutic dose)
 Toxic dose: Should be avoided

 Single dose: Only one dose is sufficient to treat a disease

Ex: Albendazole for nematode infection;
Primaquine for gametocidal effect in falciparum malaria
 Daily dose: Most of the drugs for chronic diseases are administered this way
(daily single dose / daily divided doses)

 Total dose: Total dose to treat a condition is calculated ; administered as

single shot or given in divided doses
Ex: Iron Dextran injection to treat anemia; total dose is calculated based on Hb
deficiency & either given as IV infusion or IM on alternate days

 Loading dose: It is the large dose of the drug administered initially to provide
the effective plasma concentration rapidly
Ex: Chloroquine to treat malaria

 Maintenance dose: Always follows the loading dose to continue to maintain

Steady state plasma concentration (Cpss)

 Standard dose:The same dose is appropriate for most patients because

inter-individual variations are minor / drug has a wide safety margin
Ex: Oral contraceptive hormone, penicillin, chloroquine, albendazole
 Individualized dose = Titrated dose
 Continual adjustment of a dose based on patient response
 Doses are adjusted until the desired clinical effect is achieved or until an
acceptable level of adverse effect ( if maximal therapeutic effect cannot be
achieved because of intolerable adverse effects)

1]. The dose is accurately adjusted by repeated measurement of the affected

physiological parameter ( response)
Ex: antihypertensive drugs, hypoglycemic drugs, anticoagulants

OR

2]. An empirical dose aimed at attaining the target level concentration is given
in the beginning and adjustments are made later by actual monitoring of plasma
concentrations (therapeutic drug monitoring) in case the response to a drug
is not easily measurable but has been demonstrated to be obtained at a certain
range of drug concentration in plasma.
Ex: antidepressants, anti epileptics, Lithium (0.8 – 1.4 mEq / L)
 Log- Dose Response Curve ( DRC )
1]. Graded DRC - % Response ( data from one individual )
2]. Quantal DRC - % Responders ( data from population )

Graded DRC - % Response  Graph obtained by plotting the increasing

Maximal efficacy doses of a drug (in one subject) against
magnitude of the response → Graded DRC
( a rectangular hyperbola is obtained)
 If the dose is plotted on a logarithmic scale,
the curve becomes sigmoid & a linear
relationship between log of dose and the
response is seen in the intermediate (30 -
70% response) zone
 As the dose is increased, magnitude of
response also increases until a stage comes
when further increase in dose will NO further elicit increase in response -
Maximal Efficacy ( E max) &
the Corresponding Dose is known as - Maximal dose / Ceiling dose
 Information derived by Graded DRC
1. Drug Potency : Amount of drug needed to produce a certain degree of effect.
Depends on the affinity ( how well a drug can bind to the receptor) of a drug to the
receptor. A high-affinity drug will bind a greater number of a particular receptor at a
low concentration than a low-affinity drug.
EC50 of a drug is the concentration at
which 50% of receptors are occupied
% Maximal Effect

i.e. concentration that produces half the

maximal effect. when two drugs produce
equivalent responses, the drug whose
dose-response curve lies to the left of
the other (EC50 is smaller) is said to be
more potent
 Information on the potency is useful while switching the drugs
Ex: Dexamethasone is ≈ 6 times > potent than prednisone to produce anti-
inflammatory effect. If prednisone was being used at 10 mg day and now want to
switch to dexamethasone, then the starting dose of dexamethasone should be
≈1.6 mg/day
 Information derived by Graded DRC…………………………..

2. Drug Efficacy :The ability of a drug to 3.

3. Partial
Partial Agonist
agonist:
activate a receptor and generate a Agonist alone
cellular response.
Agonist in
Emax is the maximum possible effect for presence of PA
the agonist.
Efficacy is the more decisive factor in the
choice of a drug than its potency Partial agonist
(PA) alone
Drug X is > efficacious than drug Y in the
below graph

Full agonist: Maximal efficacy

% Maximal Effect

X Partial agonist: Submaximal efficacy

Y But acts as reversible antagonist to a
full agonist (agonist curve shifted
rightwards indicating that higher dose
of agonist was required to achieve
same efficacy)
Information derived by Graded DRC ………………………...
4. Reversible antagonist 5. Irreversible antagonist

Agonist +
Reversible
antagonist

Agonist +
Irreversible
antagonist

• In presence of fixed dose of an • In presence of fixed dose of an

antagonist, if the dose of agonist is antagonist, increase in the dose of an
increased, antagonism can be agonist to any extent, will not help to
overcome
overcome antagonism
• Agonist curve is shifted rightwards
(higher dose of agonist is required → • Agonist curve is shifted right wards
potency ↓) & runs parallel (efficacy ( potency ↓) but doesn’t run parallel
unaltered) ( efficacy ↓ )
 Quantal DRC ( % of Responders)

 Graph obtained by plotting the increasing doses of the drug against the number of
subjects (frequency) showing a ‘prefixed response’ (all or none response)→
Quantal DRC ( bell shaped curve)
 If the log dose is plotted on the abscissa vs, the cumulative % of subjects
responding on the ordinate, a sigmoid shaped curve is obtained.
 Provide information about the variation in the sensitivity to the increasing
doses of a drug in a given population → helps in finding a dose suitable for use in
human beings
 Provide information on the SAFETY of a drug
1. Evaluation of Drug safety: Drug safety depends on by what factor the
dose producing beneficial effect differs from dose eliciting toxic effects.
Calculated as Therapeutic ratio / Therapeutic Index (T I )
T I = LD50 T I = T D50 TI is an indication how selective a
ED50 OR ED50 drug is in producing its desired effects
over the toxic effects
 Higher TI, safer the drug is
 LD50= median lethal dose
A dose that is lethal to 50% of
subjects ( in animal studies)
 TD50 = median toxic dose
Dose that produces expected
toxicity in 50% of subjects
 ED50 = median effective
dose. Dose that produces
predetermined response in
Graph shows cumulative frequency of dose 50% of subjects
response curve of phenobarbitone in mice
2. Population Therapeutic Window ( Safety margin):
For many drugs, the concentration that achieves desired response in all the
population may produce adverse effects in some individuals due to inter individual
variations even though the drug's therapeutic index in an individual patient may
be large. Population therapeutic window may be more useful in this regard.
 Population therapeutic window expresses a range of concentrations at which
the likelihood of efficacy is high & the probability of adverse effect is low
Dose
 Therapeutic window = range
between Minimal effective dose -
Minimal Toxic dose
 Wider the therapeutic window, safer
the drug is
 For drugs with narrow therapeutic
window, dose increment should be
carefully monitored with appropriate
clinical and surrogate markers for
drug effects
 Population Therapeutic Window ( Safety margin)

Warfarin Penicillin

Warfarin: As the dose increased, there can be an overlap between the effective
therapeutic (anticoagulant) dose and toxic ( bleeding) dose of warfarin in some
individuals due to inter individual variation. Hence dose increment needs
to be carefully monitored
Penicillin: Dose can be increased to great extent without need for monitoring
 Factors influencing drug dosage & drug response

In clinical trials , average adult dose is calculated on the basis of quantity that
produces desired effect in 50% of population between 18-65 years of age &
weighing about 70Kg.
If needed, in adults, dose can be individualized
Individual adult dose = Dose x Weight ( Kg)
70

1. Age
Children
 PK factors → require lesser dose than adult
There are formulae / nomograms to calculate dose based on Age, body wt
/ surface area

 PD factors: Difficult to administer aerosol in children; Children are >

Prone for some adverse effects: muscle dystonia with metoclopramide /
stunting of growth with androgens, corticosteroids
Factors influencing drug dosage & drug response…………
1. Age
Elderly
 PK factors: Renal clearance declines progressively;
↓ Hepatic metabolism, both can result in cumulative toxicity
 PD factors: > prone for certain adverse effects: urinary retention with anti
cholinergic drugs; postural hypotension with venodilators; electrolyte
imbalance with diuretics; ototoxicity with aminoglycosides

2. Gender
Drug responses may vary in men & women
Ex: Morphine produces excitation before producing sedation only in women
Ephedrine produces more tremors and excitation in women vs men
β blockers, thiazides produce loss of libido only in men
Pregnancy, lactation- drug usage may result in adverse outcome in fetus/ infant

3. Genetic factors & Idiosyncratic reactions:

Ex: G-6-PD deficiency causing hemolysis with Primaquine
Atypical pseudo cholinesterase – Succinylcholine apnea
Factors influencing drug dosage & drug response…………

4. Racial difference: Racial differences to drug response have been observed

Ex: ACEI, Beta blockers are less effective in African Americans
Chloramphenicol ( aplastic anemia) is better tolerated by Indians

5. Time of drug administration:

Ex: Hypnotics: higher dose needed to induce sleep during day time
Glucocorticoids given as single morning dose cause less HPA axis suppression

6. Psychological factors: Non-pharmacological factors may also influence

drug response; Depending on patient’s beliefs, attitudes, expectations
• Placebo (= I please) is a pharmacologically inert substance ( lactose/
starch) given to a patient in the garb of medicine in a dosage form that
exactly resembles actual medication in size, shape, color, smell, weight.
• May produce response in some patients – relief from - anxiety, headache,
insomnia, pain – patients are called as Placebo reactors
• Placebo rarely used in clinical practice
• Placebo commonly used in “Randomized controlled clinical trials”
Factors influencing drug dosage & drug response…………

7. Tolerance:
On repeat administration, inability of the drug to be as effective as the initial dose
→ higher doses of the drug needed to produce desired therapeutic response

Mechanism underlying tolerance

 Pharmacodynamic tolerance:
1]. Desensitization / Down regulation of receptors (can be overcome by
allowing drug-free interval)
Ex: Opioids, Benzodiazepines, Salbutamol, Nitrates

2]. Physiological adaptation: Diminution of a drug's effect because of

counteracting physiological adaptation processes
Ex: Antihypertensive efficacy of thiazide diuretics is decreased due to activation
of renin angiotensin system
Adverse effects like headache, nausea to most drugs is reduced after repeat
use because of physiological adaptation
Factors influencing drug dosage & drug response…………
 Pharmacokinetic tolerance: Altered metabolism of drugs is responsible for
tolerance development
Ex: Phenobarbitone → enzyme induction →↑ its own metabolism
Nitrate → ↓ metabolism to active metabolite Nitric oxide
 Tolerance may develop to only some actions & need not to all actions
Ex: Tolerance develops to analgesic action of morphine but not to constipating /
pupillary constricting actions of morphine
 Cross tolerance: Development of tolerance to pharmacodynamically
related drugs ( When morphine is used repeatedly, patient may develop
tolerance to analgesic action of morphine. If pethidine is used in the same
patient, he may be tolerant to analgesic action of pethidine even with 1st dose)

8. Concomitant pathological conditions:

Renal disease:
 ↓Renal clearance of drugs excreted in urine → toxicity ↑ ( Aminoglycoside-
induced ototoxicity)
 Certain drugs can worsen the existing renal disease: NSAIDs, Cyclosporine
Hepatic disease: ↑Toxicity of drugs which are metabolized by liver: Morphine
Factors influencing drug dosage & drug response…………

9. Concurrent use of ≥ 2 drugs ( Drug Interactions )

When 2 or more drugs are administered concurrently, outcome can be -
o No outcome (drugs indifferent to each other)
o Amplified effect Drug Interactions
o Antagonistic effect

Outcome of drug interactions could be -

 Beneficial ( applied in therapy)
 Adverse ( drugs to be avoided / cautiously used)

Interaction between 2 drugs can take place –

 Outside the body (Penicillin & Gentamicin if taken in the same syringe
inactivate each other- chemical antagonism)
 Inside the body:
 Pharmacokinetic - at the level of absorption / metabolism / distribution /
excretion
 Pharmacodynamic (interaction at the site of action)
 Pharmacokinetic drug interactions
 Absorption: Aluminium hydroxide (antacid) → chelates tetracycline → ↓
absorption of tetracycline → ↓antibiotic efficacy of tetracycline (chemical
antagonism )
 Metabolism: Rifampicin → ↑ metabolic degradation of estrogen present in
contraceptive pill → contraceptive failure
 Distribution: Aspirin displaces warfarin from PPB → ↑ bleeding with warfarin
 Excretion: Urine alkalizing agent (NaHCO3) → ↑ excretion of acidic drug
(aspirin) → NaHCO3 used to treat aspirin poisoning (chemical antagonism)

Pharmacodynamic drug interactions

1. Amplified effect

 Summation / Additive effect: Combined effect of 2 or > drugs equals the

sum of the effect of each agent given alone
Ex: Aspirin + Codeine as analgesics
 Synergistic effect: Combined effect 2 or > drugs exceeds the sum of the
effects of each drug given alone outcome of which is potentiation of effects
Ex: Levodopa + Carbidopa to treat Parkinson disease
Pharmacodynamic drug interactions…..

2. Antagonistic effect:

 Physical antagonism:
Ex: Activated charcoal adsorbs poison in GI lumen

 Chemical antagonism:
Ex: Heparin (acidic) induced bleeding corrected by protamine ( basic)
Mesna conjugates acrolein (bladder toxic metabolite of Cyclophosphamide)
NAC conjugates NAPQI ( hepatotoxic metabolite of paracetamol)

 Physiological ( functional ) antagonism:

Ex: Prednisone induced hyperglycemia corrected by Insulin

 Pharmacological ( receptor) antagonism:

Ex: Atropine (M-receptor antagonist) is used to treat Neostigmine induced
cholinergic adverse effects
Naloxone (μ receptor antagonist is used to treat Morphine induced
respiratory depression
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Enalapril binds to enzyme ACE → AI can’t bind to enzyme → AI can’t be

converted to AII → no vasoconstriction

Enalapril

AI
AI
Enalapril
+ AI
ACE
ACE ACE

AII NOT formed

AII

NO vasoconstriction
vasoconstriction
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Physiological (functional) antagonism

Cholinergic Heart Adrenergic

Excitatory amino acid Brain Inhibitory amino acid

Cholinergic Corpus striatum Dopaminergic

Insulin Glucose Glucocorticoid

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Cholinergic Heart Adrenergic

Pharmacologic antagonism

Treat with M
receptor antagonist
Bradycardia
Physiologic antagonism
Cholinergic
M
Heart Adrenergic
β1

Treat with β1
receptor agonist
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Morphine
Fentanyl
Efficacy & Potency of opioid analgesics

Pethidine
Buprenorphine
 In this graph, 3 opioid analgesics -
Fentanyl, Morphine, Pethidine show
equal efficacy.
 But the latter 2 drugs are < potent than

Pentazocine
Fentanyl
 Buprenorphine and Pentazocine show
lower efficacy than other 3 drugs

A = Agonist

B = Reversible
antagonist
C = Irreversible
antagonist
A A
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Therapeutic index:
Most drugs have a therapeutic index of 2 or higher
 TI of < 2 is a dangerous drug and the patient must be watched carefully
for signs of toxicity
 TI of 5 or 10 - safer drugs
 TI of 50 to 100 - drugs with great selectivity and minimal toxicity

Calculate the therapeutic index

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Placebo commonly used in “Randomized controlled clinical trials”

Group 1 – receive placebo

Group 2 – receive active drug

Group 1 & 2 subjects are blinded = they won’t know what they are receiving if
placebo or the active drug because both look similar

At the end of the study, statistical analysis will be done

 If the active drug group produced statistically significant better result than the
placebo group, the active drug is considered useful and will be marketed
 If the difference in the results between the 2 groups is NOT statistically
significant → therapeutic benefit obtained by the active drug will be
attributed to the placebo action and NOT to its pharmacological action →
drug will not be marketed