Factors Altering Drug Response 8/20/25

Vocabulary flashcards covering key factors that modify drug response, including tolerance, tachyphylaxis, drug interactions, placebo effects, genetics, metabolism, routes of administration, age, and precision medicine.

Biological factors that modify drug response

Age; body weight/composition; gender & race; environment/time of drug administration; psychological and emotional factors; genetic factors & idiosyncrasies; metabolic & pathologic disturbances; route of drug administration.

Repeated administration of single drug response

tolerance, tachyohylaxis

concurrent administration of two different drugs

synergism, antagonism

Tolerance

Slowly-developing decrease in responsiveness after repeated drug administration; higher dose is often needed for the same effect; does not affect all effects equally; dose–response curve shifts to the right and the maximal response may be lower.

Age

extremes of age group being highly sensitive because:

• Infants: organ immaturity

• Elderly: organ degeneration, coexistence of multiple disease leading to polypharmacy, and increased susceptibility to adverse effects due to:

- Declining hepatic and renal function leading to diminished elimination

- Inadequate supervision

- Poor patient compliance

- Use of drugs with narrow safety margin

Infants/neonates:

Absorption: may be enhanced or impeded

from GI tract; slow and erratic following

IM injection

• Distribution: low albumin leads to higher

free levels of highly protein bound drugs;

blood-brain barrier immature so drugs can

enter the CNS

• Hepatic metabolism: low; dose

adjustments for drugs metabolized in liver

• Renal excretion: significantly reduced;

adjust dose for drugs undergoing renal

excretion

Body weight/composition

• Adult dose calculated for an average adult of 18-65 years, weighing about 70 kg (150 lbs.)

• Children need lesser doses compared to adult - must be calculated

Gender and race

• Drug responses vary in men and women with same drugs for some unknown reasons.

―E.g., Morphine and barbiturates produce excitation in women prior to sedation

• Some drugs (clonidine, ketoconazole, diuretics) produce loss of libido only in men.

• African Americans are resistant to antihypertensive effects of ACE inhibitors compared to Caucasians.

• Race specific FDA approval: isosorbide dinitrate plus hydralazine in treatment of heart failure for African American patients.

Environment and time of drug administration

• Higher doses of sedative/ hypnotics needed to induce sleep during day light.

• Glucocorticoids taken as a morning single dose, minimize the risk of pituitary adrenal axis suppression.

Psychological and emotional factors

• Non-pharmacologic factors also influence drug response.

• Some individuals responds to administration of pharmacologically inert substances called placebos

Placebo

- Pharmacologically inert; no physiological or biochemical properties

- Mainly used in randomized controlled clinical trials

- Responses to placebo can be positive or negative

- 30-35% patients will respond to a placebo; response may exceed that directly due to some drugs (e.g.,antidepressants)

- Placebo effect was the most important benefit from visiting the doctor throughout the known history

Idiosyncrasies

• A small population respond to drug in an entirely different and unpredictable fashion; one that is very rare in occurrence.

• The etiologic origin of such abnormal idiosyncratic responses remain unknown.

• Classified as ‘type B’ (bizarre) adverse drug reactions. ex)

1. Malignant hyperthermia with halothane and succinylcholine

2. Neuroleptic Malignant Syndrome (NMS) with haloperidol and other antipsyhcotics

genetics

• Genetic alterations in drug-metabolizing enzymes and drug targets can lead to altered drug response.

• The study of genetic differences leading to altered individual drug response is called “pharmacogenomics”

• Some known genetic variations in drug response are:

1. Inherited differences in coagulation factors enhance DVT (deep vein thrombosis) risk in women using oral contraceptives

2. Genetic variations in K+ and Na+ transporters predisposes individuals to drug-induced prolonged QT syndrome (torsades de pointes)

metabolic and pathologic disturbances

• Low acidity: ↓ iron and aspirin absorption

• Liver disease: ↑ bioavailability of drugs with high first pass metabolism

• Renal disease: ↓ excretion of drugs like aminoglycoside antibiotics causing toxic effects

• Thyroid disorders: response to digitalis, morphine and sympathomimetics altered.

• Diarrhea/ vomiting: orally given drugs ineffective

route of drug administration

A drug may exhibit different response by different route of

administration. For e.g.

• MgSO4:

―Oral: purgation

―Topical: reduces swelling

―Intravenous (IV): CNS depression and hypotension

• Oxytocin:

―IV: induction of labor

―Intramuscular (IM): controls postpartum bleeding

―Intranasal spray: milk let down reflex (historical use)

Tachyphylaxis

Rapid decrease in drug response with repeated dosing over a short period; usually cannot be overcome by simply increasing the dose; mechanisms include mediator depletion, receptor internalization, or uncoupled signal transduction; maximum response is reduced.

Cross-tolerance

Tolerance to one drug extends to other drugs in the same pharmacologic class. ex) morphine tolerancy → also tolerant to heroin and other opiates

Innate (natural) tolerance

Genetically determined lack of sensitivity to a drug; often evident on first exposure;

ex) some populations tolerant to purgative action of castor oil.

Acquired tolerance

Tolerance that develops after repeated exposure in someone who was priorly responsive; includes pharmacokinetic (drug disposition) and pharmacodynamic (cellular adaptive) components; may also include acute tolerance (tachyphylaxis).

Pharmacokinetic (drug disposition) tolerance

Tolerance due to changes in absorption, distribution, metabolism, or excretion of the drug (e.g., enzyme induction increasing metabolism).

• Occurs when a drug reduces the absorption or enhances the metabolism (by microsomal enzyme induction) of its own or other co-administered drugs. ex) alcohol and barbiturates

Pharmacodynamic (cellular) tolerance

Cellular adaptive tolerance from repeated drug exposure, such as receptor down-regulation or other receptor/signal changes.

• Results due to some type of adaptive changes that takes place within the system after repeated drug administration. ex) Drug induced changes in receptor density (down regulation of receptors

Acute acquired tolerance (tachyphylaxis)

Rapid development of tolerance (decrease in responsiveness) within hours to days after repeated dosing; depends on dose/frequency; reduces maximum response.

Results from an intermediate required for the response being depleted, receptors getting internalized, or signal transduction becoming uncoupled

tachyphylaxis vs tolerance

TACHYPHYLAXIS

• Rarely seen in clinical practice. Demonstrated experimentally in lab.

• Develops faster due to doses repetition in quick successions.

• Original effect of drug cannot be obtained even by ↑ the dose.

• E.g., indirectly acting sympathomimetics like ephedrine, amphetamine, tyramine

TOLERANCE

• It is seen in clinical practice.

• Develops slowly on long term drug administration.

• Original effect of the drug can be obtained by ↑ the dose.

• E.g., opioids, caffeine, alcohol, barbiturates

Concurrent administration: Summation (Addition)

The combined effect of two drugs is the algebraic sum of their individual effects.

• Administration of multiple drugs at the same time can lead to one of the following effects:

1. Summation/ Addition

2. Potentiation

3. Synergism

4. Antagonism

summation/addition

• The combined effects of two drugs given together is the

algebraic sum of their individual effects. E.g.,

- Acetaminophen (+) with Oxycodone (+++) = Analgesia

++++

- Acetaminophen (+) with Aspirin (+) = Analgesia ++

Potentiation

A potentiating agent increases the potency or efficacy of an agonist without producing a direct effect itself; acts via a different pathway to modulate the other drug.

Synergism

Combination of two drugs produces an effect greater than the sum of their individual effects (e.g., Levodopa + Carbidopa for parkinsons).

Antagonism

One drug reduces or blocks the effect of another when given together.

mechanism of variability in drug response

• Change in concentration of drug reaching the receptor

• Variation in concentration of an endogenous receptor ligand

• Changes in post-receptor physiologic regulation or biochemical process in target organ system

• Alteration in number or function of receptors such as:

1. Receptor desensitization

2. Receptor down-regulation

3. Receptor up-regulation and supersensitivity

Desensitization

• A gradual reduction in receptor mediated response to drugs or hormones over seconds or minutes after reaching an initial high despite the presence of the agonist.

• Usually reversible as opposed to “receptor down-regulation”

• A self defense mechanism by nature to avoid over stimulation of cells.

down regulation

• Prolonged exposure to high concentration of agonist leads to reduction in number of receptors available for activation.

• Results due to endocytosis or internalization of receptors from cell surface.

• E.g., diminished responsiveness to albuterol over time in asthmatics.

up regulation and supersensitivity

• Prolonged exposure to high concentration of antagonist leads to increase in number of receptors available for activation with increased receptor sensitivity.

• Results due to externalization of receptors on cell surface.

• Examples:

1. Thyrotoxicosis leads to up-regulation and supersensitization β1adrenoceptors on heart causing tachycardia and palpitations

2. Rebound hypertension after abrupt discontinuation of antihypertensive drugs clonidine and beta blockers.