DRUG TOLERANCE Tolerance Tolerance Definition Tolerance

DRUG TOLERANCE

Tolerance: • Tolerance Definition: Tolerance can be defined as decreased responsiveness to a drug following repeated exposure , requiring an increase in dosage to produce the initial response. It is the most common response to repetitive use of the same drug. Tolerance is widely occurring adaptive biological phenomenon

Important characteristics of Tolerance It mainly occurs with drugs acting on CNS. Opioids , Benzodiazepines, Alcohol. It can be overcome by increasing the dose. As higher dose is required to produce the initial response , obtained at a lower dose , so DRC shifts to right. e. g. Diazepam produces sedation at 5 -l 0 mg. On repeated use after prolonged period, some people may require much larger doses. Tolerance does not develop equally to all effects of a drug. It develops more rapidly to some effects than to others.

Examples: Morphine. Tolerance develop readily to Euphoric , Analgesic & respiratory depressant effect. Tolerance does not develop to papillary constriction, constipation. Phenobarbitone : Tolerance develops readily to sedation but not to antiepileptic effect. Chlorpromazine: Tolerance develops to sedative effect but it does not develop to Antipsychotic effect.

Types of Tolerance Natural / Innate Tolerance: Genetic insensitivity to a drug, observed on first administration of drug. Exp: a) Black races are tolerant to Mydriatics b) Rabbits are tolerant to Atropine Acquired Tolerance : After repeated use of a dug in an individual who was initially responsive to it.

Main mechanisms of Acquired Tolerance: Pharmacokinetic (Dispositional or Metabolic)changes Pharmacodynamic / cellular changes. Physiological adaptations

Pharmacokinetic (Dispositional or Metabolic) changes. Some changes in pharmacokinetic properties may occur on repeated administration so that plasma concentration becomes lower so effective concentration at target site is insufficient. It may be due to changes in: a. Absorption i. e. Alcohol , arsenic trioxide. b. Metabolism / elimination i. e. enzyme induction --- auto induction carbamazepine , barbiturates.

Pharmacodynamic / cellular tolerance: It refers to the adaptive changes at receptor level/ site of action or Less responsiveness of target organs Down regulation / desensitization of receptors Receptor uncoupling e. g Opioids. Depletion of tissue thiol compounds that leads to decreased libration of nitric oxide from Nitrovasodilators. ↓ number of receptors e. g. β 2 agonist ( Salbutamol ).

Physiological adaptation: The effect of a drug may be decreased by a homeostatic mechanism. Example: the blood lowering effect of thiazide diuretics is limited because of a gradual activation of renin – angiotensin system

Main types of Acquired Tolerance: Pharmacokinetic (Dispositional or Metabolic) tolerance. Pharmacodynamic / cellular tolerance. Cross tolerance Reverse tolerance

Cross tolerance: It is development of tolerance to the pharmacologically related drugs. If a patient develops tolerance to one drug , he may be partially tolerant to the other drugs of the same group. Example: Opioids : Morphine, Methadone Cross tolerance may also occur with drugs of different groups belonging to same class. Example: CNS depressants: Morphine & Barbiturates

Reverse tolerance Sensitization / Upregulation of receptors is called reverse tolerance. The dose response curve shifts to left.

Tolerance is an important component of drug dependence. As tolerance develops readily to euphoria in a Morphine addict so they require ever increasing doses to obtain the same degree of euphoria.

Tachyphylaxis : Tachy--- fast , Phylaxis – Protection. Definition: It is rapidly developing reduction in response when same doses of some drugs are repeatedly given over short intervals / in quick succession. Usually seen in experimental animals.

Mechanism of Tachyphylaxis Depletion of stores of mediators. eg. Indirectly acting sympathomimetics. e. g. Tyramine , Amphetamine , Ephedrine. Change in receptors due to slow dissociation. eg. Suxamethonium Tachyphylaxis can be overcome by: Increasing the interval between doses.

Differences between tolerance & tachyphylaxis:

Cumulation : Some drugs tend to accumulate in the body after frequent administration, due to slow metabolism. So intake exceeds elimination. This is due to Strong PPB. Binding or affinity for certain tissues. Examples: Digitoxin ---- highly PPB Chloroquine , accumulates in melanin containing tissues ---large doses for prolonged periods can produce retinal damage. Halogenated hydrocarbons (DDT) can accumulate in fat depots Heavy metals (lead, radium, thorium, strontium) can accumulate in bones. Metallic silver accumulates in skin

Emotional / Psychological Factor: Patient’s response may be affected by : 1. Patient’s beliefs , attitude & expectations , Sympathetic attitude of Doctor. 2. Use of placebo. Patient’s beliefs , attitude & expectations may be applicable to drugs acting on CNS. A nervous & anxious patient requires more amount of General anesthetic to produce anesthesia. In animals, Alcohol generally impairs performance , but after punishment (which induces anxiety) it actually improves the performance

Placebo: (Latin ---- I will Please) Placebo is a dummy drug, it is an inert substance which is made to appear identical with the active drug in physical properties like shape, odor & color. Substances used as placebo are: Lactose Tablets / capsules Distilled water Injections.

Mechanism of Placebo Effect : It is independent of chemical nature or dosage of the administered substance. Generally placebo acts by psychological means. Sometimes placebo may induce physiological responses eg. They can release endorphins in brain causing analgesia , because placebo analgesia can be blocked by Naloxone --- An opioid antagonist. However placebo effects are highly variable in the same patient. , placebo may induce sleep on first night but not subsequently.

Uses: As a control in scientific evaluation of drug during clinical trials. Limited role in practical therapeutics to benefit or please a patient with: Mild psychological disorders. Chronic incurable diseases.

Placebo reactor: An individual who feels improvement in physical & mental state after taking Placebo: 35% of physically ill > 40% of the mentally ill. NOCEBO: It is the converse of placebo. It refers to the negative psychodynamic effect evoked by loss of faith in the medication & the physician. It can oppose therapeutic effect of active medication.