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Transcript
RELATION BETWEEN DRUG DOSE & CLINICAL RESPONSE Dose & Response in Patients A. Graded Dose-response Relations: To choose among drugs and to determine appropriate doses of a drug, the clinician must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect Graded Dose-response Relations (cont’d) Graded dose response curves relate doses of drugs to a particular therapeutic effect, eg, lowering of BP, increased urinary sodium excretion Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect Graded Dose-response Relations (cont’d) Potency of a drug depends in part on: 1. the affinity (KD) of receptors for binding a drug and in part on 2. the efficiency with which drugreceptor interaction is coupled to response It is necessary to distinguish between a drug’s potency and its efficacy Graded Dose-response Relations (cont’d) The clinical effectiveness of a drug depends on its: - potency - maximal efficacy - ability to reach the relevant receptors In choosing a drug, clinicians must consider relative effectiveness than potency. Potency is important only if the drug has to be administered in inconveniently large amounts Graded Dose-response Relations (cont’d) The potency of a drug is expressed in dosage units, usually in terms of a particular therapeutic end point (eg, 50 mg for mild sedation) Maximal efficacy is the the maximum effect a drug can bring about, regardless of the dose Relative potency Graded Dose-response Relations (cont’d) Maximal efficacy is determined by: 1. drug’s mode of interactions with receptors (see partial agonists) 2. characteristics of the receptor-effector system involved (eg, diuretics that act on one portion of nephron may produce much greater excretion of sodium than diuretics that act elsewhere) 3. efficacy is limited by the drug’s ability to cause a toxic effect (eg, cardiac arrhythmia with a positive inotropic drugs) B. Quantal Dose-Response Curves Limitations of the graded dose-response curve: Graded dose-response curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death. Graded dose-response curves obtained in a single patient may be limited in application to other patient (variability of severity of disease and patient responsiveness to drugs) B. Quantal Dose-Response Curves Determining the dose of a drug required to produce a specific magnitude of effect in a large number of individuals (animals) and plotting the cumulative frequency distribution of responders versus the log dose represents quantal response (eg, relief of headache, death in experimental animals). B. Quantal Dose-Response Curves The quantal dose-effect curve is often characterized by stating the median effective dose (ED50): the dose at which 50% of individuals exhibit the specified quantal effect The dose required to produce a toxic effect in 50% of animals is called median toxic dose(TD50) If the toxic effect is the death of the animal, the median lethal dose (LD50) may be experimentally defined B. Quantal Dose-Response Curves Such values allow to: 1. compare potencies of drugs (how?) 2. obtain index of selectivity of drug action (eg, suppression of cough against analgesia for opioids drugs) 3. estimating the margin of safety: Therapeutic index = TD50/ED50 B. Quantal Dose-Response Curves The therapeutic index in humans is almost never known with real precision; clinical trials and experience reveal sometimes overlap between therapeutic and toxic doses (e.g. warfarin) The clinically acceptable risk of toxicity depends critically on the severity of the disease Ratio of the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. The range between the minimum toxic dose and the minimum therapeutic dose is called the therapeutic window and is of greater practical value in choosing the dose for a patient Variation in Drug Responsiveness Individuals may vary considerably in their responsiveness to a drug; A single individual may respond differently to the same drug at different times during the course of treatment Occasionally, an unusual or idiosyncratic drug response may be observed. It may be caused by genetic differences in drug metabolism or by immunologic mechanisms, including allergic reactions Variation in Drug Responsiveness (cont’d) A clinician must be prepared to change either a dose of a drug or a drug, depending on the patient’s response Quantitative variations (common): hyporeactivity/hyperreactivity Tolerance Tachyphylaxis Variation in Drug Responsiveness (cont’d) - Factors that may help in predicting the direction and extent of variations in responsiveness: Age Sex Body size Disease state Concurrent drug administration Propensity of a drug to produce tolerance Variation in Drug Responsiveness (cont’d) 1. 2. 3. 4. Mechanisms contributing to variation in drug responsiveness: Alteration in concentration of drug that reaches the receptor Variation in concentration of an endogenous receptor ligand Alterations in number or function of receptors Changes in components of response distal to receptor Variation in Drug Responsiveness (cont’d) 1. Alteration in concentration of drug that reaches the receptor Pts may vary in the rate of absorption, distribution, clearing the drug from the blood May be predicted on the basis of age, sex, disease state, liver & kidney function and, more recently, by testing for genetic differences in drug metabolism Repeated measurements of drug conc. in blood may be helpful Variation in Drug Responsiveness (cont’d) 2. Variation in concentration of an endogenous receptor ligand E.g. Saralasin, a weak partial agonist at AngII receptors, ↓BP in pts with HTN caused by ↑ AngII production, but ↑BP in pts who produce low amounts of Angiotensin. Propranolol: pheochormocytoma vs. well trained athlete Variation in Drug Responsiveness (cont’d) 3. Alterations in number or function of receptors Particularly important for receptors for hormones, neurotransmitters, biogenic amines a. Change in receptor number may be caused by other hormones: Eg, in thyrotoxicosis the number of βadrenergic receptors to catecholamines is↑ and also the sensitivity of heart muscle to catecholamines Variation in Drug Responsiveness (cont’d) Alterations in number or function of receptors (cont’d) b. In other cases, the ligand itself causes down-regulation/desensitization of receptors These mechanisms contribute to two important phenomena: 1. Tolerance or tachyphylaxis 2. “overshoot” phenomena on withdrawal of certain drugs (eg, hypertensive crisis from clonidine withdrawal) Variation in Drug Responsiveness (cont’d) Alterations in number or function of receptors c. Genetic factors also can play an important role in altering the number or function of specific receptors e.g a specific genetic variant of 2C-adrenoceptor when inherited with 1-adrenoceptor greatly increased risk of CHF which can be reduced by early intervention using antagonist drugs Pharmacogenetics Variation in Drug Responsiveness (cont’d) 4. Changes in components of response distal to the receptor Patient factors that may limit the clinical response: age, general health, and severity & pathophysiologic mechanism of disease (eg, heart failure will not respond to positive inotropic drugs if mitral valve stenosis is not corrected) Drug therapy will be successful if directed at the pathophysiologic mechanism Variation in Drug Responsiveness (cont’d) Once the diagnosis is correct and the drug is appropriate: Any unsatisfactory therapeutic response may be due to a compensatory mechanism that opposes the beneficial effect of the drug (e.g, fluid retention and ↑sympathetic tone with use of vasodilators in HTN) Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs Drugs are only selective, rather than specific in their action What does that mean??? Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs (cont’d) Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo; The selectivity is usually considered by separating effects into: therapeutic and toxic There are three possible relations between the therapeutic and toxic effects of a drug based on analysis of the receptor-effector mechanisms: Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs (cont’d) A. Beneficial and Toxic Effects Mediated by the Same ReceptorEffector Mechanism A direct pharmacologic extension of the therapeutic action of the drug ( eg, bleeding with anticoagulant, hypoglycemic coma due to insulin). Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs (cont’d) B. Beneficial & Toxic Effects Mediated by Identical Receptors But in Different tissues or by Different Effector Pathways E.g. digitalis produces positive inotropic effect, but also arrhythmias, GI effects, changes in vision (inhibition of Na/K ATPase), bone marrow toxicity with antineoplastic agents Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs (cont’d) Therapeutic Strategies: - Use of lowest doses possible - Use of adjunctive drug that produces different toxicities may allow dose ↓of the first drug (eg, use of additional immunosuppressant in inflammatory disorders) - ↑ drug conc. at the site of action (eg, aerosols in asthma, arterial infusion of anticancer agents) Clinical Selectivity:Beneficial Versus Toxic Effects of Drugs (cont’d) C. Beneficial & Toxic Effects Mediated by Different Types of Receptors Synthesis of new therapeutic classes with improved receptor selectivity allow to overcome this problem (eg, α & β selective adrenoceptor antagonists, receptor-selective steroid hormones) Exercise END OF CHAPTER-2