Download Variation in Drug Responsiveness

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