Transcript (lec 8) adverse d..

Variations in Drug
responsiveness
By
11Dr.Abdul latif mahesar 2008
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When a drug is administered usually there is normal
predicted response
OR
there may be
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reduced response
increased response OR
altered response
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Individuals may vary considerably in their responsiveness.
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Even a single individual may respond differently to the same
drug at different times.
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Variations (changed response )
Tolerance
Tachyphylaxis
Drug resistance
Hypersensitivity reactions (intolerance)
Desensitization
Anaphylactic reaction
Idiosyncrasy
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Tolerance
It is a gradual decrease in responsiveness to repeated administration of a
drug.
It is slow in onset( takes days or weeks to develop)
e.g. Salbutamol ( beta 2 –agonist )
Diazepam ( anxiolytic )
Morphine ( opioid analgesic )
Original effect can be obtained by increasing the dose. Which may lead to
dependence and later addiction with some drugs.
a)
b)
c)
d)
e)
This reduced effect of drug may be due to
step down regulation of receptors
exhaustion of the mediator
increased metabolic degradation
physiologic adaptation
active extrusion of drug from cells
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Tachyphylaxis
It is rapid decrease in response to a repeated administration of a
drug
Its onset is rapid
Original effect cannot be obtained even with larger doses of drug
e.g. Exhaustion of epinephrine by ephedrine.
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Drug resistance
It is a complete loss of effectiveness of a drug.
e.g. antimicrobial drugs
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Hypersensitivity ( more than normal response of
the body to a drug)
This can be corrected by
Desensitization
( if a person is allergic to a drug ,he can be administered
a small amount of drug to which he is allergic and
then it is to be gradually increased until the normal
dose is tolerated)
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Anaphylaxis:
It is immediate hypersensitivity reaction on exposure to specific
antigen or hapten leading to life threatening respiratory
distress followed by vascular collapse.
e.g. Penicillin
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Idiosyncratic reactions
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It is an inherent qualitative abnormal reaction
It is an increase in response with a therapeutic dose.
It is due to genetic change
It is usually harmful .
occurs in small proportion of populations
e.g. chlormaphenicol causes aplastic anemia
1 in 50,000.
G6PD deficiency leads to hemolysis caused by primaquaine.
hepatic porphyria ( abnormal haem synthesis) caused by
carbamzepine.
Malignant hyperthermia caused by suxamethonium and
inhalational anesthetics.
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Keeping this responsiveness of individual drug,
there should be change of the drug or dose.
These includes propensity( particular behavior )
of particular drug to produce tolerance or
Tachyphylaxis as well as effects of age, sex ,
body size , diseases state and simultaneous
administration of other drugs.
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Mechanism: which may contribute to variations in
drug responsiveness among patients or among
individual patient at different times.
A) Alteration in concentration of drug that reaches
receptor.
B) Variation in concentration of an endogenous
receptor ligand.
C) Alteration in number and function of receptors
D) Changes in components of response distal to
receptor
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A) Alteration in drug concentration
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A) Patient may differ in rate of absorption,
distribution, and elimination of drug. By
alteration of concentration of drug that
reaches relevant receptor may alter clinical
response.
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Some difference can be produced on the basis of
age, weight ,sex ,diseases state liver and kidney
function, drug metabolizing enzymes.
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variability in response to pharmacologic
antagonist
e.g. Propranolol( β-blocker) will markedly slow the H.R of
patient whose endogenous catecholamine are elevated
(pheochromocytoma ), but will not affect the resting H.R of
well trained marathon runner.
.
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Alteration in number of receptors
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There occurs change in responsiveness caused by increase or
decrease in number of receptor sites or alteration in efficiency
of coupling of receptor to distal effectors mechanism.
e.g. 1) Receptors for hormones
Thyroid hormones cause increase in number of β-adrenergic
receptors and hence increase in cardiac sensitivity to
catecholamines
ii) Agonist ligand induces a decrease in number( down
regulation) or coupling efficiency of its receptors.
e.g Albuterol
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iii) Receptor specific desensitization mechanism act physiologically
to allow cells to adopt to changes in rates of stimulation by hormones
or neurotransmitters .
These mechanisms contribute to tacyphylaxis or tolerance and over
shoot phenomena that follows with drawl of certain drugs .
This may occur with agonist or antagonist
Antagonists (up regulation) increase the number of receptors
e.g. Propranolol
Agonists (Down regulation) decrease the number of receptors.
This may be dangerous t o discontinue certain drugs. therefore drugs
are to be with drawn slowly
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Other factors which may cause variation
in responsiveness.
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age
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general health specially severity and pathologic mechanism of disease.
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Drug therapy always be most successful when it is accurately directed at
pathophysiologic mechanism responsible for disease.
There may be no benefit due to compensatory mechansim
e.g. Vasodilator drug for hypertension leads to reflex tachycardia and
sodium retention by kidneys.
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Adverse Drug reactions
By. Dr. Abdul Latif Mahesar
Dept. of Medical Pharmacology
King Saud University
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The drugs prescribed for disease may
themselves be the cause of diseases( adverse
reactions) This may range from mere
inconvenience to permanent disability to and
death.
such as
Nausea and vomiting with any of the drug
Deafness with aminoglycosides
Death
with penicillin's
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How much diseases they cause and why they cause ?
So that preventive measures can be taken.
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Which adverse effects are avoidable and which are
not ?
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Some patients with history of allergy to drugs, are up
to 4 times more likely to have another adverse
reaction.
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It is also useful to discover the cause of adverse
reaction ,so that ,that can be avoided.
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Side effects: many unwanted effects , are
medically minor and need not to stop the drug,
called side effects.
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Adverse reactions: harmful or seriously
unpleasant effects occurring at therapeutic
doses and which call for reduction of dose or
withdrawal of the drug and /or forecast hazards
from future administration.
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Toxicity: Direct action of the drug, often at high dose
, damaging cell.
e.g. liver damage from paracetamol over dose,
8th cranial nerve damage from gentamicin .
All the drugs are said to be toxic in over dose
Some times drugs in ordinary dose may become
toxic due to under lying abnormality in patient
e.g. in renal impairments
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Classification
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Type “A” OR Type “1”
Generally these are excessive therapeutic effects
75% of all adverse reactions.
they can occur in every one
they are common
they are predictable
they are dose dependent
skill management can reduce their incidence
they are mostly part of normal pharmacology of drug.
e.g. Hypoglycemia
Insulin
Hypotension
Propranolol
Bleeding
warfarin
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There may be adverse effects unrelated to
main pharmacological actions of drugs
belonging to this group but these are not
serious and reversible.
e.g Morphine ( an opioid analgesic) causes constipation during
its use as analgesic.
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These adverse effects may be
irreversible
like paracetamol hepatotoxicity
aminoglyside 8th cranial nerve damage
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Or
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Reversible
like morphine poisoning reversed by administration
of Naloxone.
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Type “B” ( Bizarre) like
Hypersensitivity and Idiosyncrasy.
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they are less than 25% of adverse effects
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only occur in some people ( only in minority of patients)
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not a part of normal pharmacology of drug
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can not be predicted.
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non dose related
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Adverse effects may be unrelated to normal
pharmacology of the drug.
As paracetamol hepatotoxicity
Aspirin induced tinitus
Thalidomide induced phaecomelia
Primaquine induced haemolysis.
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These are due to unusual attributes of patient
interacting with drug.
These may be inherited abnormalities
( idiosyncrasy ) and immunological process
(drug allergy)
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These accounts for most drug fatalities.
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Type “C”( continuous) due to long term use
of drugs
e.g. analgesic nephropathy
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Type”D” (delayed)
e.g. teratogenesis , thalidomide causing
phecomelia
carcinogenesis ,stilboestrol cause
adenocarcinoma of vagina in female offspring.
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Type “E”( ending of use) where discontinuous
is too abrupt.
e.g. Rebound adrenal insufficiency.
over shoot of blood pressure due to propranolol
withdrawal.
Note : some authors include Type C,D&E as
type “B”
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