Variations in Drug responsiveness

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Variations in Drug responsiveness By Dr.Abdul
latif mahesar 200811
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• When a drug is administered usually there is
  normal predicted response
• OR
• there may be
• reduced response
• increased response OR
• altered response
• Individuals may vary considerably in their
  responsiveness.
• 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.
• This reduced effect of drug may be due to
• a) step down regulation of receptors
• b) exhaustion of the mediator
• c) increased metabolic degradation
• d) physiologic adaptation
• e) 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

• 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

• 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.
• 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( ß-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

• 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
  ß-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.

• .
• age
• general health specially severity and pathologic
  mechanism of disease.
• 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.
• Which adverse effects are avoidable and which
  are not ?
• Some patients with history of allergy to drugs,
  are up to 4 times more likely to have another
  adverse reaction.
• 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.
• 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

• 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
• Or
• Reversible
• like morphine poisoning reversed by
  administration of Naloxone.

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• Type B ( Bizarre) like
• Hypersensitivity and Idiosyncrasy.
• they are less than 25 of adverse effects
• only occur in some people ( only in minority of
  patients)
• not a part of normal pharmacology of drug
• can not be predicted.
• 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)
• These accounts for most drug fatalities.

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• Type C( continuous) due to long term use of
  drugs
• e.g. analgesic nephropathy
• TypeD (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,DE as type B