ADR

• ADRs


  Any response to a drug which is noxious and unintended and which occurs at doses normally used in Man for prophylaxis, diagnosis or therapy
• It is very difficult to be certain how commonly ADRs occur
• Representative figures for ADRs

  • Hospital in-patients: 10-20% suffer ADRs
  • Death in Hospital in-patients: 0.24-2.9% are due to ADRs
  • Hospital admission: 0.3-5% of hospital admission are due to ADRs
• ADRs are a considerable problem
• Classification of ADRs


  • Type A (normal pharmacological effects which are undesirable)
  • Type B (effects unrelated to the pharmacological effect of drug)
  • Type C (chronic long term effects)
  • Type D (delayed effects)
  • Type E (end of use or withdrawal effect)
  • Type F (failure of therapy)

  
• Type A ADRs


  • Are usually dose-dependent and fairly predictable
  • Are an important cause of morbidity but death is unusual
• Type A ADRs


  • Haemrorhage with Anticoagulants (Heparin & Warfarin)
  • Hypoglycemia with (insulin, sulfonylurea)
  • Bradycardia with beta adrenoreceptor blocker
• Type B ADRs


  • Are rare, unpredictable
  • Generally unrelated to dose
  • Are often severe or fatal
• Type B ADRs


  • Malignant hyperthermia of anesthesia
  • Immunological reactions
• Factors that increase risk of ADRs

  • Multiple drug therapy
  • Age (old and very young more susceptible)
  • Gender (women generally at greater risk)
  • Intercurrent disease including patients with renal or hepatic failure and HIV-positive patients
  • Race and genetic polymorphism
• Pharmacogenetics


  Deals with variations in drug response that are hereditary control
• Causes of pharmacogenetic variations

  • Pharmaceutical variations
  • Pharmacokinetic variations
  • Pharmacodynamic variations
• Quantitative alterations in the absorption, distribution, metabolism and elimination may lead to alterations of drug at site of action with corresponding changes in its pharmacological effects
• Factors that can influence absorption

  • Dosage and pharmaceutical factors
  • GIT motility
  • Absorptive capacity of GI mucosa
  • First pass metabolism
  • Rate of Gastric emptying
  • Regional blood flow
  • Plasma protein and tissue binding
• Reduced elimination leads to drug accumulation, potential toxicity due to increased plasma and tissue levels
• Causes of reduced elimination

  • Impaired glomerular filteration such as patients with intrinsic renal disease, elderly and neonates
• Potential toxic drugs due to reduced elimination are digoxin, ACE inhibitors and aminoglycosides
• Occurrence of these ADRs may be minimized by adjusting dosage given to individual patients on the bases of their renal function
• Phases of drug metabolism

  • Phase I (oxidation, reduction or hydrolysis)
  • Phase II (sulphation, glucuroniation, acetylation or methylation)
• Genetic or environmental influences applies for oxidation, hydrolysis and acetylation
• Competition for glucuronidation may occur when 2 drugs metabolized by this pathway
• Drug metabolism occurs mainly in ER of liver by Cytochrome P450 enzyme
• Poor metabolizers


  Tend to have reduced first pass metabolism, increased plasma levels and exaggerated pharmacological response
• Rapid metabolizers


  May require higher doses for a standard effect
• Succinylcholine metabolism


  1. Normally metabolized in plasma by non-specific esterase called pseudocholinesterase

  2. In some individuals, the pseudocholinesterase is abnormal and does not metabolize the succinylcholine so rapidly

  3. This results in respiratory paralysis (Scoline apnoea) requiring prolonged ventillation until it is cleared from the blood
• The abnormality in succinylcholine metabolism is inherited in an autosomal recessive fashion
• Drugs whose acetylation is genetically determined

  • isoniazide
  • hydralazine
  • procainamide
  • dapsone
  • some sulfonamides
• Slow acetylators


  May have enhanced response to treatment but also an increased risk of drug toxicity
• Determining acetylator status


  Give a sulfonamide orally and measure the relative proportions of acetylated and total sulfonamide in a sample of urine passed 5-6 h later
• Some drugs (e.g morphine, paracetamol and ethinylestradiol) are eliminated by glucuronide conjucates
• Glucuronyltransferases are inducible and administration of inducing drug can lead to loss of efficacy
• Causes of ADRs


  • Pharmaceutical causes
  • Pharmacokinetic causes
  • Pharmacodynamic causes
  • Presence of degradation products of active constituents
  • Non-drug components (excepients, colouring agents, preservatives...etc)
• No documented type B adverse reactions that can be attributed to abnormalities of absorption or distribution
• Mostly, bioactivation of drugs to yield reactive species is responsible for type B ADRs. Bioactive metabolite lead to direct or immune-mediated toxicity
• Unusual drug reactions


  Can occur in individuals whose RBCs are deficient in any one of three different but functionally related enzymes: G6PD, GSH reductase, methemoglobin reductase
• Lack of G6PD in RBCs

  1. Reduced production of NADPH

  2. Consequently oxidized GSSG accumulate

  3. If RBCs exposed to oxidizing agents, hemolysis occur, probably because of unopposed oxidation of SH gps in the cell membrane, which are normally kept in reduced form by the continuous availability of reduced GSH
• The genetic basis for the abnormal enzyme being heterogenous, most of the variations causing the enzyme to be unstable
• Severe hemolysis occurs on the first administration and is maintained with continued administration
• Favism


  The reaction resulting from eating broad beans which contain an oxidant alkaloid
• Warfarin and phenylbutazone have also been implicated in G6PD deficiency