Pharmacology: Adverse Drug Reactions

Allergic Reaction

• An adverse reaction to a chemical caused by previous sensitization to that chemical or a similar one
• It is caused by antigen-antibody reactions
• Often occurs at low doses of the chemical
• Can be severe and even fatal

Idiosyncratic Reaction

• Genetically determined abnormal reactivity to a chemical
• May involve extreme sensitivity to low doses or extreme insensitivity to high doses
• Example: standard dose of succinylcholine in certain patients can produce prolonged muscle relaxation and apnea due to atypical pseudocholinesterase in plasma.
• Sensitivity to Nitrites and other methemoglobinemia causing chemicals can occur due to a deficiency of NADH methemoglobin reductase (autosomal recessive trait)

Toxic Effect

• Damage to a biological system or process caused by a poison or drug at high doses

Xenobiotics

• Substances that do not enter biological processes or are not used as a source of energy or nutrition
• Considered foreign compounds
• Examples: drugs, heavy metals, insecticides

Tolerance

• Decreased responsiveness to a toxic effect of a chemical due to prior exposure to that chemical or a structurally related chemical
• There are two major mechanisms:
  • Decreased amount of toxicant reaching the site (dispositional tolerance)
    • Examples: CCL4 (decreased formation of reactive metabolite trichloromethyl radical) and Cadmium (induce metallothioneine)
  • Reduced responsiveness of a tissue to the chemical

Detoxification of Protein Toxins

• Proteases are involved in the inactivation of toxic polypeptides and venoms
• Example: Thioredoxin reduces the disulfide bond of erabutoxin and phospholipase

Log Dose-Toxic Response Effect

• Binding of the ultimate toxicant with a target molecule at the target site leads to the development of a toxic response
• According to log doses of toxicant, there is either a graded or quantal (all or none) toxic response.
• Quantal LDR is mainly used for determining ED50, TD50, LD50 and for estimating the safety of drugs

Mechanism of Toxicity of Toxicant

• Direct damage effect by an irritant toxin: Riot gasses, strong acid or alkalis.
• Displacement of some important element by competition for binding: disturbance or damage to biological systems.
  • Examples:
    • Lead and Calcium in children's CNS leading to encephalopathy
    • Sulphonamide and Hypoglycemic drugs (plasma protein [albumin]) leading to hypoglycemic coma.
• Inhibition of some important enzyme: inhibition of biological processes
  • Examples:
    • Cyanide: inhibits cytochrome oxidase leading to histotoxic anoxia
    • Lead: inhibits ALAD (aminolevulinic acid dehydratase) leading to Anemia
• Induction and Oxidative change or lipid peroxidation in certain tissues: damage to cell membrane and necrosis or DNA damage (mutation)
  • Examples:
    • CCL4: affects the liver
    • Ozone (O3): Oxidative stress in tissues

Toxicity Rating

• Super Toxic: Oral LD50 in rat < 5mg/kg (Example: Strychnine)
• Extremely Toxic: Oral LD50 in rat 5-50mg/kg (Example: Opium)
• Very Toxic: Oral LD50 in rat 50-500mg/kg (Example: Phenobarbitone)
• Moderately Toxic: Oral LD50 in rat 500-5000mg/kg (Example: Kerosene)
• Slightly Toxic: Oral LD50 in rat 5000-15000mg/kg (Example: Ethanol)
• Practically Non Toxic: Oral LD50 in rat > 15000mg/kg (Example: Linseed oil)

Factors Affecting Toxicity

• Physical and Chemical Nature:
  • Physical form (gas, liquid, solid, radiation) affects absorption by different routes
  • Chemical form (due to metabolism or isomerization) also affects toxicity (Examples: Carcinogens)
• Single or Repeated Exposure:
  • According to dose and exposure (acute, subacute, subchronic, chronic)
  • Chronic exposure can lead to the development of resistance (tolerance), allergy, and accumulation
• Species: Different species have different effects due to differences in anatomy (monogastric and ruminant) and metabolism (lacking of some enzymes)
• Size, Age, and Sex:
  • LD50 varies according to animal weight
  • Young and old animals are more susceptible to toxicity due to low metabolism, excretion, and resistance
  • Sex has a low effect, but in rats, it may be more significant due to physiological performance and resistance.
• General State of Health: Diseased and debilitated animals are more susceptible to toxicity
• Diet: Any change in diet (vitamins, minerals, protein, fat) will affect toxicity
• Route of Administration: Different routes have different absorption rates; some poisons are only toxic by certain routes (snake venom)

Treatment of Poisoning

• General Treatment:
  • Decontamination: Remove the poison from the body by using methods like inducing vomiting, gastric lavage, or administration of activated charcoal.
  • Enhancing elimination: Increase nonspecific elimination from the body by using diuretics, ion trapping, or dialysis (hemodialysis, peritoneal dialysis, or hemoperfusion).
  • Supportive and symptomatic treatment:
    • Aim to keep the vital functions of the body working until the poison is neutralized by the antidote or eliminated
    • Treat symptomatically, for example:
      • Coma: Stimulant (amphetamine)
      • Convulsion: Anticonvulsant (Phenobarbitone)
      • Dehydration due to diarrhea or vomiting: IV physiologic solution
• Specific treatment by antidote:
  • Mechanism 1: Antidote complex with poison making it inert
    • Aims to reduce the concentration of free poison and dissociate it from tissues
    • Examples:
      • Chelating agents (BAL, pencillamine, EDTA-Ca) are used to treat heavy metal poisoning (As, Hg, Cd, Pb)
      • Pralidoxime (2PAM) + atropine for organophosphate insecticide poisoning (irreversible choline esterase inhibitor)
      • Specific antitoxin and antibodies for botulinum toxin, tetanus toxin, diphtheria toxin, and snake venom poisoning
  • Mechanism 2: Antidote accelerates metabolic conversion of poison (detoxification)
    • Leads to a non-toxic product
    • Example: Thiosulfate treatment for cyanide poisoning
  • Mechanism 3: Antidote blocks metabolic formation of poison (intoxication) from less toxic precursor
    • Examples:
      • Ethanol for Methanol poisoning
      • Acetate – monocetin for Fluoroacetate (rodenticides) poisoning
  • Mechanism 4: Antidote specifically accelerates excretion of poison
    • Examples:
      • Chloride for Bromide poisoning
      • Calcium salts for Strontium poisoning
  • Mechanism 5: Antidote competes with toxicant agent for essential receptor (Displacement competition)
    • Examples:
      • Oxygen (O2) for Carbon Monoxide (CO) poisoning
      • Nalaxone for Morphine and related narcotics poisoning
  • Mechanism 6: Antidote blocks receptor responsible for toxic effect (causing blocker)
    • Example: Atropine for cholinesterase inhibitors poisoning (neostigmine, edrophonium)
  • Mechanism 7: Antidote restores normal function by repairing of damaged processes or by bypassing the effect of poison by compensation with the inhibited end product
    • Examples:
      • Methylene blue for agents that produce methemoglobinemia (NO2, Cl, Sulphonamide, Acetnilide)
      • Purine for Mercaptopurine (anticancer-DNA antagonist) to inhibit purine synthesis by bypassing the effect

Scope of Toxic Effect

• Local versus Systemic Effect:
  • Local effect occurs at the site of application (example: caustic chemicals, inhalation of irritant chemicals like Riot gasses)
  • Systemic effect requires absorption and distribution to the organ or site of toxic effect (target organ) (example: Hg, Cd)
  • Some toxic agents show both local and systemic effects (snake venom)
• Reversible versus Irreversible Effect:
  • The ability to regenerate determines whether the effect is reversible or irreversible (example: Liver, CNS)
• Immediate versus Delayed Effect:
  • Some toxic agents need a latent period (years) to exert their effect (example: Carcinogens like diethylstilbestrol, this is called a delayed effect)
  • Most toxic agents show an immediate toxic effect depending on the dose (example: CN)