DRUG TOXICITY

HASHMI FURQAN

TOXICITY OF DRUGS
Toxicity may be the result of Interactions (drug-drug, drug-food) Side effects Adverse drug reactions (type-A, type-B) In other words the TOXICITY is the consequence of the above mentioned mechanisms

TOXICITY
Related to the principal pharmacological action of the drug (predictable, dose related) e.g. bleeding with anticoagulants Unrelated to the principal pharmacological action of the drug (pt. factors) e.g. liver damage with paracetamol

TOXICITY TESTING

Animal testing of new drugs Wide range of tests in different species Long-term administration of drugs Regular monitoringphysiological & biochemical abnormalities Detailed postmortem examination gross or histological abnormalities

Doses well above the expected therapeutic range are used Determines which organs or tissues are likely TARGETS of toxicity Recovery StudiesAssessment of Toxic effects are Reversible or Irreversible More attention is given to Irreversible effects (carcinogenesis, neurodegeneration etc)

Toxicitiesrange from negligible to severe precludes further development of the compound Intermediate levels of toxicity acceptable for drugs intended for serious illnesses e.g. AIDS Decision whether to continue development is often difficult

Safety of a drug The safety of a drug can only be established during use in humans

MECHANISM OF TOXICITYCELL DEATH

Toxic concentration of drugs or drug metabolites can cause NECROSIS APOPTOSIS (programmed cell death or cell suicide) Chemically active metabolites form covalent bonds with target molecules or may interact by non-covalent bonds Some metabolites do both

LIVERmajor site of drug metabolism thats the reason of development of Hepatotoxicity KIDNEYSdrugs & metabolites are excreted or reabsorbed making the kidneys more susceptible towards development of toxicity Nephrotoxicity

NON-COVALENT INTERACTIONS

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Cytotoxicity caused by: Lipid peroxidation Generation of toxic oxygen radicals Reactions causing depletion of glutathione (GSH) Modification of sulfhydryl groups

LIPID PEROXIDATION

Polyunsaturated lipids undergo peroxidation by reactive metabolites or reactive oxygen species Lipid peroxyradicals (ROO) can produce lipid hydroperoxides (ROOH)---producing further lipid peroxy radicals Disruption of the lipid membrane eventually result in the cell death by action of lipid peroxidase with the proteins Glutathione & Vitamin-E protect against lipid peroxidation

TOXIC OXYGEN RADICALS

Reduction of molecular oxygen to superoxide anion This is followed by enzymatic conversion to hydrogen peroxide or reactive spp such as hydroperoxy (HOO) & hydroxy radicals These reactive oxygen spp are highly cytotoxic

DEPLETION OF GLUTATHIONE

GSH redox reaction is a protective cycle that minimizes the cell damage Depletion of GSH is known as OXIDATIVE STRESS This is a disturbance in the pro-oxidant/antioxidant balance in the favor of pro-oxidant state. GSH is normally maintained with its disulfide GSSG Oxidizing spp convert GSH to GSSG GSH is regenerated by NADPH-dependent GSSGreductase When cellular levels of GSH fall to 2030% --cellular defence against toxic compound is impaired & cell death occurs.

MODIFICATION OF SH GROUPS

Oxidizing spp alter the SH groups reversibly or by covalent interactions SH have critical role in catalytic activity of enzymesmodification in of SH groups result in inactivation Cytoskeltal protein Actin, Glutathione reductase & Ca-transportation ATPase in plasma membrane & ER are commonly affected by the reactive oxygen spp High levels of Ca cause the activation of degenrative enzymes i.e. protein kinases (proteases, endonucleases) lead to the damage to the cytoskeleton.

COVALENT INTERACTIONS
Targets to Covalent Interaction DNA Proteins / peptides Lipids Carbohydrates Interaction with the DNA is the basic mechanism of action of mutagenic chemicals

GENERAL MECHANISM OF CELL DAMAGE & CELL DEATH

Drug induced damage is often a result of reactive metabolites that interact both by non-covalent and / or covalent interactions Cell death is often self inflicted via triggering of apoptosis Usually Mutagenesis is the result of covalent interaction Examples: Covalent bond formation between the metabolite of paracetamol (N-acetyl-p-benzoquinone imine) & the target cell Covalent binding to proteinsimmunogens Binding to DNAmutagenesis

Some non-mutagenic chemicals also form covalent bonds resulting in the cell damage Cholinesterase inhibitors bind cholinesterase at the neuromuscular junctions and cause the necrosis of the skeletal muscles Toxin in the toadstool binds actin causing actin-depolymerization) also to the RNA-polymerase causing inhibition of protein sysnthesis

HEPATOTOXICITY

Hepatocytes are exposed to reactive metabolites produced by CYP-450 enzymes Liver damage can be produced by general mechanism of cell injury e.g. covalent & non-covalent Some drugs can cause reversible cholistatic jaundice Immunological mechanisms are sometimes implicated

Clinical Manifestation of liver damage Hepatitis (inflammation of hepatocytes) Laboratory abnormalities (enzyme levels etc) Paracetamol, Isoniazid, Halothane, Phenytoin cause hepatotoxicity Genetic differences in drug metabolism have been implicated (Isoniazid, Phenytoin) Mild drug induced abnormalities of liver functions are not uncommon but the mechanism of liver injury is often uncertain Its not always necessary to discontinue the drugs on mild abnormalities

Irreversible liver disease as Cirrhosis require extreme caution e.g. low dose of Methotrexate for various autoimmune diseases Reversible obstructive jaundice Chlorpromazine & Androgens

HEPATOTOXICITY CAUSED BY PARACETAMOL TOXIC DOSE

Toxic dose of paracetamol (mixed function oxidases CYP450) [reactive oxygen species] N-acetyl-p-benzoquinone imine (NAPBQI) This is formed by lipid peroxidation, SH depletion Resulting in increased membrane permeability Cell death occurs ultimately by the Oxidative stress.