Drug Metabolism and Excretion

Glycine Conjugation

• Glycine conjugation is a characteristic pathway for certain aromatic acids, such as salicylic acid, isonicotinic acid, and p-amino salicylic acid.
• These drugs are also metabolized by other pathways.

Methylation

• Adrenaline is methylated to metanephrine by catechol-o-methyl transferase.
• The source of the methyl group is s-adenosyl methionine.

Excretion of Drugs

• Excretion of drugs means the transportation of unaltered or altered form of the drug out of the body.
• The major processes of excretion include renal excretion, hepatobiliary excretion, and pulmonary excretion.
• The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, nails, and hair.
• The rate of excretion influences the duration of action of a drug.
• A drug that is excreted slowly maintains its concentration in the body and continues to produce effects for a longer period.

Renal Excretion

• Renal excretion is a major part of excretion, and it involves glomerular filtration, active tubular secretion, and passive tubular reabsorption.
• The function of glomerular filtration and active tubular secretion is to remove the drug from the body, while tubular reabsorption tends to retain the drug.
• Glomerular filtration is a process that depends on the concentration of the drug in the plasma, molecular size, shape, and charge of the drug, and glomerular filtration rate.
• Only the drug that is not bound to plasma proteins can pass through the glomerulus.
• All drugs with low molecular weight can pass through the glomerulus, e.g., digoxin, ethambutol, etc.

Physiological Antagonism

• Physiological antagonism occurs when the physiological effect of a drug is antagonized by another drug acting on two different types of receptors.
• Examples include acetylcholine, which causes constriction, while adrenaline causes dilatation of the pupil.
• Importance of drug antagonism includes correcting adverse effects of drugs, treating drug poisoning, and predicting drug combinations that would reduce drug efficacy.

Repeated Administration and Drug Cumulation

• If a drug is excreted slowly, its administration may build up a sufficiently high concentration in the body to produce toxicity.
• To avoid cumulation, one must know if a drug is eliminated slowly or rapidly, stop the drug administration at the appearance of the first warning symptoms, and carefully select the form in which the drug is to be administered.
• It is also important to check liver and kidney function before and during drug administration, as even an otherwise non-cumulative drug would produce cumulation in the presence of hepatic and renal damage.

Drug Tolerance

• Drug tolerance occurs when an unusually large dose of a drug is required to elicit an effect ordinarily produced by the normal therapeutic dose of the drug.
• Tachyphylaxis is a rapid development of tolerance on repeated administration, e.g., ephedrine, amphetamine, and nitroglycerine.

Emotional Factors

• Emotional factors, such as placebo response, can influence the effect of a drug.
• Placebo is a tablet that looks exactly like the active treatment but contains no active component, and it is originally used to please the patient when no specific treatment was available.

Cholinergic System

• Acetylcholine is synthesized inside the cytoplasm of nerve fibers from acetyl coenzyme A and choline through the catalytic action of the enzyme choline acetyltransferase.
• Once synthesized, it is transported from the cytoplasm into the vesicles to be stored, and when the action potential reaches the terminal and the latter undergoes stimulation, acetylcholine is released to the synaptic cleft.
• After release from the presynaptic terminal, the molecule binds to and activates an acetylcholine receptor (cholinergic receptor) located on the effector cell.
• Finally, it is hydrolyzed into choline and acetate by acetylcholinesterase enzyme, and thereby the action of the transmitter is terminated.
• Cholinergic receptors are classified into muscarinic and nicotinic cholinergic receptors.
• The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic, whereas the responses in parasympathetic and sympathetic ganglia, as well as responses of skeletal muscle, are nicotinic.

Cholinergic Drugs

• Carbachol is a cholinergic drug that is completely absorbed from the gastrointestinal tract and is stable towards hydrolysis by cholinesterase enzyme.
• It can be given both orally and parenterally with almost similar dosage.
• It has similar actions to those of acetylcholine, with pronounced effects on the gastrointestinal tract and the urinary bladder.
• Indications for carbachol include glaucoma, retention of urine (postoperative), and paralytic ileus.

Anticholinesterase Drugs

• The commonly used cholinesterase inhibitors fall into three chemical groups: simple alcohols bearing quaternary amines, carbamate and related quaternary or tertiary amines, and organic derivatives of phosphates.
• Physostigmine is a cholinesterase inhibitor that is completely absorbed from the gastrointestinal tract and is highly distributed throughout the body.
• It can pass the blood-brain barrier and inhibit the enzyme cholinesterase, increasing and prolonging the effect of endogenous acetylcholine at different sites.
• Indications for physostigmine include glaucoma and atropine overdose.
• Neostigmine is a cholinesterase inhibitor that is poorly absorbed from the gastrointestinal tract and is poorly distributed throughout the body.
• It cannot pass the blood-brain barrier and has a direct nicotinic action on skeletal muscles.
• Indications for neostigmine include myasthenia gravis, paralytic ileus, reversal of the effect of muscle relaxants, and postoperative urine retention.