Pharmacology: Metabolism, SAR, and Drug Classification

Posted on Jun 19, 2026 in Biotechnology

Drug Metabolism

Drug metabolism is a biochemical process that converts drugs into metabolites by altering their solubility or toxicity. This biotransformation aims to convert lipid-soluble drugs into water-soluble, polar metabolites to avoid reabsorption in renal tubules and facilitate excretion. While most drugs are lipid-soluble and undergo metabolism, some hydrophilic drugs are excreted unchanged.

Metabolic Phases

  • Phase 1: Oxidation, hydrolysis, and reduction reactions increase drug polarity.
  • Phase 2: Conjugation reactions (synthetic) involve endogenous substances like glucuronic acid, sulfate, or glycine to facilitate excretion.

Primary Sites and Enzymes

The liver is the primary site for drug metabolism, followed by the kidneys, intestines, lungs, and plasma. Microsomal enzymes, such as cytochrome P450 oxidase and glucuronyl transferase, located in the smooth endoplasmic reticulum, are responsible for most biotransformations.

Factors Affecting Metabolism

  • Enzyme Induction: Increased metabolic ability due to higher liver size, blood flow, or enzyme stability.
  • Enzyme Inhibition: Decreased metabolic ability due to direct interaction or reduced enzyme synthesis.
  • Biological Factors: Age, diet (e.g., high protein), sex, and stereochemical aspects.

Beta-Blockers

Beta-blockers antagonize the effects of drugs acting on beta-receptors and are primarily used as antihypertensive agents.

  • B1-Selective: Atenolol, betaxolol, bisoprolol, esmolol, metoprolol.
  • B2/Non-selective: Propranolol, nadolol, labetalol, carvedilol.

Structure-Activity Relationship (SAR)

  • Alkenyl group: Presence at the ortho position on the phenyl ring provides beta-antagonist activity.
  • Carbon chain: The -OCH2 group is essential for activity; if replaced by an aromatic ring, it forms arylethanolamines.
  • Amino group: Isopropyl and butyl groups increase nucleophilicity and activity.

Sympathomimetic Agents

These agents mimic the sympathetic nervous system. SAR of norepinephrine includes:

  • Aromatic ring: OH groups at the 3,4-position provide maximum alpha/beta activity.
  • Beta-carbon: OH groups decrease CNS activity but increase alpha/beta activity.
  • Alpha-carbon: Substitution blocks MAO metabolism, increasing the duration of action.

Physicochemical Properties and ADME

Key factors include ionization (Henderson-Hasselbalch equation), absorption, distribution, solubility, partition coefficient, and protein binding. Other concepts include chelation, bioisosterism, and stereochemistry (optical and geometrical isomerism).

Antiepileptic and Antipsychotic Drugs

Antiepileptics

Used to prevent seizures by inhibiting excitatory signals, enhancing inhibitory signals, or interfering with ion channels. Types include generalized and focal epilepsy.

Sedatives and Hypnotics

Used to reduce mental excitement and induce sleep. Classes include benzodiazepines and barbiturates, which act primarily via GABA receptors.

Antipsychotics

Used to treat psychosis by competitively binding to dopamine receptors to block excessive dopaminergic activity. Classes include phenothiazines, butyrophenones, thioxanthenes, and atypical antipsychotics” atypical antipsychotics.