Pharmacokinetics is “What The Body Does To The Drug”. Like how the drug is Absorbed, Distributed, Metabolized, and Excreted by the body. (Drug Disposition)

Absorption, Distribution, Metabolism, and Excretion in short ADME determine the,

• Onset (The length of time it takes for a medicine to start to work)
• Intensity (Plasma peak concentration)
• Duration of the drug action (The length of time that particular drug is effective)

Absorption

It is the process of entry of drug from site of administration into systemic circulation. The rate and efficiency of absorption depend on the route of administration.

The Bioavailability of the drug depends on the extent of the absorption.

Bioavailability: The term bioavailability means “the fraction of administered drug that reaches in the systemic circulation in a chemically unchanged form”.

Bioavailability of different routes of administration

The drugs transfer form site of administration by Filtration, Diffusion, Carrier Mediated Absorption, Phagocytosis, and Pinocytosis.

Filtration: Filtration means the passage of drugs through aqueous pores. For this, the drug;

• Size should be less than the pore size
• Has to be water soluble

For example: Glucose, Caffeine

Diffusion: In diffusion, the drug supposed to pass the membranes. A drug will undergo diffusion if;

• The drug is lipid soluble
• Has a high partition co-efficient &
• High absorption rate

For example: Cyclosporine and Chlorinated aromatics.

Carrier mediated absorption: They are two types: Facilitated Diffusion and Active transport.

Facilitated Diffusion

Active transport

• Use ATP & carrier proteins.
• Against to the concentration gradient.
  • For example: levodopa & methyldopa from the gut.

Phagocytosis & pinocytosis: Process by which large molecule are engulfed by the cell membrane forming a vesicle & releases them intracellularly.

For example: protein, toxin etc.

Factors affecting the absorption

pH of media & pKa of the drug:

• Ionized drugs are poorly absorbed while unionized drugs are lipid soluble and well absorbed.
• Acidic drugs remain unionized in acidic medium of the stomach and are rapidly absorbed.
  • Example: aspirin, barbiturates.

• Basic drugs are unionized when they reaches at the basic medium of intestine, from where they rapidly absorbed.
  • Example: pethidine, ephedrine.

Area of absorbing surface

• Larger area of the absorbing surface better for absorption.

Particle size of the drug

• Small particle size is better for the absorption of drug.

Formulation

• Inert substance used with drugs as diluents like starch and lactose may sometimes interfere with absorption.

Gut motility

• When motility is highly increased as in diarrhea, drug absorption is reduced.

GI Tract blood flow

• Blood flow increases the rate of absorption.

Gastric secretion

• If gastric emptying is faster, the passage of the drug to the intestines is quicker and hence absorption is faster.

Drug interaction

• Drug Interaction is a situation in which the effect of one drug is altered by prior or concomitant administration of another drug.
• It occurs when a drug interacts, or interferes, with another drug. This can alter the way one or both of the drugs act in the body, or cause unexpected side effects.

For Example:

1. Aspirin + Warfarin → Synergism (excessive bleeding)
2. Antibiotic + Blood thinner → Antagonism (less effect)
3. Decongestants + Antihypertensive → Potentiation (high blood pressure)
4. Codeine + Paracetamol → Addition (increased analgesic effect)
5. Clavulanic acid + Amoxicillin → Synergism (increased antibiotic effect)
6. NSAID + Cox 2 inhibitors → Synergism (increased bleeding)
7. SSRI’S + Vitamin K → Synergism (increased bleeding)
8. H2 blockers + PPI’S → Alteration (increase ph. of stomach)
9. Phenobarbital + Warfarin → Antagonism (less effect)
10. Erythromycin + Warfarin → Synergism ( increased bleeding)

Distribution

After a drug reaches the systemic circulation, it gets distributed to various tissues. It should be cross several barriers before reaching the site of action.

• Various factors determine the rate and extent of distribution, they are Plasma protein binding, Tissue binding, Barriers capillary permeability, Rate of blood flow, Plasma concentration.
• Unionized and lipid soluble drugs are widely distributed throughout the body.

Metabolism

Metabolism or biotransformation is the process of biochemical alteration of the drug in the body. This process converts the drugs into more polar, water soluble compounds so that they can be easily excreted.

• Liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines.
• The chemical reactions of biotransformation can take place in two phases:

1. Phase I (Non-synthetic reactions)
2. Phase II (Synthetic reactions)

Phase I (Non-synthetic reactions): It convert the drug to more polar metabolite by oxidation, reduction, or hydrolysis. If the metabolites are not enough water soluble it undergoes phase II reactions.

Phase II (Synthetic reaction): In this phase glucoronic acid, sulfuric acid or an amino acid combine with the drug to form a highly polar compound so that it can be excreted by the kidneys. Large molecules are excreted through the bile.

Inhibitor: An enzyme inhibitor is a molecule, which binds to enzymes and decreases their activity.

Inducer: An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme.

First Pass Effect: It is a process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via the portal vein to the liver, where they undergo extensive metabolism before reaching the systemic circulation. The first pass metabolism can be bypassed by giving the drug via intravenous routes.

Drug excretion

Elimination of drugs and its metabolites from body through urinary system is called excretion.

• Drugs eliminated from the body either unchanged or converted to metabolites by excretion. The rate of excretion influences the duration of action of drugs.
• The major routes of excretion include renal excretion, hepatobiliary excretion & pulmonary excretion.
• The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid & hair.
• If the drug is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period.

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