Key Factors in Drug Absorption and Pharmacokinetics

Factors Influencing Drug Absorption

A) Factors Related to the Drug

a) Drug Properties

• Degree of Ionization: Highly ionized drugs are poorly absorbed.
• Lipid Solubility: High lipid-water partition coefficients increase absorption.
• Valency: Ferrous salts are absorbed more than ferric; Vitamin C increases iron absorption.
• Molecular Weight (MW): Low MW drugs have a faster rate of absorption; high MW drugs have a slower rate. Adding procaine to penicillin increases MW, decreases the rate of absorption, and prolongs action.

b) Pharmaceutical Form

Solutions are absorbed better than suspensions or tablets.

B) Factors Related to the Patient

• Route of Administration: Absorption from mucous membranes is very rapid from alveolar mucosa, less from sublingual, small intestinal, and rectal mucosa, and poor from gastric mucosa. I.M. absorption is greater than S.C.
• Area and Vascularity of Absorption Surface: Absorption is directly proportional to area and vascularity.
• State of Absorption Surface: Atrophic gastritis and malabsorption syndromes decrease the rate of drug absorption.
• Blood Flow: In shock, peripheral circulation is reduced, necessitating the I.V. route.
• Specific Factors and GIT Content: Intrinsic factor of the stomach is essential for Vitamin B12 absorption from the lower ileum; tetracyclines decrease Ca++ absorption through chelation.
• GIT Motility and Rate of Dissolution: Decreased gastric emptying increases the rate of absorption for slowly dissolving drugs (e.g., digoxin) and decreases it for rapidly dissolving ones (e.g., paracetamol). Metoclopramide increases gastric emptying, thereby decreasing digoxin absorption and increasing paracetamol absorption.

Significance of Plasma Protein Binding

1. Drug absorption by maintaining a concentration gradient towards plasma.
2. Drug distribution.
3. Drug elimination and duration of action.
4. Drug activity and toxicity.
5. Drug Interactions: Two drugs with affinity may compete, leading to interactions. For example, salicylates displace warfarin and oral hypoglycemics from plasma proteins.

Phases of Biotransformation

Phase I (Non-synthetic) Reactions

Includes oxidation, reduction, and hydrolysis to convert drugs into polar metabolites that are easily excreted or further conjugated in Phase II.

Results:

• Drug inactivation (most drugs).
• Conversion of inactive to active metabolite (e.g., cortisone to cortisol).
• Conversion of active to active metabolite (e.g., phenacetin to paracetamol).

Phase II (Synthetic) Reactions

Involves the addition of natural endogenous polar substances to a drug or metabolite (conjugation) to form inactive, water-soluble metabolites (e.g., glucuronidation, acetylation, methylation).

Result: Drug inactivation. Drugs may pass through Phase I only, Phase II only, or Phase I then Phase II (e.g., isoniazid passes first to Phase II, then Phase I).

Treatment of Organophosphorus Compounds

1. Atropine: Administered I.V. or I.M. every 10 minutes until pupils dilate and skin dries; antagonizes muscarinic effects (central and peripheral).
2. Cholinesterase Reactivators (Oximes): Includes pralidoxime (PAM), which does not pass the CNS, and diacetylmonoxime (DAM) via I.V. infusion. These combine with the poison in the blood and dephosphorylate the enzyme if given early (before enzyme aging); they reverse muscle weakness and are used with atropine.
3. Anticonvulsants: Such as diazepam, barbiturates, or MgSO4 injection.
4. Decontamination: Remove contaminated clothing, wash skin and mucous membranes with NaHCO3, and perform stomach washes if ingested orally.
5. Respiratory Support: Manage respiration via artificial ventilation and suctioning of secretions.