Pharmacology: Basics, Branches & Nomenclature

Pharmacology Basics

• Pharmacology involves the study of drugs and their interactions with biological systems through regulatory molecules, resulting in specific responses.
• A drug is defined as a substance that modifies a biological function by acting at a molecular level, thereby preventing and treating diseases

Branches of Pharmacology

• Pharmacokinetics is the study of what the body does to the drug.
• Pharmacodynamics is the study of what the drug does to the body.
• Pharmacotherapeutics is the use of drugs in to treat illness.
• Toxicology studies the adverse effects of drugs.

Sources and Nomenclature of Drugs

• Drugs are derived from various sources including plants, animals, microorganisms, minerals, and can be produced synthetically or through genetic engineering.
• Drug nomenclature includes chemical names, non-proprietary/generic names (e.g., Acetaminophen/paracetamol), and proprietary/brand/trade names (e.g., Panadol, Tylenol).

Routes of Drug Administration

• Enteral routes include oral, rectal, and sublingual/buccal administration.
• Parenteral routes involve intravenous (IV), intramuscular (IM), and subcutaneous (SC) injections.
• Other routes are topical, inhalational, and transdermal.
• Dosage forms are designed based on the route of administration

Advantages and Limitations of Different Administration Routes

• The oral route is convenient and economical, but absorption might be slow, subject to vomiting, and affected by the first-pass effect (FPE), limiting bioavailability (BA).
• Sublingual administration bypasses portal circulation, leading to faster absorption but may not be suited for all drugs.
• Rectal administration is useful in pediatrics and partly avoids FPE, but may cause inconsistent absorption.
• Intravenous (IV) administration offers maximum bioavailability and avoids FPE.
• Intramuscular (IM) and subcutaneous (SC) routes are useful for drugs with low oral bioavailability
• Topical route provides non-invasive, local or transdermal action while avoiding the first-pass effect.

Pharmacokinetics (PK)

• Pharmacokinetics (PK) describes the effect of the body on the drug and includes the processes of Absorption, Distribution, Metabolism, and Excretion (ADME).
• PK knowledge is vital for optimizing drug administration.

Drug Absorption

• Drug absorption involves the movement of a drug from the administration site into the systemic circulation.
• Transport mechanisms across the membrane include aqueous diffusion, passive/lipid diffusion, carrier-mediated transport, and vesicular transport.

Passive Diffusion

• Molecules spontaneously diffuse along the concentration gradient from high to low concentration areas.
• The driving force is the concentration gradient of the drug across the membrane and is best explained by Fick's Law of Diffusion.

Fick's Law of Diffusion

• dQ/dt = (DAK/h) * (CGI - Cp), where dQ/dt is the rate of diffusion, A is the surface area, h is the thickness, D is the diffusion coefficient, K is the lipid-to-water partition coefficient, and CGI - Cp is the drug concentration difference between the GI tract and plasma.
• The relationship is an expression for a first-order process.

Carrier-Mediated Transport

• Involves carrier proteins at the intestinal brush border and basolateral membrane.
• Facilitated diffusion occurs along the concentration gradient.
• Active transport occurs against the concentration gradient and is energy-consuming.

Examples of Intestine Transporters

• Amino acid transporters transport Methyldopa, levodopa, gabapentin.
• Nucleoside transporters facilitate the transport of Flurouracil.
• Peptide transporters transport Cephalexin, cefixime, captopril.
• Phosphate transporters transport Foscarnet.
• Monocarboxylic acid transporters transport Salicylic acid and pravastatin.
• P-glycoprotein efflux transporters transport Etoposide, verapamil, and terfenadine.

Vesicular Transport

• Endocytosis involves the cell membrane folding inward to take in substances bound to surface receptors, including pinocytosis ("cell-drinking") and phagocytosis.
• Exocytosis involves the process of moving substances out of the cell.

Factors Influencing GI Absorption

• Physicochemical properties such as lipophilicity, degree of ionization, particle size/mwt, solubility, and concentration.
• Anatomy and physiology of the absorption site, including pH, surface area, gastric emptying time, blood flow, and transit time (gut motility).
• Nature of the drug product (formulation factors), including dosage form, route of administration, and manufacturing procedures.
• Presence of food/other drugs (interaction, pH change, gastric emptying).

Effect of pH and pKa

• The extent of ionization influences the rate of drug transport, which is dependent on the dissociation constant (Ka) of the drug and the pH of the absorption medium.
• Absorption is determined by the extent to which the drug exists in its unionized (lipid soluble) form at the absorption site.

Henderson-Hasselbalch Equation

• For weak acids: pKa = pH + log([HA]/[A-])
• For weak bases: pKa = pH + log([BH+]/[B])

Bioavailability (BA)

• Bioavailability is the fraction of the drug that reaches the systemic circulation and F = Quantity of drug reaching systemic circulation/Quantity of drug administered, where 0 < F ≤ 1.
• Factors include the extent of absorption (f) and first-pass elimination.

Bioequivalence

• Drug products (DPs) are considered pharmaceutical equivalents if they have the same active ingredients, identical strength/conc, and same dosage form.

Drug Distribution

• Drug distribution is the movement of a drug from the systemic circulation into the tissues. Factors affecting drug distribution:
• Physicochemical properties (lipid solubility, mwt, Pka, etc.).
• Plasma protein binding (PPB).
• Presence of barriers.
• Tissue uptake and rate of blood flow.

Volume of Distribution (Vd)

• Volume of distribution: Vd = Amount of drug in the body/Plasma drug concentration.
• Vd is a measure of apparent space in the body available to contain the drug
• Relationship exists between Vd and PPB.

Distribution Scenarios

• Confined to blood compartment (~5L): higher PPB (warfarin).
• Distribution in the ECF (~14L): large water soluble (gentamycin).
• Distribution throughout the body water (~42L): small water soluble drugs (ethanol, Li⁺).
• Distribution beyond TBW (> 42L): extensively bind to tissue proteins (chloroquine, digoxin), or highly lipid soluble.

Drug Metabolism

• Main site: liver, intestine, plasma.
• Phase I (Functionalization) involves cytochrome P450 (CYP) enzymes, which catalyze oxidation, reduction, and hydrolysis to generate reactive functional groups.
• Phase II (Conjugation) involves glucuronidation, sulfation, acetylation, methylation, and glycine or glutathione conjugation.

Enzymes Involved in Drug Metabolism

• CYP enzymes, DPYD (dihydropyrimidine dehydrogenase), GST (glutathione-S-transferase), NAT (N-acetyltransferase), SULT (sulfotransferase), TPMT (thiopurine methyltransferase), and UGT (uridine diphosphate-glucuronosyltransferase).

Consequences and Factors

• Drug metabolism can result in either inactivation or activation (pro-drug) of the drug.
• Enzyme induction/inhibition and Individual variations also effect drug metabolism.

Individual Variations

Variations are based of:

• Age
• Sex
• Alcohol use
• Nutrition
• Smoking
• Drug-drug/drug-food interactions
• Disease state Route of drug administration (first pass effect) and genetics.

Drug Excretion

• Major route: Kidneys, Lungs, Hepatobiliary secretions
• Net excretion depends on glomerular filtration rate (GFR), tubular reabsorption, and tubular secretion.

Urine pH and Drug Excretion

• Trapping for a weak base in urine occurs when the urine is more acidic than the blood.
• Henderson-Hasselbalch principle applied to drug excretion in the urine.

Manipulation of Urine pH

• Weak acids (e.g., aspirin/salicylates) trapped in a basic environment.
• Overdose is treated with sodium bicarbonate to alkalinize urine.
• Weak bases (e.g., amphetamines) are trapped in an acidic environment.

Order of Elimination

• First-order elimination rate is proportional to drug concentration; constant fraction eliminated; plasma concentration decreases exponentially; applies to most drugs.
• Zero-order elimination rate is constant, constant amount eliminated; plasma concentration decreases linearly.
• Plasma concentration decreases linearly.

Drug Clearance

• Clearance (CL) is a measure of the body's efficiency in eliminating drug from the systemic circulation.
• CL = Rate of elimination of drug/Plasma drug concentration
• CL = k Vd, where k is the elimination rate constant and Vd is the volume of distribution.

Elimination Half-Life

• Elimination half-life (t1/2) is the time required for the amount or concentration of the drug in the body to fall by 50%, t1/2 = 0.693/k.
• It helps determine the percentage of drug remaining in the body and the time to reach steady-state plasma concentration.

Steady-State

• Steady-State occurs when repeated equal doses are given at constant frequency, achieving a steady-state drug concentration (Css).
• At SS, the rate of drug entering (input) equals the rate of drug leaving (output = elimination rate), i.e., dCp/dt = 0

Clinical Applications of Steady-State

• Clinically, drug activity is observed when its concentration is close to the desired (target) plasma drug concentration (e.g., Digoxin 1-2 ng/mL).
• Css is assumed to be achieved after about 4-5 half-lives.

Loading Dose

• To achieve the desired blood level rapidly (if it takes long to attain, or in case of emergency), a loading dose (DL) may be used.
• Loading dose (D₁) = (Vd x Desired plasma concentration)/Bioavailability

Overall Summary

• Understanding pharmacokinetic (PK) processes enables choosing the appropriate route of drug administration, accurately determining the dosage regimen, and avoiding or minimizing possible drug interactions at the ADME level.
• Knowledge of PK processes helps optimize drug administration to achieve the desired clinical outcomes.