Pharmacology: Intro, Sources, Nomenclature, Routes

Introduction to Pharmacology

• Pharmacology deals with drugs and their interactions with biological systems via regulatory molecules, resulting in responses.
• A drug is a substance that modifies biological function through molecular action and helps prevent and treat diseases.
• Pharmacology branches include pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology.

Sources of Drugs:

• Drugs can be derived from plants, animals, microorganisms, minerals, synthetic processes, and genetic engineering.
• Examples include Digoxin, Heparin, Penicillin-G, Ferrous sulphate, Aspirin, and Growth hormone.

Drug Nomenclature

• Chemical name: Based on the drug's chemical structure (e.g., N-acetyl-para-aminophenol for acetaminophen).
• Non-proprietary/generic name: Acetaminophen (paracetamol).
• Proprietary/brand/trade name: Varies, for example, Panadol®, Tylenol®, Panadrex®, Paramol®

Routes of Drug Administration

• Enteral: Includes oral, rectal, sublingual, and buccal routes.
• Parenteral: Involves intravenous (IV), intramuscular (IM), and subcutaneous (SC) injections.
• Other routes: Topical, inhalational, transdermal.
• The dosage form of a drug should be appropriate for its administration route.

Routes of drug administration

• Oral Route: easy, convenient, usually safer, economical but also has a slow absorption, it subject to first pass effect (FPE) that limits the bioavailability(BA).
• Sublingual Route: fast, bypasses portal circulation , but isn't applicable for all drugs
• Rectal Route: suits for pediatric use, partly avoids FPE, but has an inconsistent absorption
• IV Route: use in emergency cases, max BA, avoids FPE, for drugs w/ poor oral absorbtion, but requires technical person, has challenge to reverse and hypersensitivity reactions.
• IM & SC Route: Suitable for drugs w/ low oral BA. The injection site has pain, hypersensitivity and irritant drugs
• Inhalational Route: rapid absorption, with affect of inhaler technique on BA
• Topical Route: easy, non-invasive, lack FPE, but with slow absorption

Pharmacokinetics (PK)

• Pharmacokinetics studies the body's effect on a drug.
• PK processes include Absorption, Distribution, Metabolism, and Excretion (ADME).
• PK knowledge is essential for optimizing drug administration.

Plasma concentration-time curve terminology

• MEC (Minimum Effective Concentration)
• MTC (Minimum Toxic Concentration)

Drug Absorption

• Drug absorption is the movement from the administration site into systemic circulation.
• Transport mechanisms across membranes: aqueous diffusion, passive/lipid diffusion, carrier-mediated transport, vesicular transport.

Passive Diffusion

• Molecules spontaneously diffuse along the concentration gradient from high to low.
• The driving force is the drug concentration gradient across the membrane.
• Fick's Law of Diffusion explains this process.
• Rate of diffusion (dQ/dt) is proportional to the surface area (A) and concentration difference, and inversely proportional to thickness (h).

Fick's Law of Diffusion Equation variables

• D is the diffusion coefficient.
• K is the lipid-to-water partition coefficient.
• CGI - Cp is the drug concentration difference between the GI tract and plasma.

Carrier-Mediated Transport

• Carrier proteins are at the intestinal brush border & basolateral memb.
• Includes facilitated diffusion that follows conc. gradient
• Includes active transport using energy, against the conc. gradient
• Selective, saturable, competitive inhibition exists

Intestine transporters

• Amino acid transporter: Methyldopa, levodopa, gabapentin
• Nucleoside transporter: Flurouracil
• Peptide transporter: Cephalexin, cefixime, captopril
• Phosphate transporter: Foscarnet
• Monocarboxylic acid transporter: Salicylic acid, pravastatin
• P-glycoprotein efflux: Etoposide, verapamil, terfenadine

Vesicular Transport

• Endocytosis: Cell membrane folds inward to take in substances bound to its surface receptors.
• Pinocytosis: Engulfing of ECF by cells, "cell-drinking".
• Phagocytosis: Large molecules are engulfed by cell membrane.
• Exocytosis: Process of moving substances out of the cell

Factors Influencing GI Absorption

• Physicochemical properties: Lipophilicity, ionization, particle size, solubility, concentration.
• Anatomy & physiology of absorption site: pH, surface area, gastric emptying time, blood flow, transit time.
• Drug product: Dosage form, route of administration, manufacturing procedures.
• Presence of food/other drugs: Interactions, pH change, gastric emptying.

Effect of pH and pKa

• For weak acids or bases, the extent of ionization influences their transport.
• Ionization depends on the drug's dissociation constant (Ka) and the medium's pH.
• Absorption depends on the drug's existence in its unionized (lipid-soluble) form at the absorption site.

Henderson-Hasselbalch equation

• pKa = pH + log ([Protonated]/[Non - protonated])
• Influence of pH on the distribution of a weak acid between plasma and gastric juice

Bioavailability (BA)

• BA = AUCoral/AUCıv, is the fraction of the drug that reaches the systemic circulation.
• F = Quantity of drug reaching systemic circulation / Quantity of drug administered. 0 < F≤1
• Factors affecting bioavailability include extent of absorption (f) and first-pass elimination. BA = F = f(1-ER), where ER is the extraction ratio.

Bioequivalence

• Drug products are pharmaceutical equivalents that must have same ingredient, strength/conc, and dosage.
• Pharmaceutically equivalent DPs are bioequivalent when the bioavailability of the active ingredient in the DCs are not significantly different.

Drug Distribution

• Drug distribution is the movement from systemic circulation into tissues.
• Factors affecting drug distribution include:
• Physicochemical properties (lipid solubility, molecular weight, pKa).
• Plasma protein binding (PPB): albumin (acidic drugs), α1 - acid glycoprotein (basic drugs)
• Presence of barriers -Tissue uptake and blood flow rate

Volume of Distribution (Vd)

• Apparent space in the body available to contain the drug.
• Vd = Amount of drug in the body / Plasma drug concentration
• There is a relationship between Vd and PPB.
• Confined to blood compartment (~5L) with higher PPB is Warfarin.
• Distribution in the ECF (~14L) of a large water soluble is Gentamycin. -Throughout the body water (~42L) of small water soluble drug is ethanol, Li+. -Beyond TBW (>42L), the drug extensively binds to tissue proteins with chloroquine, digoxin, or highly lipid soluble.

Drug Metabolism

• The main site: liver, intestine, plasma
• Phase I [Functionalization]: -Cytochrome P450 (CYP) enzymes catalyze oxidation, reduction, and hydrolysis.
• Generates reactive functional groups [hydroxyl, thiol, amine...]
• Phase II [Conjugation] -Glucuronidation, sulfation, acetylation, methylation, glycine or glutathione conjugation

Drug metabolism, the fraction of used drugs metabolized by phases I & II

• CYP: cytochrome P450;
• DPYD: dihydropyrimidine dehydrogenase
• GST: glutathione-S-transferase;
• NAT: N-acetyltransferase
• SULT: sulfotransferase
• TPMT: thiopurine methyltransferase
• UGT: uridine diphosphate-glucuronosyltransferase

Drug metabolism

• Phase 1 includes oxidation, Hydroxylation, Dealkylation, Deamination, Hydrolysis
• Phase 2 includes Conjugation

Consequences and enzymes

• Biol. activity: inactivation or activation (pro-drug)
• Enzyme induction/inhibition: impact on biological activity

Factors Affecting Drug Metabolism

• Individual variation: age, sex, alcohol use, nutrition, smoking.
• Route of drug administration is the first pass effect.
• Genetics: N-acetyltransferase 2 (NAT2) Vs Isoniazid with risk of peripheral neuropathy.
• Drug-drug/drug-food interactions
• Disease state

Drug Excretion

• Major route: kidneys, can also use lungs, hepatobiliary, secretions.
• Net excretion depends on:
• Glomerular filtration rate (GFR)
• Tubular reabsorption
• Tubular secretion

Glomerular Function

• 1. Filtration
• 2. Reabsorption
• 3. Secretion
• 4. Excretion

Drug Excretion

• Trapping of a weak base in urine as the urine is more acidic than the blood
• Henderson-Hasselbalch principle applied to drug excretion in the urine
• Weak acids, e.g. aspirin/salicylates (treated with sodium bicarbonate).
• Weak bases, e.g. amphetamines (treated with ammonium chloride).

Order of Elimination

• First-order: rate of elimination drug conc, constant fraction eliminated, exponential plasma conc. applies to most drugs
• Zero-order: rate of elimination is constant, constant amount eliminated, linear plasma conc, examples are phenytoin, aspirin, ethanol.

Drug Clearance (CL)

• Clearance is a measure of the body's efficiency in eliminating a drug.
• 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 (t1/2)

• t1/2 is the time required for the drug amount or concentration to fall by 50%.
• t1/2 = 0.693 / k = 0.693 × Vd / CL
• Helps determine the percentage of the drug remaining in the body.

Steady-State (SS)

• SS is reached when the dose frequency is constant.
• Rate of drug entering = rate of drug leaving.
• Clinically, drug activity is observed when concentration is close to the desired plasma concentration.

Steady-State figures

• Drug activity is observed when its conc. is close to desired plasma drug conc., like with Digoxin 1-2 ng/mL
• CSS is assumed to have achieved after about 4-5 half-lives
• Plasma drug conc. will be about 75% of the Css (at 2t1/2), 90% of the Css (at 3.32t1/2), and 95% of the Css (at 4.32t1/2)

Loading Dose

• It is used to achieve the desired blood level rapidly
• Loading dose = (Vd x Desired plasma concentration) / Bioavailability For an IV infusion, D₁ = R/k, where R is the infusion rate, and k is the elimination rate constant.