Introduction to Pharmacology

Basics of Pharmacology

• Pharmacology involves the study of drugs and their interactions with biological systems through regulatory molecules to produce responses.
• A drug is a substance that modifies biological function through its action at the molecular level, helping to prevent and treat diseases.
• The primary branches of pharmacology are pharmacokinetics, pharmacodynamics, pharmacotherapeutics, and toxicology.

Sources of Drugs

• Drugs can be sourced from plants, animals, microorganisms, and minerals.
• Drugs can also be synthetically created or derived from genetic engineering.
• Examples of drug sources include Digoxin, Heparin, Penicillin-G, Ferrous sulphate, Aspirin and Growth hormone.

Drug Nomenclature

• Drugs have different types of names: chemical, non-proprietary/generic, and proprietary/brand/trade.
• An example of a drug and it's associated names:
  • Chemical: N-acetyl-para-aminophenol
  • Non-proprietary/generic: Acetaminophen (paracetamol)
  • Proprietary/brand/trade: Panadol®, Tylenol®, Panadrex®, Paramol®

Routes of Drug Administration

• Enteral routes include oral, rectal, and sublingual/buccal administration.
• Parenteral routes include intravenous (IV), intramuscular (IV), and subcutaneous (SC) administration.
• Other routes of administration: topical, inhalational, and transdermal
• Dosage forms for drug admission should be designed appropriately.

Dosage Forms

• Common dosage forms include tablets, capsules, and suppositories.
• Other dosage forms: oral solutions, injectables, transdermal patches, inhalers, and lotions and creams.

Drug Administration Routes: Advantages vs. Limitations

• Oral:
  • Advantages: easy, convenient, generally safer, and economical.
  • Limitations: slow absorption, potential for vomiting, and subject to the first-pass effect, limiting bioavailability.
• Sublingual:
  • Advantages: rapid absorption; bypasses portal circulation.
  • Limitations: may not be applicable for all drugs.
• Rectal:
  • Advantages: suited for pediatric use; partly avoids the first-pass effect.
  • Limitations: inconsistent absorption rates
• IV:
  • Advantages: suitable for emergency cases; maximizes bioavailability; avoids the first-pass effect.
  • Limitations: requires trained personnel; challenges in reversing effects.
• IM & SC
  • Advantages: For drugs with low oral bioavailability and relatively rapid effects.
  • Limitations: Site pain, potential hypersensitivity and irritating drugs.
• Inhalational:
  • Advantages: rapid absorption; allows for local use
  • Limitations: The effectiveness can be affected by inhaler technique, and also affects bioavailability.
• Topical:
  • Advantages: easy, non-invasive, avoids the first-pass effect, patient acceptance.
  • Limitations: slows absorption

Pharmacokinetics

• Pharmacokinetics describes the effect the body has on a drug.
• Key processes of pharmacokinetics are absorption, distribution, metabolism, and excretion (ADME).
• Knowledge of pharmacokinetics is essential to optimize drug administration.

Plasma Concentration-Time Curve

• The plasma concentration-time curve illustrates drug concentration in the plasma over time after a single oral dose.
• Key parameters:
  • MEC (Minimum Effective Concentration)
  • MTC (Minimum Toxic Concentration).
• The therapeutic window lies between the MEC and MTC.

Drug Absorption

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

Passive Diffusion

• Passive diffusion involves molecules spontaneously diffusing along a concentration gradient.
• Net transfer occurs from an area of high concentration to low concentration.
• The driving force is the drug concentration gradient across the membrane.
• Explained using Fick's law of diffusion.

Fick's Law of Diffusion

• Fick's Law Equation: dQ/dt = (DAK/h) * (CGI - Cp)
  • 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 of the drug.
  • CGI - Cp is the drug concentration difference between the GIT and the plasma.

Permeability Coefficient

• Permeability coefficient (P) combines D, A, K, and h as a constant under usual absorption conditions: P = DAK/h
• The relationship between drug concentration at the absorption site and time is expressed as dQ/dt = P(CGI).
• The relationship is an expression for a first-order process

Carrier-Mediated Transport

• Carrier proteins are involved at the intestinal brush border & basolateral membrane. Facilitated diffusion occurs along a concentration gradient.
• Active transport occurs against a concentration gradient and requires energy.
• Selective, saturable, and subject to competitive inhibition.

Vesicular Transport

• Endocytosis: cell membrane folds inward to take in substances bound to its surface receptors.
  • Pinocytosis involves engulfing of extracellular fluid by cells (cell-drinking).
  • Phagocytosis engulfs large molecules by the cell membrane.
• Exocytosis: process of moving substances out of the cell.

Important Transporters

• Different transporters carry different drugs in the intestine.
• Ex:
  • Amino acid transporter: Methyldopa, levodopa, gabapentin
  • Peptide transporter: Cephalexin, cefixime, captopril
  • P-glycoprotein efflux: Etoposide, verapamil, terfenadine

Factors Influencing GI Absorption

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

pH and Pka

• The extent of ionization influences rate of transport for drugs that are weak acids or bases.
• This influence depends on the dissociation constant (Ka) of the drug, and the pH of the absorption medium.
• Absorption is determined by if the drug exists in its unionized (lipid soluble) form at the absorption site.

pH and Calculations

• Henderson-Hasselbalch equation applies to weak acids and bases:
  • pKa = pH + log([Protonated]/[Non - protonated]).
• 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.
• F = Quantity of drug reaching systemic circulation / Quantity of drug administered, where 0 < F ≤ 1
• Factors affecting bioavailability include the extent of absorption (f) and first-pass elimination (expressed by extraction ratio ER).
• BA = F = f(1-ER)

Bioequivalence

• Drug products (DPs) with the same active ingredients, identical strength/concentration, and same dosage form is considered pharmaceutically equivalent.
• Pharmaceutically equivalent DPs are considered bioequivalent when the bioavailability of the active ingredient in the DPs is not significantly different under identical test conditions.

Drug Distribution

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

Volume of Distribution (Vd)

• Volume of distribution is a measure of the apparent space in the body available to contain the drug.
• Determined by the amount of drug present and the drug concentration in systemic circulation.
• Equation: Vd = Amount of drug in the body / Plasma drug concentration
• There is a relationship between Vd and PPB.

Drug Distribution Examples

• Confined within blood - High PPB: warfarin, 5L confined
• ECF - large water soluble drugs exhibit this (14L) - Gentamycin
• Distributed throughout all body water
  • 42L -Small water-soluble drugs exhibit this = Ethanol, Li+
• Beyond total body water = highly tissue-bound drugs - choloroquine or highly lipophilic (42L +)

Drug Metabolism

• Main sites of drug metabolism are the liver, intestine, and plasma.
• Phase I reactions (Functionalization): oxidation, reduction, or hydrolysis.
  • These reactions are primarily mediated by cytochrome P450 (CYP) enzymes.
• Phase II reactions (Conjugation): involves glucuronidation, sulfation, acetylation, methylation, or glycine/glutathione conjugation.

Phase I

• Oxidation, P450 dependent:
  • Hydroxylation: Amphetamines, barbiturates, ibuprofen, phenytoin, propranolol, warfarin.
  • N-dealkylation: Caffeine, morphine, theophylline.
  • O-dealkylation: Codeine.
• Oxidation, P450 independent:
  • Amine oxidation: Epinephrine.
  • Dehydrogenation: Chloral hydrate, ethanol. Hydrolyses
  • Esters -- Aspirin, clofibrate, procaine, succinylcholine.

Phase II

• Glucuronidation -- Acetaminophen, diazepam, digoxin, morphine, sulfamethiazole.
• Acetylation -- Clonazepam, dapsone, isoniazid,mescaline, sulfonamides.

Drug Metabolism Outcomes

• Drug metabolism can result in inactivation or activation (prodrugs).
• Enzyme induction/inhibition can significantly impact biological activity of drugs.

Factors Affecting Drug Metabolism

• Individual variation: age, sex, alcohol use, nutrition, or smoking habits.
• Route of drug administration (first-pass effect)
• Genetics influences drug metabolism, e.g., with N-acetyltransferase 2 (NAT2) and Isoniazid.
• Drug-drug/drug-food interactions.
• Disease state.

Drug Excretion

• Major route: kidneys, lungs, hepatobiliary system, secretions.
• Net excretion depends on: glomerular filtration rate (GFR), tubular reabsorption, and tubular secretion.

Drug Excretion in relation to PH

• Weak acids, eg. aspirin/salicylates.

  • Treatment: Trapped in basic environment.
    • Treat overdose with sodium bicarbonate to alkalinize urine

• Weak bases, eg amphetamines, Trapped in acidic environment.

  • Treat overdose with ammonium chloride to acidify urine

Elimination Order

• First-order elimination:
  • Rate of elimination is proportional to drug concentration.
  • Constant fraction eliminated.
  • Plasma concentration decreases exponentially.
  • Applies to most drugs.
• Zero-order elimination:
  • Rate of elimination is constant.
  • Constant amount eliminated.
  • Plasma concentration decreases linearly.
  • Examples: phenytoin, aspirin, ethanol.

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= k Va

Elimination Half-Life

• Elimination half-life (t1/2) occurs when the drug amount/concentration falls by half.
• Equation: t1/2 = 0.693/k = (0.693 × Vd)/CL.
• Determines % of drugs remaining in body, and helps reach steady state.

Steady State

• A steady state (SS) occurs when repeated equal doses of any drug (Css) at constant intervals are administered.
• At SS, the rate of drug administered will equal elimination, i.e., dCp/dt = 0.
• Plasma drug concentration 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

• To achieve the desired blood level rapidly (if it takes long to attain or in case of emergency), a loading dose (D₁) may be used.
• Equation: Loading dose = (Vd × Desired plasma concentration)/Bioavailability
• For a drug given by an IV infusion, D₁ = R/k (R: infusion rate, k: elimination rate constant).

Summary of Understanding Pharmacokinetics

• Understanding pharmacokinetic (PK) processes enables choosing the appropriate route of drug administration.
• Accurately determine the dosage regimen, prevent or minimize possible drug interactions at ADME level and optimize drug administration and clinical outcome.