Pharmacokinetics Principles

• The lecture introduces the principles of pharmacokinetics, which is crucial for understanding drug behavior in the body.
• M. Kampamba, a Clinical Pharmacy Specialist at the University of Zambia, is the lecturer for the PGY 4210 course.

Learning Objectives

• Pharmacokinetics, its purpose, scope, and impact on drug therapy needs description
• Principle pharmacokinetic parameters are to be described
• Rate and extent of drug absorption, distribution, metabolism, and excretion must be quantified
• Factors affecting pharmacokinetic parameters have to be described
• Principles of pharmacokinetics must be applied to achieve clinical goals of drug therapy

Overview of Drug Transport

• Drugs undergo Absorption, Distribution, Metabolism, and Elimination (ADME) within the body.
• ADME involves drug movement between the blood stream, tissues, and sites of metabolism and excretion.

What is Pharmacokinetics?

• Quantitative study of ADME of drugs and their mathematical relationships was defined by Dots F.H. in 1953.
• Pharmacokinetics deals with the dynamics of ADME of drug molecules in the body.
• It forms the scientific basis for understanding the time course of drug action, drug dosing, and dosage adjustment.

Objectives

• ADME of drugs administered through a particular route, time, or formulation must be predicted
• Pharmacokinetic parameters of new drugs or formulations should be determined for optimal use
• New methods of investigating drugs or formulations should be evaluated, validated, and applied, including establishing guidelines for Bioavailability and Bioequivalence.

Pharmacokinetic Parameters

• Absorption corresponds to Bioavailability (F).
• Distribution corresponds to Volume of Distribution (Vd).
• Metabolism corresponds to Elimination rate / Clearance (Cl).
• Excretion corresponds to Total Body Clearance (Cl).

Drug Absorption

• Drug absorption is the movement of drug molecules from the administration site through biological barriers into the central compartment (blood stream), and the extent to which this occurs.

Mechanisms of Drug Absorption

• Simple diffusion (passive diffusion)
• Active transport
• Facilitated diffusion
• Pinocytosis (Endocytosis).

Simple or Passive Diffusion

• Water-soluble drugs (ionized or polar) are readily absorbed via aqueous channels or pores in the cell membrane.
• Lipid-soluble drugs (nonionized or nonpolar) are readily absorbed via the cell membrane itself.
• Simple diffusion is very common.
• It occurs along the concentration gradient, is non-selective, and is not saturable.
• Simple diffusion requires no energy or carrier, depends on lipid solubility, and depends on the pKa of the drug and the pH of the medium.
• Only the nonionized form of a drug is absorbable.
• The nonionized/ionized fraction is determined by pH and pKa based on the Henderson-Hasselbalch equation.

PKa and PH

• Pka of a drug is the pH at which half of a substance is ionized and half is unionized.
• pH of the medium affects the ionization of drugs.
• Weak acids are best absorbed in the stomach.
• Weak bases are best absorbed in the intestine.

Clinical significance of PH and PKA

• Weak acids such as Aspirin are mostly unionized in the acidic pH of the stomach and thus well absorbed from the gastric mucosa.
• Weak bases like Theophylline are absorbed from regions with alkaline pH, such as the ileum and duodenum.
• Renal elimination can be enhanced by changing urinary pH, which increases drug ionization and inhibits tubular reabsorption.
• Alkalinization of urine increases excretion of acidic drugs like salicylate in case of poisoning.
• Acidification of urine increases excretion of basic drugs like amphetamine in toxicity cases.

Active Transport

• It occurs against the concentration gradient.
• Active transport requires a carrier and energy.
• Active transport is specific and saturable.
• Examples include iron absorption and uptake of levodopa by the brain.

Carrier-Mediated Facilitated Diffusion

• Occurs along the concentration gradient.
• Requires carriers and is selective and saturable.
• It does not require energy.

Phagocytosis (Endocytosis & Exocytosis)

• Endocytosis is the uptake of membrane-bound particles.
• Exocytosis is the expulsion of membrane-bound particles.
• These processes are used for high molecular weight or highly lipid-insoluble drugs.

Drug Absorption Question Time

• Small intestine is where most of the absorption of an oral drug occurs
• 90% of drugs absorption is by passive diffusion

Routes of Drug Administration

• Parenteral routes: Intravenous (I.V), Intramuscular (I.M), Subcutaneous (S.C), Intrathecal (I.T), Intra-arterial (I.A).
• Enteral routes: Oral (P.O), Sublingual, Buccal, Rectal, Nasal.
• Other routes: Topical/Transdermal, Inhalation, Vaginal.
• Intravenous administration results in highest drug concentrations in blood, followed by intramuscular than subcutaneous

Enteral vs. Parenteral Routes

• Enteral route advantages: Most common method, safer, convenient, economical.
• Enteral route disadvantages: Absorption limited by dissolution, solubility, pathology, affecting enterohepatic circulation, GIT irritation, patient compliance is essential.
• Parenteral route advantages: More rapid, extensive and predictable bioavailability; accurate and effective dosing.
• Parenteral route disadvantages: Asepsis required, typically painful, cost and skill is needed, has stability concerns

Bioavailability

• It calculates unchanged drug released from formulation that reaches the systemic circulation and becomes available pharmacologically.
• It can be calculated by comparing the area under the plasma concentration-time curve after IV administration with that observed when the same dose is given by another rote.

Bioequivalence

• Two drug products are considered pharmaceutical equivalents with the same active ingredients (API), identical strength and concentration, dosage form, & Route of Administration.
• implies the rate and extent of bioavailability of API in the two products are not significantly different under suitable test conditions.
• Plasma Concentration-Time curves are valuable tools for determining fundamental pharmacokinetic parameters and predicting/comparing drug performance.

Factors Affecting Bioavailability

• Physicochemical properties of the drug such as molecular weight, lipophilicity, pKa, and stability in GIT contents.
• Formulation factors including disintegration time, dissolution rate, and excipient effects.
• Patient factors inclusive of pH in GIT, gastric emptying rate and transit time, absorption surface area, GIT disease, and drug interactions.

First-Pass Hepatic Metabolism

• Metabolism of absorbed drug in a single passage through the liver, gut wall, or lungs before reaching systemic circulation.
• It results in significant loss of total drug absorbed and available for therapeutic effect.
• Organic nitrates (e.g. GTN), Propranolol, and Piroxicam and some other drugs are extensively metabolized through the 1st pass effect in liver.
• Isoprenaline and Tyramine are first-pass effect through intestinal mucosa
• Isoprenaline and Nicotine can have pulmonary drug metabolism after aerosol inhalation

Drug Distribution

• Movement of drugs in the blood to the site of action.
• Drug distributes into interstitial and intracellular fluids, achieving distribution equilibrium.
• Physicochemical properties (e.g., drug lipophilicity) and physiological factors (e.g., cardiac output, regional blood flow) affect drug distribution.

Role of Plasma Proteins

• Drugs circulate in the bloodstream bound to plasma proteins.
• Albumin majorly carries acidic drugs.
• Alpha 1-acid glycoprotein binds basic drugs.
• Plasma binding of drugs is a nonlinear, saturable process.
• Binding is non-selective with high binding capacity and the binding process is competitive

Clinical examples of drug distribution

• Aspirin displaces Warfarin from albumin binding sites, increasing bleeding risk.
• Sulfonamides displace bilirubin from albumin binding site, increasing risk of bilirubin encephalopathy in newborns.

Volume of Distribution (Vd)

• Vd is the apparent volume that would accommodate all the drug in the body if its concentration was the same as in the plasma.
• Calculated as Amount of drug in the body / Plasma concentration.
• Depends on lipid solubility and plasma and tissue protein binding.
• V.d estimates the extent of extravascular tissue uptake of drugs.
• Small V.d indicates limited tissue uptake while Large V.d indicates extensive tissue distribution
• Drugs with high V.d not dialysable because of extensive distribution while drugs with low V.d are dialysable since most of the drug is in circulation
• V.d can be used to calculate size of loading dose and estimates fluctuations in plasma levels during repetitive dosing.

Drug Metabolism (Biotransformation)

• Refers to chemical changes drug molecules undergo after absorption until excretion.
• Liver (chief organ) is the site of drug metabolism
• Intestinal lumen and mucosa, lungs, plasma, skin and kidney are also sites
• Drug metabolism abolishes or terminates activity in most drugs

Consequences of Drug Metabolism

• Metabolism promotes, activates or increases activity of drug with Prednisone converting to Prednisolone, and pro-drugs converting to precursors
• Active drugs converts to another active substance such as Codeine converting to Morphine

Types of Biotransformation Reactions

• Phase I (Non-synthetic): Converts parent drug to more polar metabolite for excretion or subsequent Phase II reactions.
• Reactions involve oxidation, reduction, hydrolysis.
• Involve microsomal mixed function oxidase enzymes (e.g., Cytochrome P450 enzymes) and other non-microsomal enzyme systems.

Cytochrome-P450 Enzymes

• CYP3A4 alone is responsible for the metabolism of over 50% of administered drugs metabolized by the liver.

Phase II (Synthetic)

• Conjugation reaction of Phase I metabolites with endogenous substance.
• Makes highly polar and rapidly eliminates the conjugates
• Involves transferase enzymes in the liver.
• Glucuronidation, Acetylation, Sulfation, Methylation, and Glutathione conjugation are processes.
• Phase II products are always inactive.

Factors Affecting Drug Metabolism

• Individual variations (genetic polymorphism).
• Age (extremes of age).
• Sex (Estrogen and Testosterone).
• Pathological states (e.g., liver disease)..
• Diet & Environment charcoal-broiled foods, cruciferous vegetables, smoking, pollutants etc..
• Drug-Drug Interactions. (Enzyme-inducers and Inhibitors)

Drug Elimination & Clearance

• Polar drugs/metabolites are easily filtered from blood by kidneys to urine.
• Non-polar drugs are generally reabsorbed or distribute into fat tissue.
• Half-life (t1/2): time taken for plasma conc. of drug to reduce by 50%. In single compartment, 1st order kinetic model: t1/2 = In2 / k
• t1/2 increases as CL decreases (at constant V.d) and it is a good metric to know when steady drug concs are reached
• Drug t1/2 provides means to estimate appropriate dosing interval
• Volume of biological fluid (e.g. plasma) from which all drug is completely removed per unit time (ml/min/kg) called clearance
• the measure of body’s ability to eliminate drugs,

Clearance

• Calculated as Rate of elimination multiplied by Volume of Distribution
• Calculation with AUC single dose drugs with complete bioavailability and first-order elimination kinetics
• Calculation with Css with dosing rate multiplied by drug fraction then it is devided by the concentration after a steady state is reached
• Kidneys, liver, lungs, and skin major organs involved in this

Processes

• Hepatic clearance - biliary excretion.

• Renal clearance – Glomerular filtration & Active secretion.

• Total body clearance is the sum of all individual organ clearance i.e. renal clearance and non-renal clearance.

• CLsystemic = CLrenal + CLliver + CLother

• Designing rational regimen for long-term drug administration for maintence of steady-state drug concentrations in a therapeutic window

• First order pharmacokinetics i.e is where the clearance is dependent on drug concentatrion

• In Zero Order however, the clearances are independent of the concentration