Pharmacology Lecture 2: Pharmacokinetics

Pharmacokinetics

What the body does to the drug

Absorption

Distribution

Metabolism

Excretion

Drug specificity in pharmacokinetics

For a drug to be useful it must be able to get to target sites w/ enough concentration w/o being broken down

Pharmacokinetics studies

Measures changes in drug concentration over time in 1+ different regions of body in relation to dosing

Concentration vs time curves

Drug concentration in blood plasma used to individualise dose

First-pass metabolism

Drugs administered orally enter the stomach & sit for 30-45 minutes before entering intestines where all intestinal blood is taken to the liver for detoxification 

Liver metabolises & destroys 90% of oral drugs before it reaches the heart

Drug is biotransformed extensively & bioavailability is reduced

Bioavailability

Percentage of an administered drug that reaches systemic circulation without alteration

IV = 100% bioavailability

Oral administration

Little absorption into blood until small intestine

Some lipophilic drugs can be absorbed across buccal mucosa

Passive transfer - depends on lipid solubility & ionisation

Some are carrier mediated ie. phenylalanine carrier & vit D dependent carrier

About 75% absorbed within 1-3 hours

Slow or fast release particles

Oral administration absorption influences

Gut content

GI motility

Particle size or formulation of drug

Splanchnic (viscera) blood flow

Splanchnic blood flow increases after a meal & decreases in heart failure

Bulk flow

Drug movement (travelling) via fluids

Cerebrospinal fluid (CSF), lymph, blood

pH in drugs

Many drugs are weak acids or weak bases

Ionised drugs

Hydrophilic

Poor absorption

Unionised drugs

Lipophilic

Absorbed well

Weak base that hasn’t accepted a proton

Weak acid that hasn’t donated a proton

Acid dissociation constant (pKa) for drugs

pH where a drug exists as 50% ionised & 50% unionised

Acidic drug absorption

Best absorbed in acidic environments

Near or below pKa

ie. aspirin

Basic drug absorption

Best absorbed in alkaline environments

Near or above pKa

ie. diazepam

Drug barrier crossing

Diffusion

Ion channels

Pinocytosis

Carriers/transporters

Pinocytosis

Plasma membrane forms vesicle around substance and brings it into cell

Occurs for larger drug molecules ie. insulin

Drug movement via ion channels

Drug enters cell via aqueous channels ie. aquaporins

Drug transporters/carriers

Solute carrier (SLC) transporters:

Passive, secondary active, tertiary active

OCT2 in proximal renal

Tubules; concentrates cisplatin in cells; nephrotoxic

ATP-binding cassette (ABC) transporters:

Active transporters

P-glycoproteins & anticancer drug resistance

Drug distribution factors

Boundary permeability

Binding

pH

Lipid content

Presence of other drugs

Drug binding in plasma

Bound form = drug bound to plasma proteins

Drugs not active in bound form & cannot enter tissues or excreted

Many drugs exists mainly in bound form in plasma

Binding in aqueous solution is often greater than 99%

Small differences in bound concentrations cause large effect on the free drug concentration & effect

Albumin & globulins

Drug binding factors

Concentration of free drug

Affinity for binding site

Concentration of plasma protein

Drug-drug interactions in binding

Competition between drugs to bind plasma proteins

Albumin can bind tons of drugs

Drug can reduce another drug’s binding & resulting in higher free plasma concentration

Drug occupies large fraction of free binding sites

Sulphonamides occupy 50% of sites at therapeutic concentration; causes harmful interactions w/ warfarin

Blood brain barrier (BBB) & drugs

Many drugs cannot access

Inflammation can disrupt it allowing for drugs ie. IV penicilin to treat meningitis

Ultrasound waves can be used to temporarily open BBB in AD

Chemoreceptor trigger zone (CTZ)

Area postrema

Dorsal surface of medulla oblongata that detects drugs in blood & CSF & triggers vomiting reflex

Outside of BBB to monitor bloodstream

Sends signals to vomiting centre of brain when stimulated

Domperidone accesses CTZ to prevent emesis

Volume of distribution (V_d)

Vd = Q/Cp

Vol that would contain the total body concentration of the drug (Q) at concentration observed in the plasma

Drug’s tendency to stay in plasma or distribute into tissues/fluid

High Vd = more distribution

Low Vd = limited distribution

Drug metabolism

Occurs mostly in liver but in many other tissues as well

Drug becomes more polar (water soluble)

Produces metabolites: inactive, active, therapeutic or toxic

Phase 1 metabolism: functionalisation

Catabolic - breaks down drugs

Direct modification of drug via oxidation, reduction, hydroxylation, dealkylation, deamination or hydrolysis

Reveals reactive groups (OH) → point of attack for conjugation

Largely in liver incl. first pass metabolism

Drug metabolising enzymes are embedded in smooth ER but drug must cross plasma membrane ie. CYP family

Polar drug metabolism

Polar drugs (partly) excreted unchanged

Phase 2 metabolism: conjugation

Anabolic - binds molecules together (mainly in liver)

Covalent bonding of polar groups to nonpolar molecules (drug)

Makes drug derivative water soluble for excretion

Glycoronyl, sulphate, methyl & acetyl groups transferred

Product is usually inactive

Normally occurs after phase 1 but can be single phase metabolism

Metabolism factors

Genetic polymorphisms in CYP:

CYP2D6 allele varies w/ ethnicity & affects metabol for 50% of drugs

Drug-drug interactions:

Enzyme inhibition enhances activity of other drugs

Enzyme induction reduces activity of other drugs ie. St John’s wort & CYP3A4

Drug half life (t_1/2)

Time taken for drug concentration in blood to fall by half

Drug excretion

Renal, exhaled from lungs & perspired from skin

Most unbound drugs undergo glomerular filtration in kidneys

Lipophilic drugs are not excreted as readily as polar/charged drugs

Many drugs are actively secreted into renal tubule for faster excretion, especially weak acid or base drugs

Weak acids excreted faster into alkaline urine & weak bases excreted faster into acidic urine (pH partition)

Lipophilic drugs are passively reabsorbed across tubule

One drug can reduce the renal clearance of another

Drug clearance

Rate active drug is removed from body (mL/min)

Total clearance (Cl_tot) = drug elimination

Renal clearance (Cl_ren) = vol of plasma filtered of active drug by kidneys in unit time 

Cl_ren = (C_u x V_u) / C_p