Module 3 Concept Map

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Pharmacokinetics

Absorption

Passive movement

Solute carrier

E.g. Organic cation transporters

Mediate the movement of dopamine and choline

Facilitates transport single species IN THE DIRECTION of its electrochemical gradient

Aquaporins

Diffusion is the mechanism used by most drugs

Facilitated diffusion is passive with no energy

Active transport

Pinocytosis

Specific carriers

ABC transporters

Mediate removal of drugs from cells

E.g. P‐glycoprotein transporters

Primary group of ABC transporters

Transport AGAINST concentration gradients

Specialized membrane proteins

Drug properties

Ionization state

Ion Trapping

Drug's ionization preference and retention

Basic drug will accumulate in LOW pH

Acidic drug will accumulate in HIGH pH

Dissociation constant

Negative value = greater proportion of non-ionized drug

Greater lipid solubility

Ratio between dissociated ions and drug

Ionized dissolve aqueous fluids than uncharged

Lipid solubility

High soluble = higher membrane penetration

Too lipid-soluble = retained in membrane

Metabolism

Pro-drugs

Higher activity

Different absorption or distribution properties than precursors

Gain full drug activity after metabolic processing

Inactive drug precursor

First pass effect

Reduces bioavailability prior to systemic circulation

Occur in gastric mucosa or liver

Almost all drugs entering the body from the GI tract

Bioavailability

Amount of drug reaching the systemic circulation

Phase 2

Produces polar molecule ready for excretion

Conjugation of site chains

Glycine or water addition

Methylation

Glutathione addition

Sulphation

Glucuronidation

Involves altering drug structure

Normally results in inactive product (some exceptions)

Reduce intrinsic efficacy for excretion

Mainly in the liver

Can also occur in other tissues like lungs and kidneys

Phase 1

Metabolic enzymes generally alter drugs to activate them and make them more water soluble

Cytochrome system

P450 enzyme levels regulated by external factors

E.g. grapefruit juice and Brussels sprouts

Genetic variations exist

Primary cause of patient response variation

Net effect of cytochrome p450 cycle is addition of oxygen or hydroxyl

3 main CYP gene families

CYP3

CYP2

CYP1

Nonpolar drugs go through phase 1 more than polar

Need to cross cell membrane to reach cytochrome systems

Mainly in liver

Can also occur in other tissues or plasma

Hepatic cytoplasmic microsomal enzymes

E.g. cytochrome systems

Most common residue is hydroxyl

Mediated by cytochrome system associated with ER

Oxidation (also reduction and hydrolysis)

Distribution

Endothelial cells

Blood brain barrier

Diffusion is PRIMARY for drugs crossing BBB

Active transport by carriers

AA, glucose, amines and purines

Highly lipophilic drugs able to readily pass through

Molecule must pass through at least 2 membranes

Fenestrations

Gaps that allow solute diffusion

Apparent volume of distribution (Vd)

Large Vd drug likely to enter body compartment

Drug with very low Vd likely to still be in circulation

Gives estimate where drug is (tissues or circulation)

Dose divided by measured plasma concentration

Absorption reservoir

Plasma, body fat and interstitial water

Fat ~20%

Intracellular water ~35%

Interstitial water ~16%

Plasma water ~5%

Transcellular water ~2%

Comprises CSF, intraocular, peritoneal, pleural and synovial fluids and digestive secretions

Excretion

Movement of drugs into and out of the body strongly influenced by:

pH of the compartment

Drug pKa

Drug lipid solubility

Drug elimination

Includes loss of drug by metabolism and any other excretory routes

Measure of loss of drug mass from the circulation per unit of time

Plasma clearance

Reduced clearance

Indicative of function impairment of excretory organ

Drug excretion by liver or kidneys is best described by clearance

Volume of blood cleared of a drug through an organ per time

Indicator of efficiency of drug removal from plasma

Clearance is a constant for any given drug

Urine pH

Artificial alteration of pH is used to increase excretion of certain drugs

Alkaline urine increases acidic drug excretion

Acidic urine increases basic drug excretion

Ion trapping to increase drug retention in urine

pH of urine can change dramatically

Due to diet or drug intake

Mode of secretion

Tubular secretion involve specific transporter proteins

Highly lipophilic drugs or non-ionized absorbed via passive diffusion

Glomerular ultrafiltration

Unbound fraction exhibits pharmacologic effects

Small molecules readily pass and are cleared

Drugs with high affinity protein slower excretion

Less free drug for filtration and diffusion

Level of plasma protein binding to drug

Plasma proteins too large to pass renal luminal barrier

Retained in circulation

Enterohepatic circulation

Drugs may be excreted in the bile after transport by the solute carriers and ABC transporters

Results in prolonged drug action

Account up to 20% of total drug in the body

Most excretion occurs in kidneys

Most drugs excreted in urine or bile (lesser extent)

Drug clearance rate via renal greatly differ