Pharmacokinetics - ADME Flashcards by Harry Quinn

What is the pharmacokinetic process?

Getting the drug to the site of action

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What is the pharmacodynamic process?

Producing the correct pharmacological effect

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What four events happen as part of the pharmacokinetic process?

Absorption
Distribution
Metabolism
Excretion

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What is drug absorption?

movement of the unchanged drug from site of administration to systemic circulation

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What is Tmax?

time taken for a drug to reach peak concentration in the body

comes earlier if absorption if the drug is more rapid

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What is Cmax?

peak concentration of the drug in the body

affected by increases in dosage

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What is AUC?

the amount of the drug that reaches the systemic circulation

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What is bioavailability?

the amount of a drug that reaches systemic circulation and is available for action

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What is the therapeutic range of a drug?

the area where drug concentration if safe and active

above = toxicity
below = ineffective

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What are the factors that effect the bioavailability of oral absorption if drugs?

formulation
physiological barriers
gastrointestinal effects
first pass metabolism

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What type of drugs are absorbed through diffusion?

Non-ionised drugs (weak acids/bases, changes in pH change ability to diffuse)

Lipophilic drugs (must be lipid-soluble to diffuse through lipid membranes)

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What must drugs resemble in order to be absorbed by active transport?

Naturally-occurring compounds

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What is the main gastrointestinal factor that influences drug absorption?

Motility;

speed of gastric absorption
affected by food/drink/illnesses

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What illnesses can affect GI motility?

Coeliac disease (gives rise to malabsorption)

- Migraine (reduces the rate of stomach emptying)

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What is the first pass metabolism?

the metabolism of a drug before it can reach the systemic circulation

i.e. a drug could be fully metabolised before reaching the blood, e.g. insulin (reason for IV administration)

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Why are other routes of drug absorption used?

absorption rate can be changed with different formulation
drugs with small volumes
blood flow differences
avoiding the first pass metabolism

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Name four sites of drug administration, other than oral

Sublingual/Buccal
Rectal
Nasal
Transdermal

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What is drug distribution?

the reversible transfer of a drug between blood and extravascular fluids/tissues in order for it to become active

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What factors can influence drug distribution?

Plasma protein binding
Tissue perfusion
Membrane characteristics
Transport mechanisms
Diseases
Other drugs
Elimination

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What is plasma protein binding?

when drugs bind to plasma proteins such as albumin, nullifying their effects

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What can affect the amount of a drug that is bound to plasma proteins?

renal failure
hypoalbuminaemia
pregnancy
other drugs (by displacement)

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Name three parameters of the therapeutic range

Apparent volume of distribution (Vd)

Clearance (Cl)

Half-life (T1/2)

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What is apparent volume of distribution?

theoretical volume needed to contain the total amount of a drug in the blood plasma if the drug was present in the same concentration throughout the body (L/Kg)

What is caused by a greater Vd?

greater ability of a drug to diffuse to/through membranes

What is clearance?

volume of fluid from which a drug is completely removed over a period of time (ml/min)

What does renal clearance depend on?

- concentration | - urine flow rate

What does hepatic clearance depend on?

- metabolism | - biliary excretion

What is the half-life of a drug?

time taken for the drug concentration to decline by half its current value

What does T1/2 depend on?

- clearance | - apparent volume of distribution

What is drug elimination?

removal of active drug/metabolites

What processes can drug elimination be divided in to?

Metabolism (liver) Excretion (kidneys/biliary system/gut)

What four processes make up drug excretion?

- glomerular filtration - active tubular secretion - passive tubular reabsorption - biliary secretion

What sort of drugs are excreted by glomerular filtration?

unbound drugs, provided their size/shape/charge is relatively small

Where does active tubular secretion occur?

in the proximal tubule

What sort of drugs are excreted by active tubular secretion?

- acidic/basic drugs | - protein bound cationic/anionic drugs

Where does passive tubular reabsorption occur?

in the distal tubule and collecting duct

What sort of drugs are excreted by passive tubular reabsorption?

unionised/highly concentrated drugs (diffusion across the concentration gradient)

What occurs during biliary secretion?

drugs are passively/actively secreted into bile

What is entero-hepatic circulation?

Drug reabsorption to circulation from bile

What is drug metabolism?

biochemical modification of pharmaceutical substances by living organisms (usually by specialised enzymatic activity)

How does drug metabolism work?

Lipophilic and non-polar substances are converted to hydrophilic and polar substances to allow them to undergo excretion instead of being passively reabsorbed

What are prodrugs?

drugs with active metabolites which only become active after metabolism e.g. codeine (converted to morphine during metabolism)

How can toxic drug metabolites affect the body?

- direct toxicity - carcinogenesis - teratogenesis

Describe pharmacokinetic enzymes in terms of specificity and presence in the body

- have a wide substrate specificity | - constitutively expressed or induced by presence of substrate

What processes occur during Phase 1 of drug metabolism?

Oxidation Reduction Hydrolysis - increases polarity - gives an active site for Phase 2 to occur

What enzyme family is active during Phase 1 of drug metabolism?

Cytochrome P-450

Name three subfamilies of the cytochrome P-450 enzyme active during Phase 1 of drug metabolism

- CYP3A4 - CYP2D6 - CYP1A2

What is the function of CYP3A4?

- drug metabolism in the liver - pre-systemic metabolism in the gut - e.g. diazepam/methadone

What is the function of CYP2D6?

- antidepressant/antipsychotic metabolism - conversion of codeine to morphine - can be reduce/absent in some people (genetic polymorphisms)

What is the function of CYP1A2?

- induced by smoking - metabolism of theophylline - therefore smokers need a higher dosage of theophylline than non-smokers

What processes occur during Phase 2 of drug metabolism?

Conjugation - attachment of substances to Phase 1 metabolites e.g. glucuronic acid/glutathione/sulphate/acetate

What factors can affect drug metabolism?

- other drugs - liver disease - hepatic blood flow - age - sex - ethnicity - pregnancy - genetics

What can cause enzyme induction?

- smoking - alcohol - St John's Wort (may take weeks)

What can cause enzyme inhibition?

- erythromycin - clarithromycin - grapefruit

What are the four possible phenotypes of CYP2D6 polymorphism?

- poor metabolizers (PM) - intermediate metabolizers (IM) - extensive metabolizers (EM) - ultrarapid metabolizers (UM)