Drug Metabolism Flashcards
What are the three phases of drug action + what do they entail?
- Pharmaceutical Phase: Disintegration of the pill / capsule in gastrointestinal
tract (GI), release of the drug, dissolution of drug - Pharmacokinetic Phase: Absorption from GI tract into bloodstream and
what the body does to the drug - Pharmacodynamic Phase: Mechanism by which the drug interacts with the
molecular target. What the drug does to the body
What makes a good drug in terms of pharmacokinetic?
Absorbed well by the
body
* Reaches target easily
* Not modified, inactivated,
or removed from the
body too quickly
What makes a good drug in terms of pharmacodynamic?
- Effective at targeting the
disease process - Not toxic
What is meant by potency?
o Dose required to achieve the
effect.
o Measured as the 50% effective
concentration (EC50).
o Units of concentration
What is meant by efficacy?
o The maximal effect.
o Measured as “response.”
o Usually a percentage.
What does A in ADME stand for?
Absorption: Process of drug entering
the body and therapeutic agent
entering the blood
What does D in ADME stand for?
Distribution: Drug may reversibly leave
the bloodstream and distribute into the interstitial and intracellular fluids
of various compartments in the body
What does M in ADME stand for?
Metabolism: Biotransformation /chemical conversion of drug
molecules.
What does E in ADME stand for?
Elimination: Clearance of drugs and metabolites from the body (urine, bile, faeces)
What factors affect drug absorption + details?
➢Solubility: Drugs need to be water- soluble to pass into the blood for distribution
➢Ionisation: Drugs need to be close to neutral to pass through membranes
➢Stability: Drugs need to be chemical stable until they reach their site of action
What factors affect distribution? + details
➢Plasma solubility: Including binding to plasma proteins (bind and release)
➢Lipophilicity: Balance between water and fat solubility. Influences drug levels
in blood, muscles, adipose tissue, and organs
➢Perfusion: Level of blood flow to a tissue. Major organs (heart, liver . . .) well perfused, but brain is a special case – blood-brain barrier.
What are the minor and major routes of excretion?
- Major routes: Urine (renal), faeces (biliary)
- Minor routes: Exhalation (lungs), sweat / other bodily fluids
Why are minor metabolites important? + examples
- Minor metabolites are also important – accumulation of minor
metabolites can be extremely toxic
❖No metabolites – sodium cromoglicate
❖1 major metabolite – oxazepam glucuronide
❖> 10 major metabolites - chlorpromazine
What is involved in phase 1 of metabolism?
Phase I Transformations:
➢Mostly in liver
➢Chemical Modifications
➢Oxidation, Reduction, Hydrolysis
What is involved in phase 2 of metabolism?
Phase II Transformations:
➢ Mostly in Liver
➢ Conjugation with an excretion-promoting group
➢ E.g. glucuronic acid, sulfate, glycine (hydrophilic)
➢ E.g. bile acids (hydrophobic)
What happens in phase 1 of metabolism?
Chemically diverse small molecules transformed to more polar compounds
+ CYP- P450 Reactions + NON CYP reactions.
What are CYP-P450 reactions?
➢Hydroxylation
➢Epoxidation
➢Dealkylation
➢Deamination
➢Oxidation
➢Dehalogenation
What are NON-CYP-P450 reactions?
➢ Oxidation
➢ Hydrolysis
➢ Reduction
➢ Deamination
What do CYP450 enzymes do?
Mechanism of action: Split molecular oxygen so one of the oxygen atoms is
introduced into the drug, the other ends up in water
What happens in phase 1. Oxidation of exposed alkyl groups / exposed regions of cycloalkyl rings?
*Oxidation of terminal
methyl groups
*Oxidation of penultimate
carbon on alkyl substituents
*Oxidation at most exposed
or most activated region
of the cycloalkyl ring
What is phase 2?
- Oxidation of activated carbon centres (next to sp and sp2 carbons) –they are more likely to be oxidised than exposed carbon atoms
What is phase 3?
Dealkylation of amines, ethers and thioethers via oxidation of
activated carbon
What is phase 4?
Dehalogenation of alkyl halides
-Oxidation to carboxylic acids by aldehyde dehydrogenases
What is phase 5?
Oxidation of alkenes and aromatic rings.
Oxidation of unsaturated
sp2 and sp carbon centres
present in alkenes, alkynes
and aromatic rings
What compounds does phase 2 - sulphate conjugation have involved?
Less common and only involves phenols, alcohols, arylamines, N-hydroxy compounds
Catalysed by sulfotransferases, using the
cofactor 3’-phosphoadenosine-5’-
phosphosulfate
What is the details in the first pass effect?
- Drugs that are taken orally pass directly to the liver once they enter the blood supply. They are therefore exposed to metabolism before they are distributed around the rest of the body
- A certain percentage of the drug will be transformed before it reaches its
target - Drugs administered via a different route (e.g. injection, inhalation) avoid
the first pass effect – they are distributed around the body before they reach the liver
