pharmacokinetics Flashcards
termination of action: explain how drug action may be terminated. Identify the principle routes of drug metabolism and excretion
two major routes of drug excretion
kidney: most drugs by urine; liver: some drugs concentrated and secreted in bile (usually large molecular weight conjugates) and lost in faeces
drug excretion in kidney
low MW drugs ultrafiltered at glomerulus (20%); of 80% plasma passing round (including all other drugs), massive amount of active secretion of basic/acidic drugs in proximal tubule (dependent on available transporters); passive reabsorption of lipid soluble drugs in distal tubule and collecting duct (dependent on urine pH, drug pKa and extent of drug metabolism)
drug excretion in liver: biliary
large discontinuous capillary structure, so drugs can easily leave bloodstream into hepatocytes; concentrated larger molecular weight molecules, with active transport systems pumping into bile (bile acids and glucuronides) to be lost in faeces, as made more water-soluble in kidney for excretion
drug excretion in liver: enterohepatic cycling as problem of bile excretion
drug/metabolite excreted into gut via bile then reabsorbed (gut bacteria break down conjugate, releasing free drug back to lipid-soluble form and diffuses back into bloodstream)
drug excretion in liver: what does enterohepatic cycling lead to
drug persistence (once reabsorbed into bloodstream can re-enter hepatic circulation)
other excretion routes
lungs, skin, GI secretions, sweat, saliva, milk, genital secretions
reason why a drug should be lipophilic
so can access tissues (from blood and lymph) to have a therapeutic effect; all will eventually return to blood and lymph (down concentration gradient)
reason why drug should be water-soluble
so it can be retained in the blood (and lymph) and delivered more easily to excretion sites
why are drugs designed to be relatively lipid soluble
as body alters drug and converts it to metabolites (metabolism), to make it less lipid-soluble and easier to excrete
phase 1 drug metabolism aim
introduce a reactive group to drug to increase polarity and activate drug
phase 2 drug metabolism aim
add water soluble conjugate to reactive group (which serves as a point of attachment)
what reactions create new functional groups, and what are these groups
oxidation to electrophiles, reduction to nucleophiles
what reaction unmasks the new functional groups
hydrolysis to nucleophiles
what is the most common phase 1 metabolism
oxidation, which often starts with hydroxylation
where does phase 1 metabolism occur, and with what enymes; what is difficult to predict about this
liver; 57 subtypes of cytochrome P450 enzyme in smooth endoplasmic reticulum (different subtypes metabolise different drugs; proportion varies between people, so difficult to predict metabolism)
where does oxidation occur with aspirin
on -OCOCH3 acetyl group; converted to -OH (salicylic acid by removing acetyl group)
process of nicotine to cotinine
oxidation
process of cocaine to ecgonine methyl ester and benzoic acid
hydrolysis
process of chloral hydrate to trichloroethanol
reduction
what can an active parent drug be converted into
inert metabolite (no effect on body; e.g. nicotine) or active metabolite (continues/increases effect on body, so prolongs effects; e.g. cannabis)
what can an inactive parent drug be converted into
active metabolite (prodrug e.g. codeine)
example of phase 2 metabolism reactions: electrophiles (from oxidation)
glutathione conjugation
examples of phase 2 metabolism reactions: electrophiles: nucleophiles (from hydrolysis or reduction)
glucuronidation, acetylation, sulfation; conjugating agents are larger chemicals that donate side-chain onto drug
what is the most common phase 2 metabolism reaction
glucuronidation
what type of reaction is glucuronidation and drugs
low affinity/high capacity, so is more likely to occur at high drug dosages e.g. aspirin, paracetamol (20-30% metabolism but only when at high dose)
in electrophile (oxidation) phase 2 metabolism, what are the conjugation agent and target functional group of electrophiles
glutathione; electrophiles
in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in glucuronidation
UDP-glucuronic acid; -OH, -COOH, -NH2, -SH
in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in acetylation
acetyl CoA; -OH, -NH2
in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in sulfation
3’-phosphoadenosine-5’-phosphosulphate; -OH, -NH2
what type of reaction is sulfation and drug
high affinity/low capacity, so is more likely to occur at low drug dosages e.g. paracetamol (100% at low dose but 40-60% metabolism at high dose)
what must the other 10% of paracetamol (at high doses) be to undergo glutathione conjugation and drug
electrophilic or biotransformed to an electrophilic conjugate
how is paracetamol converted to an electrophile and final product
lose H groups on -OH (forming =O), ring and NH (forming C=N) to generate NAPQI, before undergoing glutathione conjugation on ring C next to COH
problem of electrophiles and impact of paracetamol overdose
NAPQI extremely reactive, so if paracetamol overdose the gluathione stores are overwhelmed so can’t conjugate, so left with very reactive NAPQI (reacts with proteins in liver, causing dysfunction); forms NAPQI glutathione conjugation if not overdose, otherwise remains as NAPQI
less common phase 2 metabolic pathways
acetylation, methylation, amino acid conjugation
in phase 2 acetylation, what is the usual R group and what enzyme is used; drug example
aromatic amine with acetyl group, N-acetyltransferase (NAT); isoniazid
in phase 2 methylation, what is the R group and what enzyme is used; drug example
methyl group, methyltransferases (MT); levodopa
in phase 2 amino acid conjugation, what are two possible reactions
with carboxylic acid group of amino acid, with amino group of amino acid
5 purposes of drug metabolism: biological half-life, duration of exposure, accumulation of compound, potency/duration of biological activity; pharmacology/toxicology of drug
biological half-life is decreased, duration of exposure is reduced, accumulation of compound in body is avoided, potency/duration of biological activity can be altered; pharmacology/toxicology of drug can be governed by its metabolism
