Pharmacokinetics Principles 3 (metabolism and excretion) Flashcards
chemical alteration of the drug in the body
biotransformation (metabolism).
transformation in biological system
biotransformation
in which order of kinetics the rate of elimination depends on dose
first order
in which order of kinetics the rate of elimination does not depends on dose
zero order kinetics
list the 4 steps of metabolism
1- converts non polar (lipid soluble) substances.
2- to polar (lipid insoluble) substances.
3- no reabsorption in renal tubules.
4- excretion in urine.
if drug A is active, and the product B is inactive.
metabolism in this case ___________
stops drug action
if drug A is active, and the product B is active.
metabolism in this case ___________, and name an example of a drug.
action is prolonged.
eg, diazepam.
if drug A is inactive, and the product B is active.
metabolism in this case ___________
activates the drug after we reach the action site.
few drugs are inactive and need conversion in the body to one or more active metabolites, such drugs are called _________
prodrug.
give an example of a prodrug?
like in parkinson’s, dopamine cannot cross the BBB so we give Levodopa
what are the 2 reactions of biotransformation
1- phase 1, non-synthetic, functionalization reactions.
2- phase 2, synthetic, conjugation.
what happens to lipophilic drugs in phase one of biotransformation?
gets converted to polar molecules.
metabolites in phase one of biotransformation are ________ (active, inactive)?
may be active or inactive.
what is conjugated to drug metabolites in phase 2?
endogenous radical
metabolites in phase two of biotransformation are ________ (active, inactive)?
mostly inactive.
what are the 5 reaction in phase 1?
1- oxidation.
2- reduction.
3- hydrolysis.
4- cyclization.
5- decyclization.
what is the most common reaction in phase 1?
oxidations.
the oxidation reaction in phase 1 is mostly carried out by _____ in the ________
monooxygenases (cytochrome P450),
in the liver.
in oxidation reactions of phase one we either add ________ or remove ________ ?
add oxygen/ negatively charged molecules.
or
remove hydrogen/ positively charged molecules.
name 3 examples of oxidation reactions?
1- hydroxylation.
2- dealkylation.
3- oxidative deamination.
name 2 examples of a monooxygenases in the liver?
1- cytochrome P450
2- CYP3A4
_________ carries out metabolism of largest number of drugs.
CYP3A4
In reduction reactions of phase one we either add______ or remove______?
add hydrogen or remove oxygen.
give an example of reduction reactions
levodopa reduced to dopamine in the brain.
what enzyme reduces levodopa to dopamine?
dopa decarboxylase.
in hydrolysis reactions of phase one we add ______ in the presence of ______ such as, ______
add water molecules in the presence of enzymes such as esterase and amidase.
list the 4 drugs that undergo hydrolysis?
1- procaine.
2- aspirin.
3- pethidine.
4- succinylcholine.
what is the most important synthetic reaction?
glucuronide conjugation.
glucuronide conjugation is carried out by which enzyme?
UDP-glucuronosyl transferase (UGTs).
gray baby syndrome is caused by a deficiency of which enzyme?
glucuronyl transferase enzyme.
gray baby syndrome is caused by the usage of which drug?
chloramphenicol use.
list the 7 drugs that undergo glucuronide conjugation?
1- chloramphenicol.
2- aspirin.
3- paracetamol.
4- morphine.
5- PABA.
6- diazepam.
7- digoxin.
list the 3 endogenous substances that undergo glucuronide conjugation?
1- bilirubin.
2- sex steroids.
3- thyroxine.
when _____ combines with paracetamol it turns it into harmless products
glutathione
in the case of paracetamol poisoning, ________ supply falls short and is unable to convert it to harmless products.
glutathione.
give examples of microsomal enzymes?
monooxygenases, cytochrome P450, UGTs
where are microsomal enzymes located?
smooth endoplasmic reticulum, in the liver, kidney and intestines.
drugs that increase activity of microsomal enzymes and increase the metabolism of other drugs or the same drug itself
liver microsomal enzymes inducers.
drugs that decrease activity of microsomal enzymes and decrease the metabolism of other drugs or the same drug itself
liver microsomal enzymes inhibitors.
list 6 examples of microsomal enzyme inhibitors?
1- allopurinol.
2- erythromycin.
3- ketoconazole.
4- cimetidine.
5- HIV protease inhibitors.
6- grape juice.
list 3 examples of microsomal enzyme inducers?
1- anticonvulsants, rifampin induce CYP3A4.
2- isoniazid and alcohol induce CYP2E1.
3- polycyclic hydrocarbons in cigarette smoke, charcoal broiled meat induce CYP1A.
the irreversible removal of drug from the body
elimination.
what does elimination involve?
1- biotransformation (drug metabolism).
2- excretion.
what are the 3 major routes of elimination?
1- hepatic metabolism.
2- biliary metabolism.
3- urinary metabolism.
the volume of blood from which the drug id cleared per unit time?
clearance
what are the 2 main routes of excretion?
1- renal excretion.
2- biliary excretion.
what are the 5 minor routes of excretion?
1- pulmonary excretion.
2- salivary excretion
3- mammary excretion via milk.
4- skin / dermal excretion via sweet.
5- tears.
what is the most important channel of excretion for majority of drugs?
renal elimination.
what organ is responsible for excreting all water soluble substances?
the kidneys
net renal exertion is expressed by?
(glomerular filtration + tubular secretion) - tubular reabsorption
what are the 3 processes involved in renal elimination?
1- glomerular filtration.
2- tubular reabsorption.
3- tubular secretion.
where are drugs and their metabolites can be excreted?
1- faeces.
2- exhaled air.
3- saliva and sweat.
4- milk.
most of the drug in faeces is derived from what?
bile.
the rate of elimination is directly proportional to drug concentration
first order kinetics.
constant _______ of drug is eliminated per unit time in 1st order kinetics?
fraction
in first order kinetics increase in does, ________ t1/2.
unalter
what is the most common order of kinetics?
1st
rate of elimination is not dependant on drug concentration
zero order kinetics.
constant ________ of drug is eliminated per unit time in zero order kinetics?
amount
increase in dose, ______ elimination in zero order kinetics.
does not increase.
increase in dose, ______ t1/2 in zero order kinetics.
increases
there is risk of toxicity in which order of kinetics?
zero order
give examples of drugs that undergo zero order kinetics
ethanol, high doses of phenytoin.
give examples of drugs that change from 1st order to zero order kinetics?
- phenytoin.
- tolbutamide.
- theophylline.
- warfarin.
T 1/2 is ____ ______ to volume of distribution and ______ _______ to clearance.
directly proportional.
inversely proportional.
rate of drug elimination equals rate of drug administration
steady state.
how many half lives does it take to reach steady state?
4-5 T1/2
Dosing rate is expressed by
DR = (C)(CL) / F
F = bioavailability
CL = clearance
C = target plasma concentration
loading rate is expressed by
LD = Vd (C) / F
Vd = volume of distribution
C = clearance.
F = bioavailability.
dose required to maintain Css
dosing rate
administered to achieve the desired plasma level rapidly.
loading dose
the measurement of plasma concentration of drugs
therapeutic drug monitoring (TDM)
what are the 6 uses of TDM?
1- drugs with low safety margin.
2- if individual variations are large.
3- potentially toxic drugs used in the presence of renal failure.
4- in cases of poisoning.
5- in cases of failure of response without any apparent reason.
6- check patient compliance.
give example of drugs with low safety margin?
- digoxin.
- anticonvulsants.
- antiarrhythmics.
- theophylline.
- aminoglycoside ABx.
- lithium.
give example of drugs with individual variation are large?
- antidepressants.
- lithium.
give example of drugs with potentially toxic drugs used in the presence of renal failure?
- aminoglycoside antibiotics.
- vancomycin.
give example of drugs with failure of response without any apparent reason?
antimicrobials.
give example of drugs that need to be check for patient compliance?
- psychopharmacological agents.
what are the 3 cases where TDM is of no value?
1- drugs whose response is easily measurable.
2- drugs that get activated in the body.
3- drugs with irreversible action.
give example of drugs whose response is easily measurable?
antihypertensives
give example of drugs that get activated in the body?
levodopa.
give example of drugs with irreversible action?
organophosphates.
