Pharmacokinetics-metabolism Flashcards
Drug metabolism
the mechanism for chemically modifying a drug without actually removing it from the body
what organs are primarily responsible for drug metabolism
the liver is primarily responsible. the small intestine and skin also play significant roles in preventing potentially harmful drugs/ compounds from exerting their effect
renal excretions role in drug metabolism
renal excretion only plays a relatively small role in elimination since most drugs are lipophilic and will be largely reabsorbed after filtration through the renal glomerulus
site of biotransformation
metabolic changes are usually a result of enzymatic reactions.
occur mainly in the liver but nearly all tissues can illicit a reaction e.g GI , kidneys
for orally administered drugs the GI and liver are the first tissues encountered and subsequently are responsible for a significant amount of metabolism ( 1st pass metabolism)
within a cell , the endoplasmic reticulum is responsible for most drug metabolism , although other areas such as mitochondria , nuclear envelope and plasma membrane may be involved.
factors altering metabolism
age
diet
co-administration of drugs
disease
stereoselectivity
timing
environmental
ontogeny ( age)
metabolism between neonates , children and adults varies markedly
foetuses and new borns are regarded as slow metabolisers
care needs to be taken when determining dosing regimens for children <12 years
gender may also play a part - effect is largely clinically insignificant except in pregnancy
drug interactions
drug-drug interactions affecting metabolism :
induction - rifampicin , induces P450 such that metabolism of other drugs increases - may necessitate dose increase to compensate . auto-induction can also occur where the drug actively induces its own metabolism e.g carbamazepine necessitating large increases in dose at initiation of therapy
Inhibition- some drugs can bind to the P450 site and inhibit the effect of the cytochrome without actually being metabolised by it -this inhibits the metabolism of other drugs such that metabolism is reduced - resulting in possible toxic side effects
inhibitors can be competitive - quinidine
or non-competitive - ketoconazole
other drug interactions
enzyme activity
- therapeutic index i.e. narrow
- choice and availability of different metabolic pathways
- inducers/ inhibitors affect on enzyme expression
- age, sex and physical development can affect enzyme activity
- disease and environmental factors
- extra-hepatic enzyme activity
- competition between differing drugs for a particular
enzymatic pathway
Disease
Diseases affecting metabolism
- Hepatic disease e.g. hepatitis, cirrhosis.
- Renal disease
Will need dose adjustments to compensate for changes in metabolism to ensure adequate efficacy without toxicity?
- Changes in liver metabolism may be transient.
- Changes to doses can be difficult due to limited strengths - How much of a dose reduction is needed? Difficult to estimate-
look for clinical signs, efficacy, side-effects to determine if a dose adjustment is needed. - Difficult to estimate effect disease/ drugs have on metabolism in a given individual. Use LFTs to determine liver damage but does not measure rate or extent of metabolism.
- Cirrhosis- 30-50% of normal liver function- may not have a clinically significant effect. – Dose reduction is a feature of low-polarity drugs when used in patients with hepatic impairment – eg propranolol (40mg starting does)
- Cardiac failure can inhibit liver blood flow- lidocaine metabolism reduced by half.
Stereoselectivity
Many drugs administered as racemates i.e. a blend of the various isomers.
Modern drug development – production of mono-isomeric drugs: usually to reduce or minimise unwanted side-effects without affecting efficacy or activity e.g. levothyroxine, dexibuprofen, levocetirizine.
However, metabolism can affect one isomer more than its’ racemate
e.g. warfarin: s-enantiomer is 5-10 times more potent than the r-enantiomer- if the ‘s’, which is metabolised by CYP2C9, is given to a person with altered CYP2C9 activity the effect would be greater than a person who had altered CYP3A4 activity (which affects the ‘r’).
Timing
Diurnal variation in drug metabolism not well understood but is known to occur.
Changes in blood flow and blood pressure occur throughout the day and this may in turn have an impact.
First-Pass Effect
Majority of drugs absorbed from the GI tract will pass through the liver before entering the main circulatory system- known as the First-Pass Metabolism.
Often responsible for poor bioavailability due to ‘removal’ of drug.
Drugs metabolised by CYP3A4 most susceptible e.g. calcium channel blockers (nifedipine)
- grapefruit juice can inhibit CYP3A4 thus resulting in potentially toxic rises in serum plasma levels.
Glyceryl trinitrate almost 100% metabolised by first-pass metabolism therefore orally inactive – give by alternative routes e.g. skin, buccal which avoid liver on absorption.
Extent dependant upon liver function i.e. liver disease may reduce to stop any first-pass metabolism.
Variability caused by changes in the hepatic extraction ratio e.g. verapamil.
Determines the relationship between IV and oral dosing- oral dose may have to be much greater compared with IV to compensate for extraction by the liver.
Inhibition or induction of liver metabolism may have to be considered.
Rate Limited Metabolism
E.g. Phenytoin, alcohol.
Metabolism can become saturated.
If a sufficiently large dose is given, the amount of drug metabolised will remain unchanged resulting in plasma levels rising exponentially.
Clearance becomes dependant upon dose i.e. small doses will have half-lives in the order of 12 hrs (phenytoin) or <1hr (ethanol) whereas large doses can have half-lives in the order of 2-3 weeks (phenytoin) or >6hrs (ethanol).
Referred to a Zero-Order or Non-Linear or Rate Limited kinetics.
