liver & metabolism - pharmokinetics Flashcards
what is pharmacokinetics?
what the body does to the drug
what does the A, D, M, E stand for in pharmacokinetics?
- absorption
- distribution
- metabolism
- excretion
what does absorption mean in terms of pharmacokinetics?
drug transfer from its site of administration to the systemic circulation (blood)
what are the enteral routes of drug administration?
- oral
- rectal
what are the oral routes of drug administration?
- sublingual
- buccal
what are the factors that influence enteral absorption?
- GI motility
- absorptive area
- GI blood flow
- drug particle size and formulation
- drug physicochemical properties
- drug binding
what type of molecules are lipid soluble?
non-ionised molecules
what types of molecules are hydrophilic?
polar molecules - ionised molecules
what types of molecules in a drug are better absorbed?
lipid soluble molecules
how does pH affect the drug physiochemical properties?
- acidic drugs are better absorbed in acidic media
- basic drugs are better absorbed in basic media
- acidic drugs are better excreted in basic media
- basic drugs can be excreted better in acidic media
what are the parenteral routes of drug administration?
- intramuscular
- subcutaneous
- intravenous
- intradermal
what are the other routes of drug administration?
- topical
- transdermal
- inhalation
- intrathecal
what is bioavailability?
fraction of the administered (oral) dose of a drug that reaches the systemic circulation
what is the equation for bioavailability?
IV area under the curve (AUC)
what is first pass (pre-systemic) metabolism?
- the metabolism of the drug prior to reaching systemic circulation
- first pass effect —> bioavailability
what is bioequivalence?
2 drugs are considered bioequivalent when there is no signifiant difference in the rate or extent of bioavailability at the same molar dose and under the same conditions
what relevance does bioequivalence have?
- different formulations from different companies
- different batches of drugs from the same company
where do most drugs end up after absorption?
systemic circulation
what is drug distribution?
process by which the drug is transferred reversibly from the systemic circulation into the tissues as concentrations in the blood increase, and from the tissues into blood when the blood concentrations decrease during elimination
where are the drugs distributed?
into vascular, interstitial and intracellular compartments
how does drug distribution occur?
- most drugs transfer by passive diffusion
- across capillary walls down a concentration gradient
- into interstitial fluid until concentration of free drug molecules in interstitium is equal to that in plasma
what are the key features of plasma protein binding?
- drugs bind non-specifically to albumin in plasma
- reversible and saturable
- unbound or free fraction distributes
- unbound portion is responsible for the clinical effect
what is the equation for plasma protein binding?
Drug + Protein Drug-Protein complex
what drugs are highly protein bound?
- warfarin
- phenytoin
- aspirin
- thyroxine
- ibuprofen
- heparin
- furosemide
what factors influence drug distribution?
- drug physiochemical properties
- lipid solubility
- water solubility
- drug particle size
- drug protein binding
- the environment; blood flow, pH
what is apparent volume of distribution?
- a concept that seeks to predict how extensively a drug is distributed throughout the body
- volume into which a drug appears to be distributed with a concentration equal to that of plasma
what is the equation for apparent volume of distribution (Vd)?
Vd = Dose (mg) / Concentration (mg/L)
why doe drugs with a large Vd need to be administered in larger doses?
to achieve a target concentration in the plasma
what do we mean if a drug has a low Vd?
Vd < 10L (warfarin)
- highly protein bound drug so retained in plasma
what do we mean if a drug has a medium Vd?
Vd = 10-30L
- water soluble drugs, low lipid solubility
- distributes into interstitial fluid but not cells
- dose on distal body weight to avoid toxicity
what do we mean if a drug has a high Vd?
Vd > 100L (amiodarone)
- fat soluble drug distributes into tissues
what are the 3 forms of the drug in phase 1 drug metabolism?
- active (pro-drug)
- inactive
- toxic
what happens in phase 1 drug metabolism?
- oxidation (P450 cytochrome)
- reduction
- hydrolysis (esterase’s)
what happens in phase 2 of drug metabolism?
drug solubilisation by conjugation:
- glucuronidation
- acetylation
- sulfation
- methylation
- eliminated in urine or bile
what do you start and end with in drug metabolism?
start: lipophilic drug
end: water-soluble metabolites
what is a prodrug?
a drug or compound that is metabolised into a pharmacologically active drug
what are some examples of prodrugs?
- enalapril to enalaprilat
- codeine into morphine
- levodopa to dopamine
what are the cytochrome P450 inhibitors?
- Amiodarone
- Ciprofloxacin
- Erythromycin/Clarithromycin
- Metronidazole
- Fluconazole
- Isoniazid
- Alcohol (acute)
- Grapefruit juice
what are the cytochrome P450 inducers?
- Carbamazepine
- Phenytoin
- Rifampicin
- Alcohol (Chronic)
what type of process is cytochrome P450 inhibitor?
a rapid process
what type of process is cytochrome P450 induction?
a slow process
what is the therapeutic index?
ration of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC)
what general combination has a potential for adverse drug interaction?
- drug metabolised by CYP450 with narrow therapeutic index/window
AND - cytochrome P450 inhibitor
what are genetic polymorphisms?
multiple genetic variants which result in different phenotypes
what do polymorphisms of drug metabolising enzymes affect?
drug handling
what is an extensive metaboliser?
two active ‘normal’ alleles
what is an intermediate metaboliser?
one normal and one abnormal allele
what is a poor metaboliser?
two abnormal alleles
what is an ultra rapid metaboliser?
duplication of normal alleles
what happens with CYP2D6 polymorphisms with ultra rapid metaboliser?
- causes opiate toxicity in some individuals even at a low dose
- this causes an exaggerated response to codeine
what happens with CYP2D6 polymorphism with poor metaboliser?
- causes inadequate pain relief by codeine in some individuals
what is the phase 2 reaction equation?
drug + glucuronidation, acetylation, sulfation and methylation ——> water soluble conjugate
what genetically determines the activity of N-acetyltransferase?
- fast acetylators at increased risk of isoniazid hepatoxicity
- slow acetylators at increased risk of isoniazid neuropathy
- slow acetylators at increased risk of drug induced lupus with hydralazine
what is drug clearance?
- the sum of all the drug-eliminating processes, principally determined by hepatic metabolism and renal excretion
- theoretical volume of fluid from which a drug is completely removed in a given period of time
what are the components of renal excretion?
- glomerular filtration: glomerulus
- secretion: proximal convoluted tubule
- reabsorption: distal convoluted tubule
what are the other excretory methods (other than urine)?
- bile (faeces)
- sweat
- exhaled air
- saliva
- breast milk
what are the causes of low drug clearance?
- normal variation
- renal impairment
- liver impairment
- enzyme inhibition
- genetic poor metaboliser
- neonate
- old age
what are the causes of high drug clearance?
- normal variation
- increased renal blood flow
- genetic hyper-metabolism
- enzyme induction
what does half-life provide information on?
- time course of drug elimination
- time course of drug accumulation
- choice of dose interval
what determines loading dose?
volume of distribution
what determines maintenance dose?
clearance
what determines dose interval?
half life
