Lecture 20 - Pharmacokinetics 2 Flashcards
protein bound drug is not eliminated - free drug is eliminated from the body
how is free drug eliminated from the body ?
Renal excretion (kidney)
Liver metabolism
the liver will metabolise a drug , most often inactivates it, but it can activate it
it will then be removed by the kidney
how does the liver contribute to drug removal
Hepatic drug metabolism: Phase I and II
Phase I and II enzmyes express mainly in the liver metabolise drugs
Phase I and II enzymes
• Metabolism drugs – increase ionic charge to enhance renal elimination
• Lipophilic drugs diffuse out of renal tubules back in to plasma
• Once metabolised, drugs usually inactivated (not always)
what are the main set of enzymes of Phase 1 metabolism ?
Cytochrome P450 (CYP450) enzymes
A large group of 50 enzymes located on cytoplasmic ER surface
they will catalyse redox reactions, diacylation and hydroxylation
they have a BROAD specificity , so metabolise a wide range of molecules
result is adding ioninc charge to products, so cannot be reabsorbed - either eliminated directly or will go to enter phase 2
CYP 1, 2, and 3
we can inhibit these enzyme if we want
pase 1 metabolism can activate drugs - 0.15% of codine is converted to morphine - far stronger pain killer
what are / is the role of Phase II enzymes ?
Hepatic enzymes
• Mainly cytosolic
• Broad specificity – more rapid kinetics that CYP450s
• Conjugation:
‒ Glucuronidation, Glutathione conjugation, N-acylation, Sulphation
• Increase hydrophilicity further, increasing charge
• Further enhances renal elimination
the aim of phase I and II enzymes is to increase charge / hydrophillicity which will in turn increase elimination of the drug
explain the possible kinetics of drug elimination
• 1st order kinetics
– Rate of elimination is proportional to drug level.
– Constant fraction of drug eliminated in unit time.
– Half life (t½) can be defined.
linear graph when we plot a logarithmic scale - curved when not logarithmic
• Zero Order kinetics
– Rate of elimination is a constant and independent of drug dose
linear scale - not logarithmic
at low doses drug removal may be first order - zero order at high doses - alcohol example
why does the mechanism of drug elimination matter ?
1st order kinetics we can predict the theraputic response from a increase in dose
1st order is majority of drugs
0 order kinetics - theraputic response can escalate suddenly once elimination mechanisms have saturated - harder to predict and hence dose
alcohol
Drug interactions in metabolism most important clinically for?
• Drugs with low therapeutic ratio
• Drug is being used at minimum effective concentration
(e.g. oral contraceptive pill)
• Drug metabolism follows zero order kinetics
what is drug clearance ?
the rate of elimination of an active drug from the body
ClearanceTotal = ClearanceHepatic + ClearanceRenal (+ ClearanceOther)
Clearance = Elimination rate/[Drug]plasma
meausred in ml/min
what is the clinical relevance of Clearance and Vd
they provide an estimate of t1/2 - the half life
this is vital when considering dosing schedules and minimising adverse drug reactions
t1/2= o.693 * Vd/ CL
we need 5 half lifves to reach steady state
so we give a bolus - loading dose - help reach the steady state quicker than 5 half lifes
what drugs are removed renally
only the free fraction of drugs is removed renally
drugs can be active secreted by the tubules
we also get some passive reabsorbtion if lipophillic also ions from OATS and OCTS
drugs that are ionsized and lipid insoluble are excreted
when can drugs be passively absorbed
• Passive reabsorption of drug is dependent on pH
• pK of drug is pH at which half of it is ionised, half is non-ionised
• Only the non-ionised moiety is lipid soluble and crosses membranes
easily
what does urine acidity impact on excretion ?
Urine pH will affect the rate of drug clearance from the body
weak acids - acidic urine will increase absorption
alkaline urine will decrease absorption
the HA —–H+ and A- equilibrium
acidic urine will shift to make more HA - reabsorbed
alkali will shift to make more H+ - excreted
weak bases - Acidic urine will decrease absorption
alkaline urine will increase absorption
B —— BH+
acidic urine - more BH+ - greater elimination
alkali urine - exist as B - less absorption
clinical example of aspirin poisoning
it is a weak acid
if acidic urine it is protonated form will reabsorb into blood
if alkaline urine - clearance is increased as it will exist in deportonated ionic form
so we treat with bicarbonate to make urine more basic
how do we prescribe for patients with a renal disease
very hard to prescribe - affects all removal factors
If drug is excreted by kidneys, half lives of drug are longer.
Lower maintenance dose of the drug
- Longer half lives also means longer time to reach a steady state (remember it takes 5 half lives to reach equilibrium).
- Loading dose can be altered.
- Protein binding can be altered
