Pharmacokinetics - Clearance & Elimination Flashcards
- PR_BK_20 Drug elimination from plasma. Mechanisms: distribution; metabolism; excretion: exhalation; renal; biliary; sweat; breast milk. Factors affecting e.g.: pathological state: renal and hepatic failure; age, including extremes of age; gender; drug interactions. Active and inactive metabolites; pro-drugs. Enzyme induction and inhibition - PR_BK_21 Non-enzymatic drug elimination: Hofmann degradation (11 cards)
What is drug clearance?
The volume of plasma completely cleared of a drug per minute (ml/min)
This is because the absolute removal (in mg/min) varies with plasma concentration & volume of distribution.
Cl (ml/min) = VD (ml) x k (/min)
The formula takes into account the maximum rate of drug removal, and the volume over which it is distributed.
This is relevant as if a pathological process affects VD or k, then the dose may need to change - for instance renal failure may increase VD through fluid overload, while also decreasing clearance.
The rate of elimination is equal to clearance multiplied by plasma concentration
Cl - Clearance
VD - Volume of distribution
K - Elimination rate constant
What is half-life and what factors affect it?
The time taken for the plasma concentration of a drug to fall by 50% of its initial value - by definition, doubling the dose of a drug will increase its duration of action by one half-life
It is affected by volume of distribution, and by changes to clearance rate
Explain first and zero order kinetics
First order kinetics
Rate of drug removal is proportional to plasma concentration - the same proportion of drug is removed per unit time - Enzymatic capacity exceeds drug concentration.
Half-life remains constant, as the drop in plasma concentration of the drug is negatively exponential
Cₜ = C₀ x e ⁻ᵏᵗ
At 4 half-lives, the process is 94% completed, and by 5, it is 96.8 completed.
Zero order kinetics
Rate of drug removal is constant - enzymatic capacity is saturated (AKA saturation kinetics) - this results in even small dose increases causing large increases in plasma concentration.
Half-life becomes progressively shorter as drug concentration drops in a linear faction, and is not useful.
For instance, alcohol is described as being metabolised by 1 unit/hr instead of in half-lives.
Phenytoin is another example - and can quickly saturate enzymes, changing from first-order to zero-order kinetics
Cₜ Concentration at time t
C₀ Concentration at time 0
e ⁻ᵏᵗ euler’s number ^ rate constant x time
How does half-life relate to the time constant?
Drug elimination example
Time constant is denoted by τ (tau)
It denotes how long it would take for a negative exponential process to complete, if the rate remained at the initial level.
This is therefore the time taken for the concentration to fall to 1/e of its original value (36.7%)
Half-life is 0.693 x time constant)
The rate constant (the maximal rate of removal) is the inverse of the time constant.
Explain context-sensitive half-time
The process that follows discontinuation of an IV infusion that was maintaining a steady-state plasma concentration, and is defined as the time taken for the plasma concentration of the drug to drop to half of the previous steady-state concentration
Context refers to the duration of the infusion - as the drug will have redistributed into other compartments, until there is no concentration gradient.
When the infusion is stopped, the drug will diffuse back from these compartments, meaning that the longer an infusion has been running, the more saturated these compartments are likely to be, and the longer it will take to clear the drug.
How does context-sensitive half-life vary between anaesthetic agents?
Following 8 hour infusion:
Remifentanil - 5 minutes
Propofol - 40 minutes
Alfentanil - 50 minutes
Thiopental - 150 minutes
Fentanyl - 250 minutes
Drug (2, 6, 9 hours) (In minutes)
Propofol 20, 30, 50
Alfentanil 40, 50, 80
Fentanyl 40, 240, 300
Why are fentanyl and remifentanil both considered safe in renal failure?
Fentanyl
Rapid redistribution due to high lipid solubility, with large volume of distribution - which becomes saturated after a long infusion.
Metabolised by the liver to inactive metabolites via CYP3A4 - only 10% directly renally excreted, so renal impairment will have only a small effect on accumulation
Remifentanil
Metabolised by highly abundant, non-specific plasma & tissue esterases into inactive metabolite - context-insensitive
This is in contrast to morphine, which is metabolsied in the liver to morphine-6-glucouronide (UGT1A3) and morpine-3-gluronide (UGT2B7). The 6-glururonide compound is active, and accumulates in renal failure.
Contrast elimination and excretion, and list common routes.
Elimination
Removal from plasma (Distribution, metabolism, excretion)
Excretion
Removal from the body
Bile
higher molecular weight molecules (>30,000 daltons) - such as rocuronium
Active against a concentration gradient - rifampicin excreted unchanged, morphine & propofol excreted as their glucuronide metabolites
Urine
Lower molecular weight molecules
Faeces
Respiratory gases
Breast milk
Tears/sweat/saliva
What 3 ways can drugs be excreted into urine?
Small, polar unbound drugs are filtered freely at glomerulus
Highly protein-bound drugs are not significantly filtered
Active transport in PCT
Acidic & basic drugs have separate mechanisms, so two basic drugs will compete for excretion, but not an acidic & a basic
Diffusion down concentration gradient in DCT
Ion trapping occurs when a molecule diffuses into the tubule & ionises, preventing return back into the cell - hence acidic drugs are more readily excreted in alkaline urine & vice versa - such as urinary alkalinisation in salicylate poisoning
What factors must be considered in a patient with renal disease?
Renally excreted drugs may accumulate - problematic if they have a narrow therapeutic range.
A historic example: Gallamine - a NDMB, which required CVVHDF to remove in renal failure
Dose may need changing, depending on the volume of distribution.
If normal VD, loading dose remains the same.
If increased, loading dose may need to be higher.
Following doses are always reduced, proportional to the reduction in drug clearance.
How can liver function be assessed?
Synthetic function
Clotting factors - INR
Albumin - Which indicates protein binding and volume of distribution of drugs
Level of inflammatory liver damage
Aminotransaminases - ALT/ALP
Albumin - Decreases in inflammatory disease
Alpha-1-acid glycoprotein increases in inflammation (acute phase protein)
Ascites
Can alter volume of distribution
Porto-systemic shunt
Increases PO bioavailability, reduced hepatic elimination
GCS
Hepatic encephalopathy increases sensitivity to sedating agents
