Drug elimination Flashcards
PK parameters of the distribution
The apparent volume of distribution (Vd) = Volume of fluid that would be required to contain the total amount of drug in the body (Q) at the same concentration as that present in the plasma (Cp)
The volume of distribution (Vd) =
The total amount of drug administered (Q) / Plasma concentration (Cp)
Factors affecting distribution
Blood perfusion of the tissue or organ.
Ability to cross a cell membrane.
Plasma protein binding ability
Blood brain barrier
Continuous layer of epithelial cells
Brain unaccessible to many drugs
Can become leaky with inflammation
The amount of drug depends on…
Concentration of free drug
Affinity for the binding site (2 per albumin molecule)
Concentration of protein
Albumin
Binds mostly acidic drugs (EG Warfarin, NSAIDS) and a small number of basic drugs (EG TCAs)
α1acid glycoprotein (AAG)
Binds mostly basic and neutral drugs. Increases inflammatory disease
Catabolism =
Break down substances by enzymes
Anabolism =
Build up of substances by enzymes
Oxidation =
Addition of oxygen and/or removal of hydrogen (loss of electrons)
Hydroxylation =
Conversion of a hydrogen to a hydroxyl group
Deamination =
Conversion of an amino group to a carbonyl group
Dehydrogenation =
Conversion of a hydroxyl group to a carbonyl group
Where does most oxidation occur?
Liver
Monooxygenases
Cytochrome P450
Alcohol dehydrogenase
Monoamine oxidases
Xanthine oxidase
Reduction =
Addition of hydrogen and/or removal of oxygen (gain of electrons)
Hydrogenation =
Conversion of carbonyl group to hydroxyl group
Hydrolysis =
Reaction with water, hydrogen binds to one compound, hydroxyl to the other.
Enzymes of hydrolysis reactions
Esterases
EG Cholinesterase, Peptidases and Amidases
Cytochrome P450 (CYP450) - Phase 1 reaction
Embedded on smooth ER
Require Oxygen, NADPH and NADPH-reductase
Large family of related but distant enzymes
Reduced P450s combined with CO = pink compound
CYP1A2
Paracetamol or caffine
CYP2C9
Ibruprofen or warfarin
CYP2E1
Paracetamol or alcohol
Variations in CYP450s
Species differences.
Genetic polymorphisms
Environmental factors
Other phase 1 enzymes
Aspirin esterase
Alcohol dehydrogenase
Butrylcholinesterase
CYP450s
Butrylcholinesterase
Aka Plasma Cholinesterase Hydrolyses Suxamethonium Structurally similar to Ach Overactivates cholinergic receptors on muscles to cause paralysis Neuromuscular blockers
Aspirin esterases
Aka Acetylsalicylate deacetylase
In plasma, hydrolyses aspirin to salicylate
Alcohol dehydrogenase
In liver cell (hepatocyte) cytoplasm
Oxidases ethanol to acetaldehyde
Requires NAD+
Phase 2 reactions
Anabolic - make up
If drug has reactive group either in the parent molecule or product of phase 1
Usually occurs in liver but also lung/kidney
Product usually inactive
PRODRUGS
Conjugation =
Attachment of a substituent group
Phase 1 reactions
Catabolic - break down
Functionalisation
Introduction of reactive group.
Products more reactive and sometimes more toxic
Examples of prodrugs
Inactive drug -> Active drug
Diacetyl-morphine -> Morphine
Valacidovir -> Aciclovir
L-Dopa -> Dopamine
Physiochemical properties of a drug
Mass transport in gut = faeces
Water soluble, filtered out by kidney = urine
Volatile gases = exhaled air
Secreted into glands = sweat and breast milk
Elimination depends on…
Physiochemical properties of drugs and metabolites
Total body CL (clearance) =
Sum of all organ CL processes.
Volume of plasma or blood cleared of the drug per unit of time to achieve overall elimination of drug from the body.
Cp
Plasma drug concentration
Co
Initial drug concentration
Elimination rate constant (Kel) =
Total clearance (CLtot) / Volume of distribution (Vd)
Vd
Volume of blood required to contain drug at plasma concentration
Elimination half life (t1/2)
t1/2 = Ln2 / Kel (On Log Scale)
Time taken for plasma drug concentration to reduce by half
In regards to steady state, 4-5 half-lives are needed to reach the point at which drug accumulation and elimination are balanced.
Major systems concerned with elimination
Kidneys
Hepato-biliary system
Lungs
Glucuronidation
Most common conjugation reaction
Important for both endogenous compounds (EG Bilirubin) and exogenous compounds
Mediated by UDP-glucuronyl transferases
Due to their polar nature, glucuronides are usually inactive and rapidly excreted
Paracetamol metabolism - Therapeutic doses
Mainly by conjugation with sulphate and glucuronic acid.
Only a minor proportion metabolised by CYP450 to a toxic metabolite (NAPQI).
Toxic metabolite normally detoxified by glutathione
Paracetamol metabolism - Overdose
Pathways of conjugation are saturated and co-factors are depleted and as such more paracetamol is metabolised via CYP450.
Toxic metabolites reacts with liver proteins instead of glutathione (depleted).
Tissue damage occurs leading to hepatic necrosis.
Endogenous factors affecting drug metabolistation: Genetic Constitution
Each member of a population will be described as either a fast or a slow metaboliser.
Can have implications for therapeutic efficacy and/or toxicity of certain drugs
Fast metabolisers
Normal enzyme activity
Lower plasma conc of the parent drug
Higher conc of the metabolite
Generally normal therapeutic response
Slow metabolisers
Low enxyme activity
Higher plasma conc of the parent drug
Lower conc of the metabolite
May lead to exaggerated therapeutic response at normal doses
Endogenous factors affecting drug metabolistation: Age
Individuals at extreme ages are affected.
Neonates (premature) - Low CYP and conjugating activity Glucuronyl transferase N-acetyltransferase Lack of use of morphine in labour
Elderly -
CYP activity declines slowly with age
More variability in half-life of many drugs
Issues for drug development
Increased half-life of diazepam (memory impairment)
Endogenous factors affecting drug metabolistation
Genetic constitution
Age
Disease
Exogenous factors affecting drug metabolistation: Drugs, smoking, alcohol/chemicals
Exposure to chemicals represents an important factor in the perturbation of drug metabolising enzymes.
These compounds either induce or inhibit drug metabolising agents.
Induction and inhibition represents two important mechanisms by which drug interactions occur.
Exogenous factors affecting drug metabolistation
Drugs
Smoking/alcohol
Environment exposure (including diet)
Induction of drug metabolising enzymes
An increased synthesis of enzymes (Phase 1 and 2).
Results in increased metabolism of inducing agent (autoinduction).
Different inducers induce different enzymes/isozymes.
Smoking and ethanol (chronic exposure) both act as inducer.
Drugs which act as inducers of drug metabolising enzymes often induce their own metabolism.
Inhibition of drug metabolising enzyme
Inhibition of the CYP system is caused by many drugs.
Reduced rate of metabolism and increased pharmacological effect.
For a drug to produce its pharmacological effect, it should achieve adequate concentrations at the site of action.
Basis of several drug-drug interactions.
Ethanol acts acutely to inhibit drug metabolism.
Glomular filtration
20% of renal blood flow filtered through glomerulus.
Drugs if MW <20,000 diffuse into glomerular filtrate.
Plasma albumin (MW 68,000) almost completely held back.
Lipid solubility and pH don’t affect GH.
Highly ppb drugs found at lower concentration in filtrate than in plasma.
ppb is a barrier to glomular filtration
Active tubular secretion
80% of renal blood flow passes the peritubular capillaries of the proximal tubule.
Drug molecules transferred to tubular lumen by two carrier systems which can transport against an electrochemical gradient.
Most effective method for drug elimination.
ppb is not a barrier to carrier mediated transport.
Many drugs share the same transporter which can lead to competition.
Low specificty
Passive diffusion / tubular reabsorption
Volume of urine = ~1% of the filtrate.
Drug concentration increases as water is reabsorbed.
Highly lipid soluble drugs have high tubular permeability and are slowly excreted.
Highly water soluble drugs have low tubular permeability and concentrate in urine.
Implications of induction
Decreased drug effectiveness on chronic exposure.
Need to increase drug dose.
In multiple drug therapy there may be problems when inducer is withdrawn from regimen.
Basis of many drug-drug interactions.
EG Rifampicilin and oral contraceptives
pH partitioning
Acidic drugs accumulate in basic fluid compartments and visa versa.
EG Aspirin is a weak acid (pKa = ~3.5) so can move through lipid membrane.
Mechanisms of elimination - Physiochemical properties of the compound.
Volatile gases are eliminated by exhalation.
Water soluble compounds are often eliminated to some degree unchanged in the urine.
Also may be excreted in the bile.
Lipid-soluble compounds typically undergo metabolism to more water-soluble metabolites that are then excreted in the urine and/or bile.
Mechanisms of elimination - Saturable elimination
Elimination mechanisms (such as enzymes) are typically not saturated at therapeutic doses of drugs, although there are a few exceptions (ie phenytoin). Increasing dose will disproportionately increase concentration (linear to non-linear kinetics). Often described with michaelis-menten kinetics.
Absorption - pH and pKa
Many drugs are weak acids (proton donator) or bases (proton acceptor).
Degree of ionisation changes with respect to pH of solution - dependent on pKa of drug.
An orally administered basic compound with pKa 8.0 will be predominantly in ionised form in the stomach.
