Drug ADME Flashcards
What does ADME mean?
Absorption Distribution Metabolism Excretion of drugs
What is Vd?
Volume of distribution indicates the extent of distribution for a drug
using the following equation:
Total amount of drug/ [plasma]
What is the significance of drug metabolism & excretion regarding dosing issues?
- Metabolism/Clearance determines the amount of drug
available at action site - Determines time taken for a drug to reach steady state
levels
Which type of drugs are absorbed most effectively?
Non ionisable, lipophilic drugs are absorbed most effectively
What is the significance of Vd?
Clinicallly important for adjusting dosage
Which drug type is least effectively absorbed?
Charged groups are absorbed less effectively
What is meant by drug absorption?
The process by which unchanged drugs enter the circulation
What are the factors affecting distribution?
- Barrier permeability
- binding in compartments
- pH
- water-fat partition
What is drug distribution?
The dispersion of a drug among fluids and tissues of the body
What does the extent of ionisation depend upon?
- pH of environment
- acid/base dissociation constant of drug
Describe 0 order kinetics
- straight line
- aka saturation kinetics
- t1/2 and clearance fluctuate with [drug]
- constant amount of drug removed
- bigger the does, longer the removal time
- as dose increases - no saturation so processes return to
1st order
What makes most drugs ionisable?
Most drugs are weak acids or bases so are ionisable
Name the pharmacokinetic parameters
t1/2 - half life
Vd - volume of distribution
CL - clearance
F - bioavailability
What is drug metabolism?
The transformation of a drug into daughter compound(s)
What is the Vd of s drug influenced by?
Lipid/water solubility and binding to plasma proteins
How is metabolism & excretion significant for safety?
- Metabolism produces new chemical entities that may
have their own effects - Components of racemic molecules (D/L enantiomers)
handled differently
What is the use of Henderson Hasselbach equations?
They predict the extent of ionisation
State Fick’s Law
Diffusion rate = surface area x [ ] difference x permeability
Describe 1st order kinetics
- constant 1/2 life (t1/2)
- constant clearance
- a constant fraction of drug is removed
- time taken to remove drug is independent of dose
- no saturation of process
What is permeability determined by?
- lipid solubility
- molecular size
- presence of charged ionisable groups
What is drug elimination?
The activity of metabolising enzymes and excretion mechanisms
What is CL?
Plasma clearance - the volume of plasma cleared of drug per time
Do polar or non polar molecules diffuse faster?
Uncharged/ non-polar groups diffuse quicker
Explain how glomerulus filtration occurs
Glomerulus filters <20kDa molecules
What is drug excretion?
The removal of drugs/metabolites from the body
Which order of kinetics do drugs follow?
Most drugs observe first order kinetics
A few observe 0 order kinetics
How does absorption occur?
Absorption can occur via
- Active transport through cells
- Facilitated diffusion through cells
- Passive diffusion (most medicines)
State the equation used to calculate CL
Rate of elimination/[drug plasma] = (ml/min)
How does the Henderson Hasselbach equation for bases differ from acids?
Bases pH = pka + log[non-ionised]/[ionised]
Acids pH is the pka - log of concentrations
How may the order of kinetics of a drug be altered?
By age and disease
State how the Henderson Hasselbach equation is used to determine acidic drugs extent of ionisation
pH = pka - log[non-ionised]/[ionised]
What is the significance of understanding the metabolism & excretion of drugs?
Knowledge can aid design of future drugs
Drug metabolites measured in substance abuse tests
When does each process occur after a drug has been taken?
The processes overlap and often occur simultaneously
e.g. removal occurs as soon as absorption occurs / during
Outline a common route of drug distribution?
- IV Dose
- > inside blood vessels
- > drug moves fast into well perfused areas
- > drug moves into poorly perfused areas
What does glomerulus filtration depend upon?
Filtration depends on levels of drug bound to plasma proteins
What is the bioavailability (F) of a drug?
The fraction of drug in the circulation compared to the dose
- measures extent of absorption
How does the drug metabolism process increase excretion?
Drug removal begins immediately
- loss of/reduced biological activity
- increased polarity - less receptor binding
- increases excretion
What is the significance of ADME?
These are the key factors in determining the onset speed of a drugs effects, duration of action and potential for problems
ADME is essential for safe use of medicines
When does drug metabolism occur?
Most drugs undergo metabolism prior to removal
What is meant by a ‘well perfused’ tissue?
A tissue with a good blood supply
Explain what is meant by 1/2 neutralisation of a drug?
pH = pKa when drug is 50% ionised
Which drugs are activated by metabolism?
Prodrugs
e.g. Enalapril into active form Enalaprilit by esterases
How does reabsorption in the kidneys occur?
As molecules pass through tubules, they are concentrated
Creating large [ ] gradients in order to make drugs more water soluble
- more drugs reabsorbed
How does the extent of drug ionisation change as pH changes
More of the acidic drugs stay unionised as pH becomes more acidic
More of the alkaline drugs stay unionised as pH becomes more alkaline
How is ADME used to ensure drug safety by doctors?
Used for:
- Treatment
- Designing dosing regimens (leaflets)
- Monitoring treatment compliance
- Substance abuse monitoring
- Medicine licensing requirement
Explain how tubular secretions occur
- Acid/base molecule carriers transport molecules into
tubular fluid - Lower levels of unbound drug in plasma
- Pushed reaction for plasma proteins to release more
free drug for secretion by carriers
Explain how much the dose needs to be increased to achieve 100% bioavailability if F=0.1?
F = 0.1 = 10% bioavailability
need to increase dose by x10 to achieve F the same as [drug]
Describe aspirin absorption at the gastric mucosa
Aspirin is a weak acid (pKa = 3.5)
Majority of aspirin remains neutral in stomach acid as its also acidic
Aspirin is absorbed readily in stomach as non polar
Becomes polar in blood stream as circulation pH = 7.4
Give an example of a drug that is eliminated unchanged
Digoxin doesn’t undergo metabolism
- produces toxic metabolites
What is the aim of multiple dose therapy?
Aim is to keep levels of drug at site of action as stable as possible
What is meant by the term ion trapping?
The build up of a [high] of a chemical across a cell membrane due to the pKa value of the drug and pH difference across the membrane
State a calculation used to determine excretion
Excretion = Fltration - Reabsorption + Secretion
What is the choice of delivery route guided by?
Bioavailability Chemical properties of drug Convenience Control of action specificity Desired onset/ duration / offset of action
Where are acidic drugs most efficiently absorbed?
Acidic drugs absorbed efficiently from stomach due to pH 1-2
How is the safety of a drug ensured before its release?
All pharmacokinetics profiles are required before any drug/pharmaceutical is in use
What are the 2 phases of drug metabolism?
- introduces chemically reactive groups
2. increases water solubility of drug for excretion
How effectively are basic drugs absorbed from stomach?
Basic drugs absorbed poorly from stomach
Absorbed better from intestine as pH 6.6 - 7.5
(many drugs absorbed from intestine)
Explain how Phase 1 of drug metabolism occurs
Oxidation within liver
- O₂ molecules added to C, N₂, S molecules in drug
structure
- carried out by Cytochrome P450 enzymes
- bind drug + O₂ molecules
(other reactions occur e.g. hydrolysis, hydration etc.)
Give the pharmacokinetic details of Paracetamol
INDICATIONS: mild to moderate pain, pyrexia
CAUTIONS: hepatic impairment, dose related toxicity -
avoid large doses
interacts with other substances e.g. alcohol
DOSE: orally 0.5 - 1g every 4-6hrs (max = 4g daily)
intravenously over 15min 1g every 4-6hrs (daily
max 4g or 60mg/kg)
SIDE EFFECTS: rare but include skin conditions
What is renal clearance?
The volume of plasma cleared of drug per unit time in one pass through the kidney
- drug is cleared from blood and appears in urine
What is the use of ADME in drug development?
ADME regulates drug development
40% of potential drugs withdrawn from development as they don’t meet
pharmacokinetics ADME guidelines
How does the distribution of a drug determine its effectiveness?
The aim of good therapeutics is to deliver medicines to their site of action at effective concentrations
How is the O₂ molecule used in Phase 1 of drug metabolism?
Drug is oxidised via 1 O₂ molecule
2nd O₂ molecule reduced to water
What are the Lipinski rules?
An orally active drug can’t violate more than one of the following rules:
- molecular weight ,500
- no more than 5H+ bond donors
- no more than 10H+ bond acceptors
- logP<5 (partition coefficient)
What is meant by drug distribution?
The dispersion of a drug among fluids and tissues of the body
How are Phase 1 metabolism reactions carried out?
Mainly carried out by CYP isoforms
How do Lipinski rules work alongside ADME?
ADME optimisation might minimise the desirable properties of the drug
Lipinski rules are just a rule based approach to optimise ADME
How can we increase plasma 1/2 life?
By decreasing renal elimination
What causes a low bioavailability of a drug?
- poor absorption
- chemical reactions at delivery site
- first-pass metabolism
Outline the drug metabolism process
- Drug/Prodrug
- -> Phase 1 - e.g. hepatic oxidation - reactive metabolite/active drug
- -> Phase 2 - conjugation - water soluble metabolite
- -> excretion
How are drugs excreted via the kidney?
- Glomerulus filtration
- Reabsorption
- Tubular secretions
Why is [drug] monitored?
- to individualise therapy
- to diagnose toxicity
- to determine presence of other drugs before starting therapy
e. g. Theophyline in an unconscious patient with Asthma “
How does Phase 2 Drug metabolism occur?
Conjugates Phase 1 products with an endogenous substance through production of
stable covalent bonds
e.g. glucorodination (rxn with glucose)
Which factors affect drug metabolism & excretion?
- Age
- Genetics
- Enzymes
- Disease
List some reasons why drugs are withdrawn from development
- Don’t meet Pharmacokinetic guidelines
- Animal toxicity
- Miscellaneous
- Adverse side effects
- Commercial reasons
- Lack of efficacy
How is metabolism & excretion affected by genetics?
45% in europe and USA and 80-90% in asia = fast acetylators
1/3000 have slow metabolism by pseudocholinesterase
What is the benefit of using a ‘multiple dosing’ dosing regimen?
Leads to a steady state
amount of drug absorbed = amount of drug eliminated
Which drug metabolism is exempt from the normal metabolism process?
Paracetamol metabolism goes straight to Phase 2 reactions
glucorodination / sulphate conjugation
What is the significance of drug absorption?
Drugs need to be absorbed unless given directly into the circulation
How does age affect excretion & metabolism?
Cyto P450 activity reduced in neonates/elderly
GFR reduced greatly in neonates/elderly
increased % fat content in elderly
How does the route taken by a drug change its outcome?
Different routes of administration
- present different barriers
- result in a different bioavailability
- differ in onset
What is drug metabolism?
The removal of lipid soluble drug molecules to prevent reabsorption by kidneys
What are the general rules for a drugs’ steady state
- Repeating doses eventually produces a steady state
(plateau) - Time to plateau = 4.5 x 1/2 life
- Steady state levels aren’t flat
- Fluctuation size is inversely proportional to no. of daily
doses - Fluctuations create potential for sub-therapeutic
treatment of toxicity
How do drug metabolising enzymes alter drug metabolism?
Can be induced by other drugs/ lifestyle factors
can be inhibited by certain drugs
How does multiple dosing work?
- Additional doses administered before [drug] falls to 0
- [drug] variations depends on 1/2 life and dose interval
How is drug metabolism achieved?
By converting drugs into water soluble molecules
What is the most common absorption route taken by drugs?
Orally
Mouth -> stomach (acid present) -> gut -> hepatic portal vein -> liver
There are metabolic enzymes present during the route which can cause the drug to lose its effects
What does multiple dose therapy comprise of?
Minimisation of drug level variability
Simplicity
Explain the effects of disease on drug metabolism & excretion
Liver disease - inhibits/impairs drug metabolism
Renal disease - alters pharmacokinetics
Where does drug metabolism occur?
Mostly in the liver
Also in lung and intestinal epithelium plasma
What is the delivery route a compromise of?
- speed of onset
- convenience (oral/IV)
- Bioavailabiltiy
- Side effects
- Action specificity
Where does absorption of drugs occur?
Most absorption occurs through cells (transcellular)
Some occurs between cells (paracellular)
Why does the effect of factors affecting metabolism & excretion vary?
Patients aren’t all the same and don’t easily fall into same categories
Patients can have the same diagnosis and prescription but differ in outcome
What does the term bioavailability mean when talking about drugs?
The proportion of drug administered reaching the system circulation
When is drug concentration monitored?
For drugs with narrow therapeutic index or [ ] that relate well to either therapeutic effect and/or toxic effect
How can onset of action for drugs with long 1/2 lives be altered?
For drugs with long half lives achievement of steady state can be
accelerated by a loading dose
e.g. Theophyline treatment (t1/2 for theophyline = 8hrs)”
What is CL?
The volume of plasma cleared of drug per unit time
- a constant clearance for drugs following 1st order
kinetics
What is Pharmacokinetics?
The body’s response to drugs
What are the different outcome variations possible?
- Drug toxic but beneficial
- Drug toxic and not beneficial
- Drug not toxic and beneficial
- Drug not toxic but not beneficial
How is CL calculated for a drug removed by liver metabolism and kidney excretion?
Plasma CL = Hepatic CL + Renal CL
What are the biological barriers faced by a drug absorbed transcellularly?
Drug has to cross semi-permeable membrane twice and aqueous cytosol
