M&R session 9: pharmacokinetics Flashcards
What factors are involved in a drug?
- Is drug getting into patient? Pharmaceuticals
- Is drug getting to site of action? Pharmacokinetics
- Is drug producing desired pharmacological action? Pharmacodynamics
- Is pharmacological effect translated into a therapeutic one? Therapeutics
Describe the pharmaceutical process
- Formulation: solid or liquid. If solid, solubility and acid stability in stomach must be considered. Rate of action depends on dissolution
- Patient compliance: important so need clear dosage or regimen instructions to maximise chance
- Site of administration:
- focal: eye, skin, inhalation. Concentrates drug at site of action so fewer systemic effects, e.g. topical steroid skin creams
- systemic: ENTERAL (uses GI tract: sublingual, oral, rectal) or PARAENTERAL (e.g. subcutaneous, intramuscular, intravenous, transdermal)
What is oral bioavailability?
The proportion of drug given orally/any other route except IV [as when IV bioavailability is 100% by definition] that reaches the circulation unchanged. Can be expressed as:
- AMOUNT: depends on GI absorption and 1st pass metabolism. Measured by area under curve of blood drug level vs time
- RATE of availability: depends n pharmaceutical factors and rate of gut absorption. Measured by peak height and rate of rise of drug level in blood
How is oral bioavailability calculated?
BA=(AUC oral/AUC injected)*100
AUC=area under curve
What is therapeutic ratio? How does this differ between warfarin and penicillin?
LD50/ED50
i.e. the maximum tolerated dose divided by the minimum effective dose
Warfarin has small therapeutic index so need to be careful when prescribing as can easily give a dose causing unwanted effects. Penicillin has a large therapeutic index so small errors are safer
Explain the concept of first pass metabolism
The drug lost between oral administration and first appearance in the systemic circulation. Blood from the gut reaches the liver by the portal system, where the liver could metabolise the drug before it gets to the systemic circulation.
Examples where this may occur include opiates, lidocaine, propranolol
Avoided by the parenteral, sublingual or rectal routes of administration
What is volume of distribution and how is it obtained?
The theoretical volume into which a drug has distributed, assuming that this occurred instantaneously. Very lipid-soluble drugs may seem to have a larger distribution volume than the whole body because the drug will have been deposited into fatty tissue.
Obtained by extrapolation of plasma levels to zero time, giving Co: the hypothetical drug concentration predicted if the distribution had been achieved instantly.
Displacement of drugs from binding sites causes protein binding drug interactions. When are these important?
- If drug is >90% bound to albumin
- If drug has a small volume of distribution
- If drug has a low therapeutic index
Describe class I and class II drugs, giving some examples
Class I: object drug. Used at a dose lower than the number of albumin binding sites. Most drugs are bound and there is a low [free drug]
Class II: precipitant. Used at doses greater than the number of binding sites so displace the class I drug if simultaneously given. Most albumin molecules contain bound drug, significant [free drug]
Warfarin (O), sulphonamides aspirin and phenytoin are all precipitants
Tolbutamide (O), sulphonamides and aspirin are precipitants
Phenytoin (O), valproate is a precipitant
So when a patient is taking an object drug, adding on the precipitant drug will temporarily cause higher free levels of the object drug causing higher risk of toxicity
Describe first and zero order kinetics
FIRST ORDER: rate of elimination is proportional to drug level, constant fraction of drug eliminated in unit time, half life can be defined. Linear when log Y axis plotted against time. At low doses drug metabolism is first order. Predictable therapeutic response as dose increases so reliable control
ZERO ORDER: rate of elimination is constant. Linear when linear Y axis is plotted against time. At very high doses drug metabolism is zero order. Therapeutic response can suddenly escalate as elimination mechanisms saturate so need to increase dose in small increments. Rare examples e.g. alcohol, phenytoin
When is a steady state achieved?
In ~5 half lives
This is irrespective of dose or frequency of administration. Important for drugs with long half life in order to predict when the steady state will be achieved; shouldn’t change drugs too frequently as need to wait until the drug is in the steady state
When is a loading dose given?
Used when a half life is long but a rapid effect is needed. Often determined by the volume of distribution
E.g. in acute atrial fibrillation a high dose of digoxin is given first to quickly reach the therapeutic threshold, then continue with maintenance dose
Describe drug metabolism
Mainly in liver
- Phase 1: OXIDATION, REDUCTION, HYDROLYSIS:
- carried out by mixed function oxidases
- enzymes are inducible and inhibitible so susceptible to drug interactions
- consists of NADPH cytochrome P450 reductase in liver microsomes. Low substrate specificity with affinity for lipid-soluble drugs - Phase II: CONJUGATION (glucuronamide, acetyl, methyl, sulphate)
- end of phase I drug is often inactivated but can be activated/unchanged
- end of phase II drugs usually inactive
- some drugs directly enter phase II
Clinically-relevant drug interactions
Drugs with low therapeutic ratio
Drug being used at minimum effective concentration, e.g. oral contraceptive pill
Drug metabolism follows zero order kinetics
Enzyme inducers:
-rifampicin: affects oral contraceptive pill
-phenobarbitone: affects warfarin (increases metabolism so decreased anticoagulation)
-cigarette smoke: affects theophylline
Enzyme inhibitor: cimetidine. Inhibits warfarin metabolism so excess anticoagulation
Describe drug excretion
Mainly in kidneys. Only the free fraction of the drug is filtered in the glomerulus. Drugs can be actively secreted by the tubules (e.g. penicillin is secreted by the proximal tubule).
Passive reabsorption: dependent on pH. pK=pH at which half is ionised. Only the non-ionised part is lipid-soluble and easily crosses membranes
Weak acids: acid urine increases absorption, alkaline urine decreases absorption. So e.g. aspirin making the drug alkaline will ionise it so less tubular absorption as stays tubule lumen
Weak bases: acid urine decreases absorption, alkaline urine increases absorption. So e.g. amphetamine make acid urine to increase excretion
