8. Drugs Flashcards
What is the first pass metabolism and how can it be avoided?
First pass metabolism is the metabolisation of the drug by the LIVER when it receives the drug via the PORTAL CIRCULATION before entering the systemic circulation.
It can be avoided by:
a) Parenteral route (i.e. not via the alimentary canal)
b) Sublingual route
c) Rectal route (however this drains into both portal and systemic circulations)
What is the therapeutic ratio of a drug?
The THERAPEUTIC RATIO of a drug is the MAXIMUM TOLERATED dose divided by the MINIMUM EFFECTIVE dose.
Or
LETHAL DOSE (LD50) divided by EFFECTIVE DOSE (ED50).
Define oral bioavailability. Give TWO ways it can be expressed.
ORAL BIOAVAILABILITY is the PROPORTION of a dose given orally (or by any route other than IV) that reaches the SYSTEMIC CIRCULATION in an UNCHANGED form.
It can be expressed as:
a) AMOUNT of oral bioavailability
b) RATE of oral bioavailability
Define the volume of distribution of a drug.
The volume of distribution is the THEORETICAL VOLUME on into which a drug has distributed assuming this has occurred instantaneously.
VOLUME OF DISTRIBUTION is therefore the AMOUNT of drug given divided by the PLASMA CONCENTRATION at time ‘0’.
When are protein binding interactions of drugs important to be considered?
Protein-binding interactions affect the FREE LEVEL of a drug, which exerts the effect. This is especially important when the drug:
a) is HIGHLY BOUND to albumin
b) has SMALL VOLUME of distribution (highly concentrated at time ‘0’)
c) has LOW THERAPEUTIC RATIO (a small therapeutic ‘window’)
Describe how protein binding interactions can affect the free level of a drug.
- OBJECT drug (class I) used at a dose much LOWER than the number of albumin binding sites.
- PRECIPITANT drug (class II) used at a dose much HIGHER than the number of available binding sites.
- Therefore precipitant drug DISPLACES object drug and causes much higher free levels of the object drug.
- Increased risk of TOXICITY from object drug (small therapeutic window)
- ELIMINATION rate rises also therefore a STEADY STATE is restored in a few days.
What is the difference between drugs which obey first order kinetics and those which obey zero order kinetics?
In most clinical situations, the drug CONCENTRATION is far LOWER than Km. When this is the case, rates of drug metabolism and elimination are directly PROPORTIONAL to drug concentration. These drugs are said to obey FIRST ORDER KINETICS.
For a few drugs, the doses are so large that drug CONCENTRATION is far HIGHER than Km. The enzymes are SATURATED and rates of metabolism and elimination are CONSTANT. These drugs are said to obey ZERO ORDER KINETICS.
In terms of drugs, what is a steady state?
A STEADY STATE is when a drug reaches a THERAPEUTICALLY EFFECTIVE plasma concentration which is maintained as long as regular doses are administered.
The regular doses match the rate of clearance.
A steady state is reached within 5 HALF LIVES of the drug.
Describe drug metabolism by the liver.
PHASE I
Oxidation, Reduction or Hydrolysis by MIXED FUNCTION OXIDASES (e.g. Cytochrome P450)
This is a low specificity process to make lipid soluble drugs reactive.
PHASE II
Conjugation by glucuronic acid, acetyl, methyl, sulphate, etc.
This step requires SPECIFIC enzymes and HIGH ENERGY cofactors. The aim is to add a polar group to the drug to allow elimination at the kidneys.
How do inducers and inhibitors affect drug metabolism?
Phase I drug metabolism at the liver involves mixed function oxidases which are inhibitable and inducible.
INDUCERS (Phenobarbitone, Rifampicin and Cigarettes) increase the activity of these enzymes therefore increase drug elimination.
INHIBITORS (Cimetidine) reduce the activity of these enzymes therefore decrease drug elimination.
Give ONE examples of inhibitors and THREE examples of inducers.
a) Inhibitors
CIMETIDINE => Warfarin and Diazepam
b) Inducers
PHENOBARBITONE => Warfarin and Phenytoin
RIFAMPICIN => Oral contraceptive pill
CIGARETTES => Theophylline
How can urine pH affect excretion of drugs by the kidneys?
Weakly acidic drugs are less likely to be reabsorbed (more likely excreted) if the urine is more alkaline.
Weakly basic drugs are less likely to be reabsorbed (more likely excreted) if the urine is more acidic.
An acid (HA) in the tubule is more likely to be in IONISED form (A-) when it encounters alkaline in the urine (B) which sequesters H+ ions, leaving A- ionised. Ionised substances are less likely to be reabsorbed.
A base (B) in the tubule is more likely to be in IONISED form (BH+) when it encounters an acid in the urine (HA), leaving A- and BH+ ionised and less likely to be reabsorbed.
