Lecture 7 Flashcards
In the kidneys during METABOLISM why are the drugs made more hydrophyllic?
- it speeds up excretion as less lipid-soluble metabolites are not readily reabsorbed in the renal tubules
- matabolites are usually less active than the parent drugs = their effect decreased
- switch drug off make more likely for excretion
What are the 3 overall effects METABOLISM has on a drug?
STOP = mechanism for termination of drug action
GO = mechanism for activation of drug action
NO CHANGE = drug elimination without metabolism e.g. simple elemental drugs
Explain the mechanism of termination of drug action during metabolism and give an example of a drug class
Occurs as a result of the drug being metabolised to biologically inactive derivatives before excretion.
An example of this drug class is the PHENOTHIAZINES
Explain the mechanism of activation of drug action during metabolism and give an example of a drug
PRODRUGS are inactive when administered and must be metabolised in the body to become active after absorption
LEVODOPA is an example of a prodrug
CODENE which is demethylated to morphine
Explain the mechanism of DRUG ELIMINATION WITHOUT METABOLISM and give an example of a drug
Some drugs are not modified by the body but continue to act until they are excreted unchanged
LITHIUM is an example of this drug class
(Is a mood stabiliser - for bipolar)
What are the SITES OF DRUG METABOLISM?
LIVER = most important organ for drug metabolism is KIDNEYS = minor site
These organs contain the cellular enzymatic complement necessary for drug metabolism.
contain bags of enzymes
Drug metabolism comprises 2 CLASSES OF ENZYMATIC REACTIONS termed Phase I and Phase II
Describe PHASE I REACTIONS in drug metabolism
- Involve the unmasking/removal of the active group (e.g. acytl group becomes -OH, NH2, SH)
- becomes a more polar metabolite
- Phase I reactions include the following reaction types
- oxidations
- reductions
- hydrolysis
- hydroxylation
- dealkylation
- deamination
Oxydation the most common pathway for PHASE I metabolism is catalysed by what enzyme?
cytochromes P450 = superfamily of haem protein enzyme isoforms
- can exist constitutively or induced by certain drugs
- it has several 100 isoforms but the 3 important families in drug metabolism =
- CYP1
- CYP2
- CYP3
Each family has several members that are specific to the metabolism of a particular drug.
Give an example of how PHASE I METABOLISM can result in the formation of active metabolites
- Sometimes drug oxidation can result in the formation of active metabolites which have a duration of action that exceeds that of the administered drug.
E.g. the metabolic conversion of DIAZEPAM to DESMETHYLDIAZEPAM
Describe and give examples of REDUCTION PHASE I REACTIONS
- susceptible functional groups such as nitro, keto, sulphoxide substituents.
- => activation/inactivation of drugs
Examples include:
- Sulindac, a prodrug whose sulphoxide group is reduced to produce sulindac sulphide.
- Prednisone, a prodrug that undergoes reduction of a ketone to an hydroxyl group to produce the active glucocorticosteroid prednisolone
Describe and give examples of HYDROLYSIS PHASE I REACTIONS
- put H2O between molecule and split in two
Many prodrugs are activated by hydrolysis.
Example include:
- Sulfasalazine is hydrolysed to aminosalicylic acid and sulfapyridine by the bacterial flora of the GI tract
- Bambuterol is hydrolysed by pseudocholinesterase in lung tissue to release the active beta adrenergic agonist terbutaline
Describe PHASE II REACTIONS in drug metabolism
- Increase water solubility of drug by congugation with polar molecule
- Such polar molecules include glucuronate, glutathione, glycine, sulphate and methyl groups.
- The resultant conjugate is almost always pharmacologically inactive and less lipid soluble than its precursor and can be readily excreted in bile or urine
Define BIOTRANSFORMATION RATE and list some factors affecting it
The alteration of a drug in the body ADME
-varies between individuals: here are some affecting factors
- Lifestyle
- Genetic factors
- Other drugs (co-administration)
How does LIFESTYLE affect the biotransformation rate of a drug?
gender can be important
- (e.g., women have lower first pass metabolism of alcohol than men)
- smoking => enzyme induction in the liver
How do GENETIC FACTORS affect the biotransformation rate of a drug?
- Metabolic difference are found between differing families or populations
Example:
- Hydrolysis of esters – succinylcholine is hydrolysed by plasma cholinesterase. Takes 5 mins in most people. However 1:2500 people have a mutated form of the enzyme => very slow metabolism = prone to neuromuscular paralysis that can last many hours.
- Acetylation of amines –
- Amines (e.g. Isoniazad, procainamide) are inactivated by acetylation.
- some Individuals deficient in acetylation capacity (“slow acetylators”) may => prolonged/toxic effects to normal doses of these drugs.
- From the inheritance of an autosomal recessive gene.
