Lecture 6.1: Drug Metabolism Flashcards
What is Pharmacology?
It is the study of drug interaction with the body
What is a Drug?
A chemical substance which produces a biological effect following its administration to the body
What is Medication or Medicine?
A drug administered to the body to cure or improve a medical condition
What is Pharmacokinetics?
What the body does to the drug
The study of the movement of drugs and their metabolites through the body
What is Pharmacodynamics?
What the drug does to the body
Pharmacokinetic Stages: ADME
Absorption
Distribution
Metabolism
Elimination
Drug Metabolism
• As soon as a drug enters the body it will start to be metabolised
• Drugs are foreign to the body & are potentially toxic
• So they need to be deactivated and eliminated
• Most drugs are lipid soluble rather than water soluble
• They need to be made more water soluble
• Thus they can be excreted directly by the kidneys
Pro-Drugs
Some drugs are made active during their metabolism
Pro-Drugs Examples: Where metabolites more pharmacologically active than the parent drug molecule
pethidine —> norpethidine
codeine —> morphine
Phase I of Drug Metabolism
Reactions that convert the parent drug to a more polar/ reactive product by unmasking or inserting a polar functional group such as ´OH, ´SH, or ´NH2
Occurs mostly in liver (most enzymes in the ER of cells), may also occur in the GI tract, kidney, lung and plasma
Converts lipophilic drugs into more polar molecules
Involves oxidation (most common), reduction and hydrolysis reactions
CYP450 Enzymes
• There are around 60 CYP enzymes (many isoforms)
• CYP 1-3 families are involved in drug metabolism
Isoforms:
• CYP3A4 accounts for ~55% of drug metabolism
• CYP2D6 accounts for ~25% of drug metabolism
Variation in CYP450 Activity: Genetic
There is a huge genetic variability in P450 enzymes amongst individuals and races, which can affect drug efficacy and the risk of side effects
• mutation in CYP2D6, involved in metabolic conversion of codeine to morphine
Variation in CYP450 Activity: Environmental
Environmental factors (diet, pesticides, other drugs etc.) may also alter P450 enzyme activity
• e.g. grapefruit juice and cimetidine act as inhibitors
• e.g. nicotine act as inducers
Phase II of Drug Metabolism
• Occurs in liver (cytosolic and endoplasmic reticulum enzymes)
• Drugs with –OH, -NH2 , -COOH groups will directly go to Phase II
• Many phase I metabolites are still too lipophilic
• Involves conjugation reactions (addition of a water soluble group to drug)
• Leads to production of inactive metabolites
Phase II of Drug Metabolism: What groups are added?
• (Glucuronate) Glucuronic acid conjugation (glucuronidation)
• Sulphate or (acetate) acetyl group conjugation
• Glutathione conjugation
• Glycine
• Methyl group
Glucuronidation
Glucuronic acid is transferred from uridine diphosphate-glucuronic acid (UDPGA) to substrate (e.g. morphine)
Metabolism of Paracetamol in normal levels
A therapeutic dose of paracetamol is metabolised in Phase II by conjugation with glucuronic acid or sulphate
Acetaminophen is conjugated to harmless glucuronide and sulphate metabolites when it is taken in recommended doses by patients with
normal liver function
Metabolism of Paracetamol during overdose
A toxic dose of paracetamol is metabolised in Phase I and Phase II
In Phase II Glutathione conjugation and sulphation
Metabolism of Paracetamol during overdose if Phase II is saturated
If glutathione stores are exhausted, however, the reactive intermediate combines with sulfhydryl groups on essential hepatic cell proteins, resulting in cell death
Prompt administration of other sulfhydryl donors (eg, acetylcysteine) may be life-saving after an overdose
What makes you more susceptible to paracetamol overdose?
In severe liver disease, stores of glucuronide, sulphate, and glutathione may be depleted
Making the patient more susceptible to hepatic toxicity with near-normal doses of acetaminophen
N-Acetylcysteine
N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose
It is thought to provide cysteine for glutathione synthesis
Possibly to form an adduct directly with the toxic metabolite of acetaminophen, Nacetyl-p-benzoquinoneimine
Metabolism of Alcohol
> 90% alcohol is metabolised and < 10% is excreted passively via urine and breath
The main route of its metabolism is via alcohol dehydrogenase
However its small amounts are also metabolised by P4502E1 enzymes in liver or by catalase in brain
Alcohol dehydrogenase oxidises alcohol to acetaldehyde and then oxidises acetaldehyde to acetate (acetic acid)
The acetate is converted to acetyl CoA by acetyl CoA- synthase
Consequences of Prolonged/ Excessive Alcohol Consumption
Liver toxicity due to acetaldehyde accumulation which leads to liver damage and dysfunction
Altered liver metabolism due to decrease in NAD+/NADH ratio and increased availability of acetyl CoA
Dysfunction of Liver
• Escape of liver enzymes such as AST (aspartate transaminase) and ALT (alanine transaminase) to blood
• Reduced taking up & conjugation of bilirubin leading to hyperbilirubinaemia
• Reduced production of urea leading to hyperammonaemia
• Reduced synthesis of proteins (albumin, clotting factors and lipoproteins)
Why Alcoholics May Have a Fatty Liver?
• Reduced levels of NAD+ in liver for fatty acid oxidation
• Increased levels of acetyl CoA will not be oxidised due to reduced levels of
NAD+
• Increased fatty acid synthesis and ketone synthesis (may lead to
ketoacidosis) from acetyl CoA
• Increased synthesis of triacylglycerols, which cannot be transported from
the liver due to reduced synthesis of lipoproteins, leads to a fatty liver
Why Alcoholics May Have Gout?
Increased blood lactate leads to lactic acidosis and reduces the kidney’s ability to excrete uric acid
As uric acid levels increase, crystals of urate accumulate in tissues leading to gout
Treatment of Alcoholism
• Disulfiram inhibits aldehyde dehydrogenase
• This increases conc of acetalderhyde
• Which in increased concs causes nasuea, vomiting, blurred vision,
palpitations…etc
• Produces acute sensitivity to alcohol
