Session 6

Question 0

What is ADME?

Answer 0

Absorption, Distribution, Metabolism, Elimination

Question 1

Define pharmokinetics

Answer 1

The study of the time course of drugs and their metabolites in the body

Question 2

Compare and contrast phase I and phase II of drug metabolism

Answer 2

Phase I:
Reactive group exposed/added,
Generates reactive intermediate
Consists of oxidation, reduction and hydrolysis
Requires cytochrome P450 and NADPH as a cofactor
Occurs mostly in liver but also in GI tract, kidney (histamine), lung, plasma (cholinesterase)

Phase II
Reactive intermediate conjugated to become H2O soluble
Conjugated with glucuronic acid, sulphate ions, glutathione
Requires enzymes and UDPGA as a cofactor
Occurs in liver by cytosolic enzymes

Question 3

Discuss the importance of the cytochrome P450 system

Answer 3

Cytochrome P450 system (CYP) has about 50 different haem containing enzymes. Isoform CYP3 A4 is most important - 55% of drug metabolism

Question 4

Explain variation in drug metabolism in the population

Answer 4

Genetic:
Polymorphisms, individual variation, enzyme deficiency (acetylation, plasma cholinesterase, dealkylation)

Environmental:
Enzyme inhibition (polytherapy, cimetidine - cranberry + grapefruit juice), enzyme induction (increased metabolism of other drugs e.g. Alcohol, nicotine, barbiturates)

Question 5

Describe the specific examples of the metabolism of alcohol and paracetamol

Answer 5

Alcohol:
Ethanol –> acetaldehyde –> acetate (alcohol dehydrogenase –> aldehyde dehydrogenase)
Damaged liver cells lose transaminases (ALT, AST) and gamma glutamyl transpeptidase = liver function test
Hyperbillirubinaemia = jaundice
Increased glutamine
Decreased albumin, clotting factors, lipoprotein
Disulfiram inhibits aldehyde dehydrogenase

Paracetamol:
Normal dose - paracetamol –> glucuronide/sulphate (non toxic)
Over dose - paracetamol –> NAPQI (toxic)
Depletes cell of glutathione (anti oxidant)
Treatment - N-acetylcysteine (<3/4 days)

Question 6

Describe the major metabolic fuels and their sources in the normal individual

Answer 6

Glucose - used by all cells, stored as glycogen in liver and muscle
Fatty acids - not used by RBC + CNS, derived from TAGs, can be converted into ketone bodies in liver
Protein - proteolysis to amino acids, can be converted to glucose and ketone bodies

Question 7

Explain how the blood glucose concentration is controlled and why this is necessary

Answer 7

Maintained in the range 4.0-6.0 mmol/L by regulating entry and removal of glucose from blood via endocrine system
It is necessary to ensure that the CNS receives an adequate supply of glucose
Hypoglycaemia = 7 mmol/L - glucose in urine, polyuria, polydipsia

Question 8

Compare and contrast the effects of insulin and glucagon on nutrient storage and metabolism

Describe the metabolic responses to feeding and fasting and explain how they are controlled

Answer 8

Insulin (feeding):
Increases glucose uptake and utilisation by muscle and adipose
Promotes storage of glucose as glycogen in liver and muscle
Promotes amino acid uptake and protein synthesis in liver and muscle
Promotes lipogenesis and storage of fatty acids as TAGs in adipose

Glucagon (fasting):
Stimulates glycogenolysis in liver to maintain BGL
Stimulates lipolysis in adipose to provide fatty acids
Stimulates gluconeogenesis to maintain supplies of glucose

Question 9

Describe the metabolic responses to starvation and explain how they are controlled

Answer 9

Starvation - fasting >10h
Decreased BGLs –> release of ACTH by pituitary –> increased cortisol

Cortisol:
Stimulates gluconeogenesis 
Stimulates protein and fat breakdown
Increased lipolysis >2 mmol/L
Fatty acids --> ketone bodies (fuel for brain)
Reduction in urea synthesis

Refeeding syndrome - protein content must be increased gradually
Death is due to loss of muscle mass, serious respiratory infections, loss of respiratory muscle