Week 6 Flashcards by Alice Neale

What does ADME represent?

Pharmacokinetics involves studying the absorption, distribution, metabolism and elimination of a drug.

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What’s the difference between pharmacokinetics and pharmacodynamics?

Pharmacokinetics is the study of the time course of drugs and their metabolites in the body
Pharmacodynamics is the effect that the drug has on the body, which depends on its free concentration and hence on its pharmacokinetics.

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Why can’t drugs be excreted in an unchanged form in the urine?

Many drugs are lipid soluble and are reabsorbed in the renal tubules - only 1% of a drug can be excreted unchanged.

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Name two drug which bypasses stage 1 metabolism and goes straight into stage 2

Morphine

Paracetamol

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What is the strategy of phase 1 of drug metabolism?

Add or expose a reactive group on the molecule to make it more reactive so it can be conjugated with a water soluble molecule in phase 2.

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What are the most common reactions in phase 1 of drug metabolism?

Hydrolysis, reduction and oxidation

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What is required for phase 1 drug metabolism?

Cytochrome P450 (CYP) system and NADPH as a cofactor.

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What is the ‘strategy’ of phase two of drug metabolism?

Conjugate the reactive intermediate from phase one with a polar molecule to make it water soluble.

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What is the most common conjugate in phase two of drug metabolism? Why?

Glucuronic acid - byproduct of metabolism.

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What substances can be used to conjugate reactive intermediates in stage two of drug metabolism?

Glucuronic acid, glutathione, sulphate ions

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What else is required for phase two of drug metabolism?

specific enzymes

UDPGA (uridine diphosphate glucuronic acid) - high energy cofactor

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Where does drug metabolism occur?

Mainly liver

Also lungs, kidneys, GI tract, plasma.

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What can cause variations in drug metabolism in the population?

Genetic differences - different levels of expression of enzymes
Environmental factors - other drugs or exposures that alter the activity of enzymes

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What is the most important enzyme in Cytochrome P450?

CYP3 A4 - accounts for 55% of drug metabolism

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What is a slow acetylator?

Someone who lacks the enzyme for acetylation in phase two, and can’t metabolise drugs that require this pathway.

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What is the consequence of low pseudocholinesterase?

Can’t metabolism drugs containing an ester bond such as suxamethonium (muscle relaxant used in anaesthesia)

What is the first pass effect?

All substances absorbed into the blood from the ileum travel directly to the liver via the hepatic portal vein.
The liver is the main site of drug metabolism, so some drugs can be metabolised before reaching their target tissues, meaning large doses are required

Why are large oral doses of paracetamol necessary?

90% of the drug is metabolised on the first pass through the liver and never reaches the target tissues.

What is the fate of dietary alcohol?

10% excreted passively in urine or breath
90% metabolised - alcohol -> acetaldehyde (alcohol dehydrogenase) -> acetate (aldehyde dehydrogenase) -> Acetyl CoA (requires ATP)
Can be oxidised by CYP2E1 (inducible)

What is the benefit of acetaldehyde dehydrogenase having a very low Km for acetaldehyde?

Acetaldehyde is toxic to cells, low km means it can be removed promptly even when present in low concentrations.

What is the consequence of accumulation of acetaldehyde following excessive alcohol consumption?

Liver damage

In what way is the NAD+/NADH ratio altered in excessive alcohol consumption and why?

Ratio is less as NAD+ is used to oxidise alcohol, and so it is present in the reduced form.

How does alcohol metabolism lead to lactic acidosis?

Insufficient NAD+ to oxidise lactate to pyruvate.
Decreased utilisation of lactate by lifer cells - lactate accumulates in blood.
Can cause lactic acidosis.

How can alcohol metabolism cause gout?

Low levels of NAD+ means lactate is not utilised in the liver as it cannot be converted to pyruvate.
Lactate accumulates in the blood.
This decreases the kidneys ability to excrete uric acid.
Crystals of urate appear in the tissues - gout.

Why do alcoholics get fasting hypoglycaemia?

Poor diet = low liver glycogen Low NAD+ means lactate cannot be converted to pyruvate for gluconeogenesis. Gluconeogenesis from pyruvate also requires NADH. Therefore cannot synthesise glucose - fasting hypoglycaemia

What causes a fatty liver in alcoholics?

Increased acetyl CoA from alcohol metabolism, cannot be oxidised due to low NAD+. Therefore rate of fatty acid synthesis and ketone body synthesis increases. Fatty acids are converted to TAGs Can't synthesise lipoproteins therefore remain in liver

Why can alcoholics get ketoacidosis?

Low NAD+ means high levels of acetyl CoA can't be oxidised for energy release, so fatty acid synthesis and ketone body synthesis is favoured. Levels of ketone body synthesis can be high enough to cause ketoacidosis.

What is used to treat alcohol dependence and how does it work?

Disulfiram inhibits acetaldehyde dehydrogenase. This causes accumulation of acetaldehyde in the tissues. This causes the symptoms of a hangover. Must be accompanied by support.

How can liver damage be diagnosed?

Presence of enzymes such as AST and ALT, and gamma glutamyl transpeptidase in the blood indicates leaky plasma membranes of damaged liver cells

Why might alcoholics get jaundice?

Liver cells damaged by acetaldehyde means cells can't take up and conjugate bilirubin leads to hyperbilirubinaemia and jaundice

What's the consequence of a reduction of the capacity of the liver to produce urea in an alcoholic?

Hyperammonaemia and high levels of glutamine (from alphaketoglutarate - inhibits Krebs)

What is the consequence of reduced protein synthesis in the liver in an alcoholic?

Reduced synthesis of lipoproteins means lipids synthesised in the liver accumulate and cause fatty liver. Reduced synthesis of albumins can lead to oedema due to reduced oncotic pressure Reduced synthesis of clotting factors leads to an increase in clotting time

What are the indirect effects of excessive alcohol consumption?

Poor dietary habits including vitamin and mineral deficiency and carbohydrate and protein deficiency.

What is the consequence of excessive alcohol consumption on the GI tract?

Damages cells- causes poor absorption of nutrients such as thiamine, vitamin K folic acid and pyridoxine. Also diarrhoea and poor appetite.

What is Wernicke-Korsakoffs syndrome?

Mental confusion and unsteady gait ?ataxia? Due to thiamine deficiency -poor absorption

Why might alcoholics be anaemic?

Damaged gut lining = poor absorption of folic acid = B12 deficiency anaemia.

What is used to treat paracetamol overdose and what does it do?

n-Acetyl cysteine (antioxidant, counters the effect of depleted glutathione) Liver transplant

How is paracetamol metabolised at therapeutic dosages?

Straight to phase 2 - conjugation with glucuronide or sulphate

What happens if a toxic dose of paracetamol is ingested?

Phase 2 pathway quickly saturated. Undergoes phase 1 produces NAPQI (N-Acetyl p-benzo quinone imine) which is toxic Then phase two conjugation with glutathione - depletes glutathione - destruction of liver cells and liver failure occurs over several days.