Session 6 Flashcards
What happens to drugs as soon as they enter the body?
- Deactivated and eliminated by metabolism
- As drugs are foreign to the body and may have toxic effects
What is pharmacology made up of?
- Pharmodynamics: how drugs work
- Pharmokinetics: Absorption
Distribution
Metabolism
Elimination of a drug (ADME)
Why is it unusual for a drug to be secreted in an unchanged form?
- Drugs are lipid-soluble, therefore would be reabsorbed into the blood in the renal tubes if they were to be excreted in aqueous urine via the kidneys
How are drugs changed during metabolism?
- Made water-soluble so that they can be excreted in urine
- Drug is usually deactivated as the metabolites are usually pharmacologically inactive (not always eg given prodrugs which are metabolised to active form)
What stages occur in drug metabolism?
- Phase I
- Phase II
What happens during phase 1 metabolism?
- Reactive group is exposed or added to the parent stable and unreactive drug molecule
- Reactive intermediate is formed which is conjugated in phase II with a water-soluble molecule to form a water-soluble complex
- Common reactions if phase I: oxidation; reduction; hydrolysis
- Requires enzyme system cytochrome P450 (CYP) system and NADPH as a cofactor
Why can some drugs bypass phase I drug metabolism?
- Already contain a reactive group in their molecule
- Eg morphine
What happens in phase II metabolism?
- Reactive intermediate from phase I is conjugated with a polar molecule
- Forms a water-soluble complex in conjugation
- Glucuronic acid is the most common conjugate (freely available as a by product of cell metabolism)
- Sulphate ions and glutathione are also common conjugated
- Requires specific enzymes and uridine diphosphate glucuronic acid (UDPGA) high-energy cofactor
Where does drug metabolism occur?
- Liver
- Hepatocytes contain all necessary enzymes
- Also: liver; kidneys; gastrointestinal tract; plasma
What are some reasons for the variation in drug metabolism in the population?
- Genetic factors
- Environmental influences
- First pass effect
How do genetic factors cause variation in drug metabolism in the population?
- Everyone differs in the level of expression of each enzyme -> each drug is metabolised at different rates in every individual -> drug effects will vary from person to person
- 50 different Haem containing enzymes in cytochrome P450 system which each differ eg CPY3 A4 is very important
- Some people lack gene that codes for a crucial enzyme eg enzyme that causes acetylation in phase I -> are slow acetylators
- Some people have lower levels of pseudocholinesterase enzymes in plasma -> affects ability to metabolise drugs containing ester bond eg suxamethonium a muscle relaxant used during anaesthesia
How do environmental influences cause variation in drug metabolism?
- Enzyme levels in the body are not fixed and can be influenced by external factors
- Enzyme inhibition or induction may occur if two drugs are given together -> metabolism of one may affect the other
- Eg some pesticides cause enzyme induction in the liver
- Ethanol, nicotine and barbiturates are enzyme inducers
What is the first-pass effect and how does it affect dosages?
- Swallowed drugs absorbed in the ileum enter the venous blood, which drains into the hepatic portal vein and is transported directly to the liver
- Are metabolised during the first pass through the liver before they can have any effect on other tissues
- Eg most of paracetamol is metabolised during the first pass through the liver so a larger dosage is needed to have an effect
What happens to alcohol in the body?
- 90% is metabolised
- 10% is excreted passively in the urine and on the breath
Where is alcohol mainly metabolised?
- Liver
How is alcohol metabolised?
- Alcohol is oxidised to acetaldehyde by alcohol dehydrogenase (low-specificity enzyme)
CH3CH2OH + NAD+ -> CH3CHO + NADH + H+
Enzyme: alcohol dehydrogenase - Acetaldehyde is oxidised to acetate by aldehyde dehydrogenase
CH3CHO + NAD+ + H2O -> CH3COO- + NADH + 2H+
Enzyme: aldehyde dehydrogenase - Acetate is converted to acetyl CoA
CH3COO- + ATP + CoA -> CH3CO~CoA + AMP + 2Pi - Alcohol can also be oxidised by cytochrome P450 2E1 enzyme (which is inducible)
What happens to acetaldehyde from alcohol metabolism?
- Is extremely toxic to cells
- Aldehyde dehydrogenase has a very low Km for acetaldehyde and removes acetaldehyde as soon as it is formed to minimise toxicity
What happens when alcohol consumption is prolonged and excessive?
- Sufficient acetaldehyde can accumulate to cause liver damage
- NAD+/NADH ratio decrease and increased availability of acetyl CoA have significant effects on liver metabolism
What are the effects of a decrease of the NAD+/NADH ratio on liver cell metabolism?
- Increased levels of NADH in the liver is caused by alcohol oxidation
- NAD+ levels are inadequate for fatty acid oxidation, conversion of lactate to pyruvate and metabolism of glycerol
- Lactic acidosis can occur as decreased lactate utilisation by liver cells causes lactate to accumulate in the blood
- Increased lactate reduces kidneys ability to excrete uric acid
- Uric acid levels increase and cause accumulation of urate crystals in tissues causing gout
- Low NAD+ and inability of liver cells to use lactate and glycerol prevents gluconeogenesis from being activated causing fasting hypoglycaemia
- Poor dietary habits can also contribute to hypoglycaemia as liver glycogen tends to be low
What are the effects of increased availability of acetyl CoA in alcohol metabolism?
- Increased Acetyl CoA which cannot be oxidised by liver cells because of the low NAD+/NADH ratio
- Increased synthesis of fatty acids and ketone bodies
- Fatty acids are converted to triacyglycerols which cannot be transported from liver cells as there is a lack of lipoprotein synthesis so contributes to fatty liver
- Ketone body production can be sufficient to cause ketoacidosis
What do damaged liver cells have as a result of toxic acetaldehyde?
- Leaky plasma membranes
- Enzymes eg transaminases and gamma glutamyl transpeptidase are lost from the cell
- Appearance of enzymes are used diagnostically in liver function tests to indicate liver cell damage
How are the functions of damaged liver cells affected?
- Produces a variety of signs and symptoms
- Reduction in capability to take up and conjugate bilirubin leads to hyperbilirubinaemia, that can lead to jaundice
- Reduction in capability to produce urea can lead to hyperammonaemia and increased levels of glutamine
- Reduced protein synthesis leads to reduced albumin, clotting factors and lipoprotein synthesis; low serum albumin leads to oedema; low clotting factors leads to increase in blood clotting time; low lipoproteins leads to fatty liver as lipids synthesised in the liver cannot be transported out
What are the indirect effects of alcohol consumption?
- Cost of alcoholic beverages and effects on CNS causes poor dietary habits to be associated with excessive consumption
- Vitamin and mineral deficiencies
- Inadequate protein and carbohydrate intake
What are the direct effects of alcohol on the gastrointestinal tract?
- High concentrations of alcohol damage cells lining GI tract -> variety of GI tract disturbances -> compound effects of a poor diet
- Loss of appetite, diarrhoea and impaired absorption of nutrients eg vitamin K, folic acid, pyridoxine and thiamine
- Signs and symptoms of a specific vitamin deficiency is often seen in alcoholics
- Thiamine and pyridoxine deficiencies -> Neurological symptoms
- Folic acid deficiency -> haematological (eg anaemia) problems
- Thiamine deficiency -> Wernicke-Korsakoff syndrome with mental confusion and unsteady gait
How is the disulfiram drug used to help treat chronic alcohol dependence?
- Inhibits aldehyde dehydrogenase enzyme
- Acetaldehyde is not converted to acetic acid (acetate)
- Acetaldehyde accumulates in the blood when patient drunks causing ‘hangover’ symptoms eg nausea
- Effective with additional support
How is paracetamol normally metabolised?
- Is an antipyretic drug which is safe with a normal dosage
- Normally metabolised by phase II conjugation with glucuronide or sulphate
What happens to paracetamol metabolism if a toxic levels is digested?
- Normal phase II pathways are quickly saturated
- Paracetamol undergoes phase I metabolism producing a toxic metabolite N-acetyl-p-benzo-quinone imine (NAPQI)
- Metabolite is toxic to hepatocytes
- NAPQI also undergoes phase II conjugation with glutathione
- Depletes cells of glutathione, an important antioxidant
- Causes destruction of liver cells and liver failure occurs over a period of several days
How should an overdose of paracetamol be treated?
- Rapid treatment with N-acetylcysteine (an antioxidant)
- Death from liver failure may be inevitable is treatment is delayed
What determines the availability of fuel molecules in the blood?
- Hormones
What are the effects of insulin (overall)?
- Lowers concentration of fuel molecules in the blood?
What are glucagon, growth hormone, cortisol and adrenaline collectively known as and what do they do (overall)?
- Anti-insulin hormones
- Raises concentrations of fuel molecules in the blood
Which out of the glycogen in the liver and muscle can be broken into ️glucose that can be used in tissues such as the CNS?
- Liver
- Link! Skeletal muscle lacks an enzyme?
What tissues can not use fatty acids as fuel?
- Erythrocytes
- Central nervous system
Where do fatty acids come from?
- Triacylglycerols in adipose tissue
Where do ketone bodies come from and when are they produced?
- Fatty acids are converted to ketone bodies in the liver
- Produced when glucose is in critically short supply eg starvation to be used as a fuel by tissues including the CNS
When is protein broken down in proteolysis?
- In shortage of other fuel molecules
- Produces amino acids to be used as fuel by conversion to glucose or ketone bodies, or by direct oxidation
- Fuel reserve for 2 weeks of normal metabolism
When does hypoglycaemia occur?
- When blood glucose drops to 3.0 mmol/L or lower
What are the signs and symptoms of hypoglycaemia?
- Trembling
- Weakness
- Tiredness
- Headache
- Sweating
- Sickness
- Tingling around the lips
- Palpitations
- Changes in mood (angry/bad temper)
- Slurred speech
- Staggering walk
- Unconsciousness
- Death
What can hypoglycaemia be confused with?
- Intoxication
When does hyperglycaemia occur?
- When fasting blood glucose levels are elevated to above 7.0 mmol/L
What systems of the body are affected by hyperglycaemia?
- Cardiovascular
- Renal
- Nervous
Why does polyuria occur in hyperglycaemia?
- Glucose is over renal threshold so is not all absorbed back into the blood from the kidney tubules
- Glucose has an osmotic effect so causes more water to stay in the kidney tubules and causes more to diffuse from the blood
- Causes polydipsia
What is hyperglycaemia associated with?
- Abnormal metabolism of glucose to products that may be harmful to cells
- Increased glycosylation of plasma proteins eg lipoproteins that leads to disturbances in function
What is the feeding/fasting cycle?
- Individuals that eat regular meals experience a regular cycle of metabolic changes
What are the effects of feeding?
- Absorption of glucose, amino acids and lipids from the gut
- Blood concentration raises
- Increase stimulates endocrine pancreas to release insulin
What actions does insulin have?
- Increase glucose uptake and utilisation by muscle and adipose tissue
- Promotes stored 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 triacylglycerols in adipose tissue
What are the effects of fasting?
- Blood glucose concentration falls
- Insulin secretion is depressed
- Reduces uptake of glucose by adipose tissue and muscle
- Also stimulates glucagon secretion from the endocrine pancreas (insulin/anti-insulin ratio decreases)
What are the actions of glucagon?
- Glycogenolysis in the liver to maintain blood glucose for the brain and other glucose dependent tissues
- Lipolysis in adipose tissue to provide fatty acids for use by tissues
- Gluconeogenesis to maintain supplies of glucose for the brain
How long does fasting last for to become starvation?
- More than 10 hours
What is the initial response to starvation?
- A prolonged version of normal fasting response
- Blood glucose falls but is maintained at 3.5 mmol/L by actions of glucagon which stimulates breakdown of hepatic glycogen
What happens when stores of glycogen are depleted?
What are the effects of various hormones on metabolism?
- Continuing reduction in blood glucose stimulates pituitary gland to release ACTH, consequently raising blood cortisol
- Cortisol maintains blood glucose by: stimulating gluconeogenesis and stimulating breakdown of protein and fat to produce substrates of gluconeogenesis (mainly alanine and glycerol)
- Glucagon also stimulates gluconeogenesis
- Both hormones together increase amounts and activities of gluconeogenic enzymes in liver cells as well as increasing availability of gluconeogenic substrates
What happens to lipolysis and lipids during starvation?
- Occurs at a high rate
- Due to fall in insulin and rise in lipolytic hormones glucagon, cortisol and growth hormone
- Free blood fatty acids rise to 2 mmol/L from normal 0.3 mmol/L
- Cortisol simulates fat breakdown
- Reduction of insulin and effects of cortisol prevent most cells using glucose so they prefer to use fatty acids
- Glycerol then provides an important substrate for gluconeogenesis to reduce the need for protein breakdown
Describe production of ketone bodies in starvation
- Fatty acids are oxidised in the liver to produce ketone bodies
- Due to decreased insulin/anti-insulin ratio
- Ketone bodies replace glucose as a fuel for the brain
- Further reduces need for gluconeogenesis in the liver and spares body protein
What are the concentrations of ketones in the fed state, after 3 days of starvation and 1-2 weeks of starvation?
- Fed state: 0.01 mmol/L
- 3 days of starvation: 2-3 mmol/L
- 1-2 weeks of starvation: 6-7 mmol/L - physiological ketoacidosis
What 2 factors become important during adaptation to starvation?
- Brain becomes able to use ketones as a fuel, reducing its glucose requirements from 140g/day to 40g/day
- Kidneys begin to contribute to gluconeogenesis
What does the brain’s use of ketones reduce?
- Reduces the need to breakdown protein for gluconeogenesis
- By 4-5 weeks of starvation gluconeogenesis reduces to around 30% of that seen in early starvation
- Urinary nitrogen excretion falls from 12g/day (mostly urea) to 4g/day (equal urea and NH4+)
What does the reduction of urea synthesis during starvation lead to?
- Decrease in the amount and activity of enzymes involved in urea synthesis in liver cells
- Must not give large amounts of protein and/or amino acids in the early stages and should be increased gradually to prevent re-feeding syndrome
What happens when all the body’s fat stores are depleted?
- System reverts to using protein as a major fuel
- Protein is rapidly used up
- Death follows shortly from a number of causes related to loss of muscle mass eg serious respiratory infections due to loss of respiratory muscle
