Define Pharmacodynamics and Pharmacokinetics
Pharmacodynamics is the action of the drug on the body
Pharmacokinetics is the action of the body on the drug
What processes are covered by pharmacokinetics?
What can be said about the activity of drug metabolites?
Give some exceptions to this rule
Normally less active
Examples of more active metabolites include:
Primidone --> Phenobarbitone
Pethidine ---> Norpethidine
Codeine ---> Morphine
What is Phase 1 of drug metabolism?
As most drugs are relatively stable and unreactive a reactive group must be first exposed or added to generate a reactive intermediate.
What are the common chemical reactions of Phase 1 of drug metabolism?
What enzyme system is utilised in drug metabolism?
What co-factor is normally used by these enzymes in phase 1 of drug metabolism?
Why do some drugs totally bypass phase 1 of drug metabolism?
Give an example of a drug that bypasses phase 1
Already have a reactive group
What is Phase 2 of drug metabolism?
The reactive intermediate from phase 1 is conjugated with a polar molecule (conjugate) to form a water soluble complex. This process is know as conjugation.
What is the most common conjugate
Give 2 examples of other conjugates
Sulphate ions, Glutathione
What is required by phase 2 of drug metabolism?
High energy cofactor (uridine diphosphate glucuronic acid) - UDPGA
What is the first pass effect?
Substances absorped through the ileum enter venous blood which drains directly into the hepatic portal vein and is transported directly to the liver
The liver is the main site of drug metabolism and contains most of the necessary enzyme systems.
Therefore any drug absorped from the ileum may be extensively metabolised by the liver during its first pass through
Give an example of the effect of first pass metabolism on a common drug
90% of paracteamol is metabolised by first pass metabolism
Describe the enzymes of the Cytochrome P450 system
Hint: Number of enzymes? Important enzymes? Variations?
Around 50 haem containing enzymes
There are polymorphisms in the human population
The isoform CYP A4 accounts for 55% of drug metabolism
The CYP cofactor is NADPH
How do genetic factors affect drug metabolism?
We all differ slightly on expression of CYP enzymes therefore drug effects vary from person to person.
Some individuals may lack a crucial CYP enzyme (EG. CYP A4) and this will have a large effect on drug metabolism.
Give 2 examples of how genetic factors may influence drug metabolism.
Some people may be slow acetylators because they lack the main enzyme for the acetylation reaction in phase 2.
This has a large effect on rate of metabolism of drugs requiring this pathway.
Some people have a low level of pseudocholinesterase enzymes in the plasma which affects their ability to metabolise drugs containing an ester group such as suxamethonium
How do environmental factors affect drug metabolism?
If two drugs are given at once then the metabolism of one drug may affect the other
Enzyme inhibition or induction can occur
Give 3 examples of enzyme inducing drugs
What class of drugs does paracetamol belong to?
Describe the metabolism of Parcetamol at a therapeutic dose
Paractamol conjugates with glucuronide or sulphate in phase 2
Describe what might happen if a toxic dose of paracetamol is taken
The normal glucuronide and sulphate conjugation pathways become saturated.
Paracetamol undergoes phase 1 metabolism instead of bypassing it as normal.
This produces a toxic metabolite
This metabolite is called:
NAPQI is toxic to hepatocytes and also conjugates with glutathione, an important liver anti-oxidant
Liver failure occurs over the course of a few days.
Where is the major site of alcohol metabolism?(C'mon freshers, this is essential knowledge right here)
Give the major pathway for alcohol metabolism and give the enzyme(s) and anything else required
Make sure to include equation(s)
Alcohol ---> Acetaldehyde ---> Acetate
Step 1: Alcohol dehydrogenase
Step 2: Aldehyde dehydrogenase
Complete oxidation forms NADH from NAD+
Acetate is converted to AcetlyCoA with ATP
ATP ---> AMP + 2Pi
What are the 3 major effects of prolonged alcohol comsumption?
Low NAD+/NADH ratio
Decreased liver function
What is the alternative method of alcohol metabolism?
CYP 2E1 is an inducible enzyme that can metabolise alcohol through oxidation
What is the effect of a low NAD+/NADH ratio?
Accumulation of lactate in the blood possibly causing lactic acidosis
This in turn will reduce the kidney's ability to excrete uric acid, crystals of urate may accumulate in tissues causing gout.
Gluconeogenesis cannot be activated and this may cause fasting hypoglycaemia
What is the effect of high AcetylCoA levels caused by alcohol consumption?
AcetylCoA cannot be oxidised due to low NAD+ therefore more ketone bodies and fatty acids are synthesised
Production of ketones may cause ketoacidosis
TAGS are produced from fatty acids and due to lack of lipoproteins cannot be transported, therefore a fatty liver develops.
What tests can be done to look for liver damage?
Explain the biochemical basis behind this.
Test blood for transaminase enzymes and gamma glutamyl transpeptidase (Liver function tests)
Damaged liver cells have a leaky cell membrane allowing these enzymes to diffuse into blood.
What is the result of reduced liver function?
Hint: 3 main points, be sure to elaborate on consequences of metabolic disfunction
Decreased uptake of bilirubin causing hyperbilirubinaemia (resulting in jaundiced appearance)
Decreased urea production causing hyperammonaemia and increased glutamine
Decreased protein synthesis (Such as albumin, clotting factors and lipoproteins)
-Decreased serum albumin may cause Oedema
-Decreased clotting factors increase blood clotting time
-Decreased lipoproteins cause lipid build up leading to fatty liver.
What are the direct effects of alcohol on the GI tract?
Loss of appetite
Impaired absorption of nutrients (Vit K, Folic acid, Pyridoxine, thiamine).
Vitamin and Thiamine deficiency results
How is alcohol dependency commonly treated?
Disulfuram is used, this is an aldehyde dehydrogenase inhibitor
If the patient drinks alcohol, acetaldehyde accumulates in blood giving 'hangover' effects very quickly.
How is blood glucose concentration controlled?
By the endocrine system
Describe the use of glucose by the CNS
140g per 24hrs
Glucose uptake relates to blood glucose concentration
Therefore blood concentration must be kept in a certain range to adequately supply CNS (4-6mM)
What is hypoglycaemia and some of the common symptoms?
Hint: Don't worry about all the symptoms, just list like, 3 of 'em or something.
Or whatever, I'm a flashcard, not your supervisor.
Blood glucose below 3mM
Acute effects include:
Slurred speech/staggering walk
Compare the effects of Insulin and Glucagon on nutrient storage.
Increase glucose uptake and utilisation by muscle and adipose tissue
Promotes glucose storage in the liver and muscle as glycogen
Promotes lipogenesis and storage of fatty acids as TAGS in adipose tissues
Promotes amino acid uptake and protein synthesis in the liver and muscle
Stimulates gluconeogensis to maintain glucose supply to brain
Stimulates glycogenolysis in the liver to maintain blood glucose
Stimulates lipolysis in adipose tissues to provide fatty acids for use in tissues
How do feeding and fasting effect hormonal control of glucose?
Feeding stimulates release of insulin
Fasting promotes release of glucagon and insulin release is depressed
How is gluconeogenesis initiated?
Blood glucose falls
This stimulates ACTH release by pituitary
This in turn stimulates cortisol release
Cortisol directly stimulates gluconeogenesis and makes gluconeogenic substrates such as glycerol and amino acids avaliable by stimulating the breakdown of proteins and fats.
Glucagon also stimulates gluconeogensis
What is the effect of Thyamine defieciency?
Can lead to Wernicke-Korsakoff syndrome - mental confusion and unsteady gait
What is significant about the action of aldehyde dehydrogenase?
Low Km which helps keep the level of toxic acetaldehyde to a minimum