Week 5 Flashcards
Agonists
A chemical that binds to receptor and activates the receptor to produce a biological response
e.g. Opiate receptor = Morphine
Antagonists
Locks or dampens a biological response by binding to and blocking a receptor rather than activating it. e.g. Opiate receptor = Naloxone
Blockers
Block the ion channel e.g. VG Na Channels = Local Anaesthetic
Enzyme inhibitors
Competitive or non-competitive
or
False substrates - Drug converted into abnormal product that disrupts the normal metabolic pathway
Beta-blockers
antagonist
Used in cardiovascular diseas.
- Heart failure, hypertension coronary artery disease
-Block signalling through the B adrenal-receptor (antagonist)
B1
G-protein coupled receptor -
Increase in cardiac rate and force
Gene = ADBR1
B2
G-protein coupled receptors
Bronchodialation, vasodialation
Gene = ADBR2
ADBR1 - What are the two variants and how do they similar?
Two common variants
p.Arg389Gly
p.Ser49Gly
Both variants result in hyper functional receptor that are less responsive to blockade that wild type
Malignant hyperthermia (MH)
Autosomal dominant, disorder of skeletal muscle
MH is triggered by volatile anaesthetics and depolarising muscle relaxants.
Muscle rigidity and a hyper-metabolic state (high temperature)
Can cause death if not treated promptly
Muscle biopsy - MH
Expose it too halothane and caffeine, the contraction can be measured, caffeine will cause the muscle to contract more than normal because of the sensitivity.
Muscle biopsy - MH
Expose it too halothane and caffeine, the contraction can be measured, caffeine will cause the muscle to contract more than normal because of the sensitivity.
What do Statins do?
Lipid lower drug Example = simvastatin, atorvastatin Pharmacokinetic SLCO1B1 - Transporters Pharmacodynamic HMGCR - Enzymes
SLCO1B1 encodes OATP1B1, What is it?
Membrane-bound sodium-independent organic anion transporter which uptakes many statins into hepatocyte
What do drugs mainly act on (RICE)?
Receptors
Ion Channels
Carrier molecules
Enzymes
What can polymorphisms effect?
Drug target can effect - pharmacodynamics
Drug transporters - Both
Drug Metabolising enzymes -Pharmacokinetics
ADBR1 - What is the p.Arg389Gly variant and how does it differ?
- Reduced response to receptor activation by agonists
- Reduced response to receptor blockage by antagonists
ADBR1 - What is the p.Ser49Gly variant and how does it differ?
- Increased receptor desensitisation after prolonged activation by an agonist
What happens when someone with high blood pressure has a variation in ADBR1?(shown in a study)
There is no significant change in blood pressure after using beta-blockade, however there is other outcomes of studies which could be related to other variants.
What is the genetic cause of Malignant Hyperthermia?
50-70% of cases is due to variation in the ryanodine receptor.
What is the symptoms of a being triggered with Malignant Hyperthermia?
Increased Heart Rate Elevated ETCO2 Decreased oxygen saturation Increased temperature Muscle Rigidity Arrhythmias
Biochemical and genetic basis of Malignant Hyperthermia
Mutation in the RYR1 gene
Altered calcium channel protein
Mutated channel opens more easily and stays open longer, thus flooding the cytosol with calcium
High intracellular levels of calcium stimulate sustained muscle contraction; high ca also stimulated breakdown of glycogen, glycolysis, and aerobic metabolism (resulting In excessive heat)
Why does local aesthetics cause uncontrolled myoplasmic calcium release in patients with malignant hyperthermia?
The aesthetic acts on the Ryanodine receptor
Normally - Magnesium is bound keeping the channel shut, then the succinylcholine causes the channel to open - causing depolarisation
Mutated - The Magnesium is not keeping the channel shut properly so when Succinylcholine is added, there is a weaker depolarisation, because they are hypersensitive.
How do statins work?
Statins form a substrate for the organic OATP transporter, which allows the transcellular movement of statin dugs inside the liver or the hepatic cell.
Statins are a HMG-CoA reductase inhibitor, which stops HMG-CoA producing Mevalonic acid, which inhibits cholesterol production.
What do variants in the SLCO1B1 cause?
The transport which takes statin up into the liver cell
- toxicity occurs when the transporter does not work as well when there is a variant.
Causing muscle degradation and kidney damage/ achy muscles
What do variants in the HMGCR (HMGCoA Reductase) cause?
Target for statins however variant in the non-coding region cause decreased response to statins.
What does HMGCR do?
It catalyses the NADP-dependent conversion of HMG-CoA to mevalonate in the rate limiting step of cholesterol production.
Modulators
Modulators - increased/decreased opening probability
e.g. VG Na channels = Veratridine
What is NAT2 in tuberculosis?
- Highly polymorphic phase 2 metabolic enzyme
- Add to aromatic amine drugs with acetyl-groups
