Lecture 5 - Pharmacodynamics Flashcards
What are the four main targets that drugs act on?
RICE Receptors Ion channels Carrier molecules Enzymes
What are the 3 types of drugs that act on receptors, and what effect does each have?
Agonists - initiates biological response
Inverse agonists - causes opposite effect to the agonist
Antagonists - prevents agonists from binding and producing a response
What are the 2 types of drugs that act on ion channels, and what effect does each have?
Blockers - prevents movement of ions through the channel
Modulators - increases/decreases probability of channel opening, or duration of channel opening
Give 2 examples of a receptor, its agonist and an antagonist
Mu-opiod receptor: Morphine and Naloxone
Oestrogen receptor: Ethinylestradiol and Tamoxifen
Beta 1 adrenergic receptor: Norepinephrine and beta-blockers
P2Y12 receptor: ADP and Clopidogrel
Give 2 examples of a channel, its blocker and an allosteric modulator
Voltage gated Na+ channel: Local anaesthetics such as lidocaine, Veratridine
ATP-sensitive K+ channels: ATP, sulfonylureas
What are the 4 types of drugs that can act on enzymes
Competitive/reversible inhibitors
Non competitive/irreversible inhibitors
False substrates
Pro-drugs
Give 2 examples of an enzyme and its inhibitor
HMG-CoA reductase: Simvastatin
Vitamin K epoxide reductase: Warfarin
ACE: Captopril
What are the 2 types of drugs that can act on transporters
Inhibitors/blockers
False substrates
Give an example of a carrier protein and its inhibitor
Proton pumps: Omeprazole
What are beta-blockers used to treat and how do they work?
Treats CVD by preventing hypertension, coronary artery disease and heart failure
Antagonise the beta adrenergic receptors
Reduce cardiac muscle contractility and decrease oxygen demand
Where are the 3 beta adrenergic receptors located and what is their role?
B1 - heart. Increases cardiac rate and force
B2 - bronchi. Increases bronchodilation
B3 - fat cell
Mutations in which gene leads to variation in beta blocker efficacy? and why do they have this effect?
ADBR1 - encodes b1 receptors. Mutation affecting the extracellular terminus leads to reduced response to agonists/antagonists. Mutation affecting intracellular terminus increases receptor desensitisation to ligands. Both lead to a hyperfunctional b1 receptor.
Why have genetic tests before beta-blocker prescription not been clinically implemented?
Conflicting evidence from other studies, not shown association between variants and efficacy. Could be due to
- other clinical variables separating the groups
- other candidate genes involved that haven’t been identified yet
What are the symptoms of malignant hyperthermia?
After administration of a volatile anaesthetic or succinylcholine, the patient goes into a hyper-metabolic state
Continuous full body muscle contraction, increased aerobic metabolism and hyperthermia
Decreased o2 saturation, elevated co2 production, increased heart rate, arrhythmia
Can cause death if not treated promptly
What is the genetic cause of malignant hyperthermia?
Mutation in the RYR1 gene (codes for ryanodine receptor)
Causes a strucutral change meaning the mg2+ block is not bound as tightly
Mutated channel opens more easily, floods cytosol with calcium to sustain muscle contraction
What is the process of skeletal muscle contraction normally?
Depolarisation of sarcolemma Depolarisation propagates down t-tubules DHP channels open - mechanically linked to RyR channels so these open also Calcium released from SR Calcium binds to troponin C...
How do volatile anaesthetics and succinylcholine trigger MH?
Volatile anaesthetics directly activate RyR
Succinylcholine activates nAchRs on sarcolemma to initiate depolarisation
Other than genetic testing, how else can MH be tested for?
Muscle biopsy and in-vitro contracture test (IVCT)
Living muscle tissue exposed to halothane - MH muscle contracts instead of relaxing
Living muscle tissue exposed to caffeine - MH muscle contracts at lower concentration
Very unpleasant test
What are the pros of genetic testing over the IVCT test for MH?
Much less discomfort
No scar
Cheaper
If someone suspected to have MH has a negative result from a genetic test, why would they still have to undergo an IVCT?
Sometimes people with MH do not have a mutation in the RYR1 receptor, therefore a negative test result for mutations in this gene does not necessarily mean they don’t have it
What is the genetic cause of neonatal diabetes?
The ATP-sensisitve potassium channel on beta cells made up of SUR1 and Kir6.2 subunits
Mutations in SUR1 prevent it closing in response to ATP
How does sulfonylureas treatment work, and why is this beneficial to treatment with insulin?
Binds to SUR1 subunit, forcing channel to close independently of ATP
No need for daily injections and improved control of blood glucose
Give an example of a drug that has its pharmacokinetics and pharmacodynamics affected by gene mutations
Which genes are responsible for which affect?
Statins e.g. simvastatin and atorvastatin
Variation in SLCO1B1 gene has pharmacokinetic changes
Variation in the HMGCR gene has pharmacodynamic changes
What are statins used to treat and how do they work?
Used to treat CVD by inhibiting cholesterol synthesis
Inhibits HMG-CoA reductase, which catalyses the conversion of HMG to-Coa to mevalonate during cholesterol synthesis
What is the function of the HMGCR gene? What happens in people with increased activity of this gene?
Encodes for HMG-CoA reductase
Increased activity can cause decreased response to statins
What is the function of the SLCO1B1 gene? What happens in people with increased activity of this gene?
Encodes for the OATP1B1 transporter which is a membrane bound, sodium independent organic anion transporter
Uptakes statin medications into the hepatocyte where they exert their effects
Increased activity can cause myopathy/muscle pain when taking statins
