Lecture 5 - Pharmacodynamics

Question 1

What are the four main targets that drugs act on?

Answer 1

RICE
Receptors
Ion channels
Carrier molecules
Enzymes

Question 2

What are the 3 types of drugs that act on receptors, and what effect does each have?

Answer 2

Agonists - initiates biological response
Inverse agonists - causes opposite effect to the agonist
Antagonists - prevents agonists from binding and producing a response

Question 3

What are the 2 types of drugs that act on ion channels, and what effect does each have?

Answer 3

Blockers - prevents movement of ions through the channel

Modulators - increases/decreases probability of channel opening, or duration of channel opening

Question 4

Give 2 examples of a receptor, its agonist and an antagonist

Answer 4

Mu-opiod receptor: Morphine and Naloxone
Oestrogen receptor: Ethinylestradiol and Tamoxifen
Beta 1 adrenergic receptor: Norepinephrine and beta-blockers
P2Y12 receptor: ADP and Clopidogrel

Question 5

Give 2 examples of a channel, its blocker and an allosteric modulator

Answer 5

Voltage gated Na+ channel: Local anaesthetics such as lidocaine, Veratridine
ATP-sensitive K+ channels: ATP, sulfonylureas

Question 6

What are the 4 types of drugs that can act on enzymes

Answer 6

Competitive/reversible inhibitors
Non competitive/irreversible inhibitors
False substrates
Pro-drugs

Question 7

Give 2 examples of an enzyme and its inhibitor

Answer 7

HMG-CoA reductase: Simvastatin
Vitamin K epoxide reductase: Warfarin
ACE: Captopril

Question 8

What are the 2 types of drugs that can act on transporters

Answer 8

Inhibitors/blockers

False substrates

Question 9

Give an example of a carrier protein and its inhibitor

Answer 9

Proton pumps: Omeprazole

Question 10

What are beta-blockers used to treat and how do they work?

Answer 10

Treats CVD by preventing hypertension, coronary artery disease and heart failure
Antagonise the beta adrenergic receptors
Reduce cardiac muscle contractility and decrease oxygen demand

Question 11

Where are the 3 beta adrenergic receptors located and what is their role?

Answer 11

B1 - heart. Increases cardiac rate and force
B2 - bronchi. Increases bronchodilation
B3 - fat cell

Question 12

Mutations in which gene leads to variation in beta blocker efficacy? and why do they have this effect?

Answer 12

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.

Question 13

Why have genetic tests before beta-blocker prescription not been clinically implemented?

Answer 13

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

Question 14

What are the symptoms of malignant hyperthermia?

Answer 14

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

Question 15

What is the genetic cause of malignant hyperthermia?

Answer 15

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

Question 16

What is the process of skeletal muscle contraction normally?

Answer 16

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...

Question 17

How do volatile anaesthetics and succinylcholine trigger MH?

Answer 17

Volatile anaesthetics directly activate RyR

Succinylcholine activates nAchRs on sarcolemma to initiate depolarisation

Question 18

Other than genetic testing, how else can MH be tested for?

Answer 18

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

Question 19

What are the pros of genetic testing over the IVCT test for MH?

Answer 19

Much less discomfort
No scar
Cheaper

Question 20

If someone suspected to have MH has a negative result from a genetic test, why would they still have to undergo an IVCT?

Answer 20

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

Question 21

What is the genetic cause of neonatal diabetes?

Answer 21

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

Question 22

How does sulfonylureas treatment work, and why is this beneficial to treatment with insulin?

Answer 22

Binds to SUR1 subunit, forcing channel to close independently of ATP

No need for daily injections and improved control of blood glucose

Question 23

Give an example of a drug that has its pharmacokinetics and pharmacodynamics affected by gene mutations
Which genes are responsible for which affect?

Answer 23

Statins e.g. simvastatin and atorvastatin

Variation in SLCO1B1 gene has pharmacokinetic changes
Variation in the HMGCR gene has pharmacodynamic changes

Question 24

What are statins used to treat and how do they work?

Answer 24

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

Question 25

What is the function of the HMGCR gene? What happens in people with increased activity of this gene?

Answer 25

Encodes for HMG-CoA reductase

Increased activity can cause decreased response to statins

Question 26

What is the function of the SLCO1B1 gene? What happens in people with increased activity of this gene?

Answer 26

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