Lecture - Pharmacology (Calcium Channel Blockers and Nitrates)

Question 1

Calcicium channel blockers (CCBs)

1. Okay, so what is the type of coltage channel that these focus on?
   - these type of channels are abundant where?
   - they have a large, sustained ______
   - do they inactivate fast or slow?
   - are there only a few of them in CV?
   - what phase of the ventricular AP are they responsible for?
   - may trigger release of what?
   - There is another type of channel found on neurons and pacemaker cells in the cells - what are they?
2. So Ca2+ channel blockers - are they heterogeneous? If yes, what kind of heterogeneity? Then what’s their common property? What’re the three we’re focussing on today?
3. What’s the general site and mechanism of action? SO they inhibit what and act on Ca entry into 4 things - what are they and what effect prodced?
4. Go read slide 9 and make sure you get it after you finish revising the full lecture
5. So dihydropyridines (eg amlodipine) - is it vasoselective or nah? Whhat action does it produce and where?
   - What about verapamil and diltiazem? What do they do and act where to do so?
6. Fill in this table
7. What are the pain therapeutic indications for CCBs? (Three of them)
   - what’s the advantages with these drugs? (compare to beta blockers)

Answer 1

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Question 2

Dihydropyridine CCBs - the ‘dipine’ drugs: Amlodipine

1. What is its MOA? Mostly inhibits what?
2. Is it vaso or cardio selective?
3. Anti-hypertensive effect due to what? So it acts primarily on what?
4. Does it have more effect on after load or pre load? Why? Look at slide 15 and explain
   - So this drug will dilate peripheral arterioles reducing total TPR (after load) and ______ __ _______
5. Does it have an effect on preload? Why not?
6. Okay, how is amlodipine become vasoselective when the L and T type channels are present in both heart and vasculature?
7. Okay so you give amlodipine to people who are hypertensive but you need to be aware in angina- why?
8. Pharmakinetics of amlodipine:
   - is it completely absorbed or is it affected by food in the GIT?
   - Does it have a slow or fast onset of action? So like, when is the peak plasma?
   - It is extensively ______ metabolised and excreted as what in what?
   - How many times a day do you take the dose to acheive clinical BP control? Does renal failure have huge effect on the active compound? Why?
   - it’s affected by interaction of a cytochrome that’s responsible for metabolising this drug - what is it?

Answer 2

4. So it doesnt really work on venous beds so there wont be much change in the amunt of blood that returns to the heart. However, it does lead to vasodilation in arterial smooth muscle so this vasodilation means it’s easier to pump blood through the pipes aka reduces the force of heart so less cardiac O2 consumption? And since SA node has L-type channels, they will affect SA node. Don’t know about AV node.
5. It directly binds to and stabalises the inactivated L-type Ca++ channel state. That makes sense, right? So it doesnt bind to activated ones or the hyperpolarised state after recovery. Now these inactivated channels are more likely to be found in arterial SM because depolarisations are longer lasting in arterial than in cardiac muscles (it’s all probability).
6. High doses of amlodipine! So dihydropyridines (like amlopidine, I guess?) can produce excessive peripheral dilation and marked hypotension. This can then provoke reflex cardiac stimulation resulting in tachycardia and increased inotropy (muscle contraction) and that will dramatically increase the myocardial O2 demand (which in angina, is bad since they can’t deliver that). Like, the SNS will increase force of contraction and then you can’t keep up with the O2 demand. ALso, some dihydropyridine are associated with peripher swelling around legs.

Renal failure has little effect on plasma levels of active compound because mostly only the inactive compound (metabolised preveiously by liver) so like, it wont matter for the active compound.

Question 3

Phenylalkylamines eg Verapamil

1. What is the MOA of Verapamil?
   - how is it relatively cardioselective?
   - what does it suppress?
2. Verapamil also acts as a ______ with selectivity for what? But like, with amlodipine, if you created a SNS tachycardia reflex (since too hypotensive) then it’s bad. But why is this reflex not a thing with verapamil?
3. How does verapamil not produce the tachycardia reflex?
4. After knowing this, what is verapamil good for?
5. What is verapamil not good for? Why?
6. Pharmokinetics of verapamil
   - what’s the oral absorption like?
   - what about first pass metabolism?

Answer 3

Because they’ll probably be open more frequently in the heart rather than the vasculature (the inactive state was much more commonly found in the vascular SM since the depolarisations last longer). This causes the upstroke so like, it’ll be inactive until the depol finishes sooooo yeah, makes sense.

4. Because it will interefere with Ca++ ion binding. It will promote inactivated channel confirmation (amlodipine will just stablaise the inactivated state by binding somwhere else on the channel). This will slow the channel recovery from inactivation sooooo it will increase the refractory period of drug-bound channel so then channel inhibiton will increase at higher heart rates since you’ll find more open during that time. LIke same with exercise, more effect since HR up so more open there

Question 4

Benzothiazipines: Diltiazem

1. What’s the MOA?
2. What does it interefere with and in what?
3. Is it suitable as an anti-arrhtymic?
4. But what is it still not suitable for?
5. From your knowledge of anti-arrthymatic lecture, why is diltiazem an effective anti-arrthymatic?
6. Why use in angina?
7. What can it reverse?
8. So it’s PKs are similar to other CCBs, but what can you say about its absorption and 1st pass metabolsim?
9. Okay, on slide 25 are the pharmacokinetic and the pharmacodynamic interactions of diltiazem, go and understand them.

Answer 4

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Question 5

What’re the general adverse effects of CCBs?

1. Mainly extension of drug action….
2. Excessive dosing can lead to….
3. What shouldnt you use verapamil or diltiazem in conjunction with?

Answer 5

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Question 6

Nitric Oxide

1. What does endothelial-derived NO actually do?
2. What does NO have to do with endothelium vasodilators?
3. How is it synthesised? Like, what synthesises it?
4. So NO is released from the endothelium and acts upon what to cause vasodilation?
5. Describe the synthesis of NO
6. Now describe how NO causes vasodilation

Answer 6

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Question 7

Nitrodilators

1. These mimic the vasodilatory actions of what?
2. What do they release in the plasma or form within the cells?
3. What’re two examples of nitrodilators (aka compounds that release NO)
4. Okay, so nitrodilators release NO by what? (two different mechansims for two different compounds said above)
5. Primary action of nitrodilators: main action is ______ dilation
   - can you in theory dilate coronary arteries?
   - reducing what?
   - therefore reduces what?
6. What do they do to systemic arterial stuff?
7. What are the types of nitrodilators? There’s two. Compare them with reference to:
   - delivery method
   - treatment of what? How long? So fast/slow
   - more useful short or long term
8. Therapeutic applications of nitrodilators:
   - why are they used for symptomatic relief of angina and MI? (maybe write a paragraph of what you understand)
   - why is it used in acute/severe chronic heart failure?
   - there are two other valuable therapeutic benefits of nitrodilators, what are they?
9. Pharmacockinets of GTN, isosorbide mononitrate and isosorbide dinitrate:
   - bioavailability so delivery method?
   - first pass metabolism
   - fast or dlow
   - half life

Question 8

1. Why can nitrates be adminstered in a lot of different ways? What way should you give it - like, what does it depend on?
2. Tolerance - when does it develop? How do you prevent tolerance?
3. Nitrates have adverse effects too:
   - dose related and mainly due to v______ - what are they? Think logically
   - why should you avoid abrupt nitrate withdrawal after prolonged use? So what should you do?
4. What’re the drug interactions of nitrates? What does it have to do with viagara? Explain the viagara thing