Smooth muscle pharmacology Flashcards
What are the two channels that mediate regulation of smooth muscle tone
L-type Ca2+ channel (opened by numerous depolarising mechanisms)
GPCR coupled to Gq/11
What does Protein kinase G (PKG) do?
- Stimulates MLCP
- Stimulates PMCA
- Stimulates SERCA
- Activates K+ channels that cause hyperpolarisation and inactivate Ca2+ channels
Angina is a condition managed by pharmacological manipulation of smooth muscle contraction. What is angina?
Inadequate myocardial oxygen supply
- Fixed vessel narrowing
- Endothelial dysfunction
What is stable and unstable angina?
Stable
-Episodic, brought on by exertion, relieved by rest
Unstable
-Symptomatic even at rest
Describe the pharmacological management of angina
- Organic nitrates act directly on the smooth muscle cell to increase nitric oxide production
- The release leads to smooth muscle relaxation, vasodilation
What does the pharmacological management of angina primarily target?
Whats the secondary target?
Veins to reduce preload and oxygen demand in the myocardium
Secondary action on the coronary collaterals to improve oxygen delivery to the ischaemic myocardium
What are the effects of organic nitrates on venodilation?
- Induce venodilation
- Reduces venous pressure and the venous return to the heart
- Reduces work of the heart (Starlings Law)
- Reduces oxygen demand
When coronary artery disease (CAD) is left untreated, what happens to the blood flow in the ischaemic myocardium compared to normal one?
Artery is blocked by Atheromatous plaque and arterioles are fully dilated. Blood flow isnt as strong
What does the nitrate dilate when treating CAD. What does this cause?
Nitrate dilates collateral
Blood flow to ischaemic myocardium increased
Name the organic nitrates that would be used for treating CAD
- Glyceryl trinitrate (GTN)
- Isosorbide dinitrate/isosorbide mononitrate
What are the characteristics of glyceryl trinitrate?
- Dont directly release NO
- GTN-NO2-NO-Guanylate cyclase
- Biologically inactive
- Half life ~40mins
- Low bioavailability if given orally
What are the characteristics of isosorbide dinitrate?
- Do not directly release NO
- Isosorbide dinitrate/mononitrate-NO2-NO-Guanylate cyclase
- Biologically inactive
- Half life ~2-4 hours
- Bioavailability varies
Nitric oxide reduced in the mouth can also affect blood pressure. How can this affect be altered?
With the use of mouthwash
Hypertension is a condition managed by pharmacological manipulation of smooth muscle contraction. What are the consequences of hypertension?
- Left ventricular hypertrophy
- Renal failure
- Stroke
What is a systolic and diastolic blood pressure in mmHg?
Diastolic- 90mmHg
Systolic- 140mmHg
What is the pharmacological management of hypertension?
Calcium channel blockers act at I-type calcium channels on vascular smooth muscle but also at I-type calcium channels in cardiac myocytes
What are the three main classes of calcium channel blockers? Give examples of each of them
- Dihydropyridines (Nifedipine and amlodipine)
- Benzothiazepines (Diltiazem)
- Phenylalkylamines (Verapamil)
How are calcium channel blockers usually administered, what’s their bioavailability and their half life?
Orally
Bioavailability 10-30%
Half life 2-4 hours
In severe cases of hypertension, what can KATP channel openers be taken with?
Beta blocker and diuretics
What do K-ATP channel openers do and give 2 examples of them?
Open K-ATP channels in the smooth muscle cell membrane and hyperpolarise the smooth muscle cell
Minoxidil and Nicorandil
a1 adrenoreceptors are the first part of the signalling cascade that ultimately leads to smooth muscle contraction following activation of the sympathetic nervous system. What do alpha 1 blockers do?
Give an example of one
a1 antagonists (blockers) prevent this signalling cascade and therefore lead to vasodilation
Prazozin
Summarise how hypertension can be managed
By preventing the rise in intracellular calcium needed to initiate cross-bridge formation by:
- Blocking calcium channels
- Opening potassium channels
- Blocking a adrenoreceptors
Summarise how angina can be managed
By exploiting smooth muscle tone through NO-mediated vasodilation
