Cardiovascular: Hypertension Flashcards
Describe the structure of resistance arteries?
- Endothelium releases vasodilators such as NO (nitro oxide) and PGI2 (Prostacyclin)
- Innervated by sympathetic nerves that surround the resistance arteries
- Noradrenaline acts on the a1 receptor on the arteries which causes the vsm to contract
Explain how a smooth muscle cell contracts?
- Thick filaments contain myosin and thin actin
- Dense bodies are Cytoplasmic anchorage points
- During contraction thick and thin filaments contract
- Process involves actin and myosin cross bridge cycling (involves calcium)
- Shortens muscle fibre, shortens and “balloons”
Explain how the contraction of vascular smooth muscle occurs?
- G protein coupled Q receptor on the surface
- Phospholipase C produces two signalling molecules called DAG and IP3
- IP3 is a signalling molecule that affects the sarcoplasmic reticulum
- IP3 binds to the sarcoplasmic reticulum to release calcium
- Sarcoplasmic reticulum (same as Endoplasmic) contains a lot of calcium
- Calcium is positively charged which is released into the cytosol via a voltage gated calcium channel
- The calcium activates the Calmodulin which activates the myosin light chain kinase (MLCK) which is part of the thick filaments of smooth muscle
- Phosphorylation of MLCK causes the real contraction
What is the endothelium responsible for?
- Causing the contraction and relaxation of the smooth muscle cells in the artery
- A rise in calcium causes an increase in contraction
- NO, EDHF and PG12 roles are to remove the calcium to cause the smooth muscle to relax
Explain the process of the endothelium dependent relaxation (aorta practical)?
- Increase in extra cellular calcium activates NO synthase, COX and EDHF
- NO diffuses to small muscle cell
- Activates soluble guanylate cyclase (SGC) which generates cGMP
- cGMP evokes relaxation by protein kinase G
- Protein kinase G prevents Ca2+ release, Ca2+ entry and regulates the myosin light chain kinase
- COX derived PGI2 diffuses to smooth muscle cell to activate the IP receptor
- IP receptor couples ot AC- cAMP generated activates pKa
- pKa regulates MLCK and activates some smooth muscle K+ channels
What is the purpose of each vasodilator drug and give examples of them?
- Relax smooth muscle with varying mechanisms
- Nitrates: produce NO
- Potassium channel activators: Hyper polarise smooth muscle to prevent the entry via voltage gated calcium channels (VGCC)
- Calcium channel blockers block VGCC
- Some prevent the action of vasoconstrictors such as angiotensin or noradrenaline
Describe how the calcium channel blocker works in hypertension?
- Block smooth muscle cell and voltage gated calcium channels
- First tier therapeutic agent in elderly and african/Caribbean populations
- Second line for people under 55
- Not used in pregnancy
What are the main drugs that block L type voltage gated calcium channels and what are they associated with?
- Vascular: (most effective): dihydropyridines such as Amlodipine
- Cardiac: Phenethylalkylamine: Verapamil
- Mixed: Benzothiazepines: Diltiazem
What are the side effects of calcium channel blockers?
- Postural hypotension
- Flushes
- Tremor
- Cardiac effects (mainly phenethylalkylamines and benzothiazepine)
- AV block
- Negative inotropic effect leads to weakened heart beat
- Nifedipine increases mortality following MI
Describe how the potassium channel blocker works?
- Decreases the positive charge in the cytoplasm that’s caused by the increase in calcium
- Acts as a break to cause hypopolarisation (increase in negative charge)
- Reduces the stimulus for the calcium channel which leads to calcium binding to calmodulin: leading to no constriction
Give an example of potassium channel activators used, what it’s used for and the side effects?
- Minoxidil
- Severe hypertension or if patient has renal failure
- Hypertension resistance to ACD strategy then use with diuretic, beta blocker or both
- Side effects:
- Reflex tachycardia (increased HR)
- Fluid retention
- Facial hair growth
Give the name of the direct acting vasodilator used and describe its clinical use and side effects?
- Hydralazine- Hypertension resistant to ACD
- Clinical usage:
- Pregnancy
- Hypertensive emergency
- Combination with beta blockers and thiazide diuretics - Side effects:
- Reflex tachycardia
- Fluid retention
- Lupus like syndrome
Describe the Dopamine D1 agonist drug, it’s clinical use and side effects?
- Fenoldopam
- More effective in renal and coronary arteries where D1 expression is high
- Increase renal perfusion and naturesis (Na excretion- highly expressed in kidneys)
- Short acting
- Clinical use
- Hospital severe hypertension
- Kidney transplant surgery (blood flow to kidneys directly) - Side effects
- Reflex tachycardia, not normally a problem due to short term use
Describe how alpha adrenoceptor antagonists work?
They block the alpha 1- adrenoceptor which means that noradrenaline cannot active the adrenoceptor
Give examples of alpha adrenoceptor antagonist drugs and describe how they work?
- Doxasozin, prazosin
- Block the action of sympathetic nervous system (noradrenaline) on “resistance” arteries: used when other drugs have failed
- Relax electrical storage vessels in venous system
- This lowers the cardiac output, venous return and preload on the heart
- Reduced stroke volume
- Less tachycardia than other drugs, postural hypotension, fatigue, dizziness
