Drugs used in vasculature + hypertension Flashcards
What does vascular smooth muscle contraction rely on?
- intracellular (+ extracellular) calcium
Which two methods increase intracellular calcium?
1) influx down electrochemical gradient
- 1.2 mmol calcium (intracellular); 1-2 x10^7 moles calcium (extracellular) - big drive to move calcium into cell
- calcium is positively charged; inside cell is -ve charged
2) calcium induced calcium release from SR within cells
How does calcium enter the cell?
- plasma membrane is impermeable to calcium (cannot enter by diffusion)
1) Voltage activated calcium channels open in response to depolarisation of muscle cell - L type calcium channels open
- Calcium moves inwards
2) G protein coupled receptor activation can callow calcium entry + contraction
- alpha 1 adrenoceptor binds to Gqg11
- causes IP3 activation
- IP3 acts on receptors in SR
- CICR from SR
Describe the stages in which calcium causes contraction
- calcium binds to intracellular calcium binding protein called calmodulin
- forms activated calcium-calmodulin complex
- converts myosin light chain kinase from inactive-active form
- MLCK phosphorylates myosin light chain (in contractile proteins)
- actin-myosin crossbridges form
- sliding filament action
- contraction
What is the role of myosin light chain phosphatase + how does it cause vascular smooth muscle relaxation?
- myosin light chain phosphatase requires activation
- this activation comes from cyclic guanosine monophosphate (cGMP)
- phosphate added to MLCK is stripped off
- myosin light chain in contractile proteins no longer phosphorylated
- cross bridges turn off
- relaxation
What does endothelium separate?
- smooth muscle from blood
Describe the properties of nitric oxide
- readily diffuses across cell membranes
- soluble
- ideal for signalling between endothelial and smooth muscle cells
- acts in paracrine manner (signals between adjacent cells)
- readily inactivated
What mediates the production of NO by endothelial cells?
VASODILATING SUBSTANCES
- bradykinin
- 5-hydroxyl tryptine (serotonin)
- ADP
What do these mediator substances do?
- modulate tone of vasculature
- act on G protein receptors (apical membrane of endothelial cell)
Increasing intracellular calcium causes what?
- binding of calcium to calmodulin - formation of calcium-calmodulin complex
What does calcium-calmodulin stimulate?
- synthesis of enzyme endothelionitric oxide synthase (eNOS)
What does eNOS do?
- binds L-arginine and O2
- converts them to nitric oxide + citrulline
Once NO diffuses across endothelial cell membrane into vascular smooth muscle what does it do?
- activates guanylate cyclase
What does gaunylate cyclase do?
- converts GTP to guanosine monophosphate (cGMP) (liberates 2 phosphates)
What does cGMP do?
- stimulates production of protein kinase G
- activates myosin light chain phosphatase
- removes phosphorylate from contractile proteins (myosin light chain)
- turns of cross bridges
- relaxation
How does NO cause hyper polarisation?
- Calcium channel is activated by NO
- Calcium dependent K+ channel activated (by depolarisation and Ca2+ entry)
- K+ flows down electrochemical gradient (leaves cells)
- hyperpolarisation occurs
- relaxation
What do organic nitrates do?
- act like a pharmacological endothelium
- bind to tissue enzymes/thiol groups in vasc smooth muscle
- allows conversion of GTP-cGMP
What type of muscle do organic nitrates relax?
- ALL TYPES OF SMOOTH MUSCLE (via their metabolism to NO)
How do clinical does of organic nitrates act upon vasculature?
- act preferentially upon vasculature
How do organic nitrates affect veins?
- causes VENORELAXATION
- decreases central venous pressure (decreased preload)
- reduces SV
Do organic nitrates affect cardiac output?
- no (SV is reduced but HR is increased to maintain CO)
How do organic nitrates affect arteries?
- arteriolar dilatation
- decreases arterial pressure
- reduces afterload
How do organic nitrates affect blood flow?
- increase coronary blood flow (in normal people)
- in angina, there is no increase in blood flow but blood is REDIRECTED TOWARDS ISCHAEMIC ZONE
What are the benefits of organic nitrates in patients with angina?
DECREASED MYOCARDIAL REQUIRMENT via:
1) decreased preload
2) decreased after load
3) improved perfusion of ischaemic zone
What is the effect of nitrates on collateral vessels?
- increases dilatation of collateral vessels
- bypasses obstruction
- increases blood flow to ischaemic area
Give properties of GTN
- short acting (30 mins)
- undergoes extensive first pass metabolism (via liver)
- therefore unsuitable for oral administration
- liver inactivates it - doesn’t enter systemic circulation
- administered sublingually (as spray/tablet)
- rapid effect before exertion (stable angina)
- can be given IV (in conjunction with aspirin) in unstable angina
- more sustained effect is obtained if delivered via transdermal patch
Give properties of isosorbide mononitrate
- longer acting than GTN
- half life = 4.5 hours
- reistant to 1st pass metabolism (can be given as tablet)
- administered orally for prophylaxis + more sustained effect
Describe unwanted effects of organic nitrates
- repeated administration may be associated with diminished affect (can be minimised by nitrate low periods e.g. at night)
- throbbing headaches (due to cranial vasodilation)
Why is GTN administered IV with aspirin in unstable angina?
- high risk of MI (due to atheromatous plaque)
- aspirin = anti-platelet drug
- relieves ischaemia + reduces risk of infarct
Describe the role of endothelium in vascular smooth muscle contraction
- altered gene expression
- releases endothelia precursors
- produces ENDOTHELIN 1
- endothelin 1 binds to endothelia A receptor (smooth muscle membrane)
- couples with Gqg11
- increase in intracellular Ca2+
- contraction
What is endothelin?
- 3 types in body
- endothelin 1 determines CVS function
- peptide synthesised by endothelial cells
- released from basal side (facing vasculature)
- cause smooth muscle contraction by acting upon G protein coupled receptors (Eta)
What factors (if increased) can cause altered gene expression (+ production of endothelin)?
- adrenaline
- angiotensin 2
- ADH (vasopressin)
What factors (if decreased) can cause altered gene expression (+ production of endothelin)?
- nitric oxide
- natriuretic peptides (A/B/C)
- shear stress
Name 2 antagonists of the ETa receptor
- ambrisentan
- bosentan
What do ET A receptor antagonists treat?
- pulmonary hypertension
What does the RAAS play a major role in the regulation of?
- sodium excretion
- vascular tone
What can increase the production of renin from the juxtaglomerular apparatus in kidney?
- increased renal sympathetic nerve activity
- decreased renal perfusion pressure
- decreased glomerular filtration
Where is angiotensinogen produced?
- liver
What does angiotensinogen do?
- converts renin to angiotensin 1
What converts angiotensin 1- 2?
- angiotensin converting enzyme (ACE)
What does angiotensin 2 bind to?
- AT 1 receptor (G protein coupled receptor)
When angiotensin2 binds to AT1 what is the effect on the organs?
- contraction of vasc smooth muscle
- cell growth (heart/arteries)
- aldosterone secretion from renal cortex
Why does angiotensin 2 cause vasc smooth muscle contraction?
- activation of smooth muscle AT1 receptors
- increased release of adrenaline from sympathetic nerves
What is the effect of aldosterone secretion from adrenal cortex?
- tubular sodium reabsorption and salt retention
Overall what are the 2 major outcomes of RAAS?
- increased MABP
- increased blood volume (+ MABP)
Where is ACE found? What is it?
- on the surface of endothelial cells
- membrane-bound enzyme
What does ACE do?
- converts inactive angiontensin 1 - active angiotensin 2 (vasoconstrictor)
- inactivates bradykinin (vasodilator in endothelin pathway)
Name 2 ACEI
- lisinopril
- enalapril
What do ACEI do?
- blocks conversion of angiotensin 1-2
- venous dilation (decreases preload)
- arteriolar dilation (decreases after load + TPR)
- Decreases cardiac load + blood pressure
What is the effect of ACEI on cardiac contractility?
- none
- CO may increase as a result of reduced TPR
What are ACEIs effect on aldosterone?
- reduce (don’t abolish) release
- promotes loss of salt and water
Where do ACEI have the greatest effect?
- angiotensin selective vascular beds (AT1 receptors)
- situated in brain/heart/kidneys: maintains perfusion of critical organs
Why do ACEIs cause dry cough?
- accumulation of bradykinin in airways
- irritation of sensory nerves in lung
- cough reflex
What are ARBs?
- angiotensin 1 (AT1) receptor blockers
Name an ARB
- losartan
What is the effect of ARB?
- similar properties to ACEI
- do not affect metabolism of bradykinin
- useful in patients with dry cough who find ACEI intolerable
Describe 3 uses for ACEIs + ARBs
1) hypertension: reduce TPR + MABP; suppression of proliferation of smooth muscle in media of resistance vessels
2) cardiac failure: associated with inappropriate activation of RAAS; decrease vascular resistance (improves perfusion); increases sodium/water excretion; regresses LVH
3) MI: similar as cardiac failure
What is an adrenoceptor?
- g protein coupled receptor
- activated by sympathetic transmitter NA/adrenaline
What do beta1 adrenoceptors do?
- increase HR; force; AV node conduction velocity
What do beta2 adrenoceptors do?
- relax vascular smooth muscle
Give an alternative name for beta blockers
- Beta adrenoceptor antagonists
What are b blockers used to treat?
- angina (stable/unstable) NOT VARIANT
- hypertension
- heart failure
Why are b1 selective agents preferred?
- decrease myocardial O2 requirement (decrease HR/SV/cardiac work)
- counter elevate sympathetic activity associated with ischaemic pain
- increase diastole (decrease HR + AV node conduction velocity) = IMPROVES PERFUSION OF LEFT VENTRICLE (via coronary arteries)
Why are b blockers used in hypertension?
- reduce CO
- reduce MAP
- CO returns to normal over time
- TPR resets itself to lower level = MAP decreases
- reduces renin release from kidneys
- reduced sympathetic activity
Why are b blockers used to treat heart failure?
- in combo with other drugs
- suppress adverse effects of elevated activity of RAAS
What are calcium antagonists mechanism of action?
- prevent opening of LTCC in excitable tissues in response to depolarisation
- reduces influx of Ca2+
What do LTCC mediate?
- upstroke of AP in SA/AV nodes (calcium antagonists reduce rate and conduction through AV node)
- Plateau phase of ventricular AP (calcium antagonists reduce force of contraction)
What are ROCs?
- receptor operated channels
- cation selective channels
What do ROCs do?
- open
- allow Na+ to enter smooth muscle
- cause depolarisation
- opening of LTCC
- Ca2+ influx
Name 3 calcium blockers
- verapamil
- amlodipine
- diltiazem
Which of these 3 calcium blockers a) reduces HR b)reduces BP?
a) verapamil + diltiazem
b) amlodipine (causes relfex tachycardia)
What is amlodipine?
- dihydropyridine compound
- relatively selective for smooth muscle LTCC
What is the effect of calcium blockers on hypertension?
- reduces Ca2+ entry into vasc smooth muscle
- arteriolar dilation
- reduced TPR/MABP
- little effect on veins
Why are drugs acting on smooth muscle LTCC preferred (e.g. amlodipine) to drugs acting on cardiac LTCC?
- minimises unwanted effects on cardiac muscle
e. g. in patients with hypertension + heart failure/block
What other conditions are calcium blockers advised for?
- angina
- systolic hypertension
What is the effect of calcium blockers in angina?
- prophylactic treatment, used in combo with GTN
- used if beta blockers are contraindicated
- peripheral arteriolar dilation; decreases afterload/O2 requirement
PRELOAD NOT CHANGED - coronary vasodilation (useful in variant angina)
What is the effect of diltiazem + verapamil on angina?
-negative inotropic effects; later offset by baroreceptor activation in response to vasodilation + increased sympathetic activity
What else can calcium blockers treat?
- dysrhythmias
- ventricular rate in rapid atrial fibrillation reduced by suppression of conduction through AV node
- verapamil is usually used
What is the contraindication of treating dysrhythmias with verapamil + a b blocker in HEART FAILURE?
Both cause reduction of conduction through AV node
Can cause heart block
Describe the mechanism of potassium channel openers
- K+ channel openers open ATP-modulated K+ channels (Katp) in vascular smooth muscle
- They act by antagonising intracellular ATP (which closes Katp channels)
- cause hyperpolarisation
- switch off LTCC
- act potently + primarily on arteriolar smooth muscle
Name 2 potassium channel openers and their mechanism of action
a) MINOXIDIL: used as a drug of last resort in severe hypertension; causes reflex tachycardia (prevented by a beta blocker) and Na+/h20 retention (prevented by a diuretic)
b) NICORANDIL: has NO donor activity; used in angina refractory to other treatments
What do alpha 1 adrenoceptor antagonists do?
- cause vasodilation
- block vascular a1 adrenoceptors
- reduced sympatehtic transmisson - decreased MABP
Name 2 alpha adrenoceptor antagonists
- prazosin
- doxasozin
What else can alpha 1 adrenoceptors be used for?
- benign prostatic hyperplasia (abnormally enlarged prostate that compresses the urethra)
- particularly indicated for hypertensive patients with this condition
Name an adverse effect of alpha1 adrenoceptor antagonists
- postural hypotension (decrease in BP upon standing)
What do diuretics do?
- act on the kidney
- increase excretion of sodium, chlorine and water
- exert additional relaxant effects upon vasculature
What is the mechanism of action of thiazide diuretics?
- inhibit NaCl absoorption in the distal tubule (block the Na+/Cl- co-transporter)
- Cause upto 5% of filtered Na+ to be excreted alongside water
- produces moderate diuresis
What is the mechanism of action of loop diuretics?
- inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle
- block Na+/K+/2Cl- co-transporter
- cause upto 15-25% of filtered Na+ to be excreted alongside water
- strong diuresis
Name a thiazide + conditions it is used in
bendroflumethiazide
- mild heart failure
- hypertension
What is the effect of loss of salt/water on cardiac output/BP?
- loss of Na+/water contracts blood volume
- initially reduces cardiac output
- cardiac output eventually returns to normal
- MABP remains depressed through lowering of TPR
Name a loop diuretic + conditions it is used in
furosemide
- acute pulmonary oedema (IV)
- chronic heart failure
Used to reduce salt/water overload associated with these conditions
Diuretic induced reduction of blood volume exerts which benefit?
- absorption of extracellular fluid (contributing to oedema) into capillaries
What condition can be treated with both a thiazide + loop diuretic?
- severe resistant oedema
What is an undesirable effect of diuretic treatment?
- loss of K+ (occurring through Na+/K+ exchange in distal tubule)
- can be corrected by co-administration of a ‘potassium sparing diuretic’ or K+ supplements
