Lec 17- Vasodilators Flashcards
Haemodynamic rationale and effect
- Preload- vasodilation and reduction of intracardiac volume
- After load- reduction in systemic vascular resistance
- Coronary perfusion- Decreases myocardial schema , increase coronary blood flow to reduce O2 demand
Preload revision
- This is the volume of blood in the ventricle before contraction
- This is based on venous pressure (venous return)
- If increase right atrial pressure then get increased ventricle filling
- Increased filling results in increased output
- This is an increase in myocardial work and O2 requirements
After-load
- Afterload is the peripheral BP that ventricular contraction must overcome
- Ventricular contraction and cardiac output will compensate for increased after load
- This is an increase in myocardial work and O2 requirement
- Long term increase in arterial pressure results in ventricular hypertrophy
Coronary blood supply
-Angina- blockage via atherosclerosis, if we increase the diameter of the vessels allows blood to pass
Coronary perfusion ‘The perfusion window’
- Blood flow to the heart muscle only occurs during diastole
- Increase HR means there is less time between beats therefore less time for blood to feed the heart so perfusion is decreases
- An increase in ventricular end diastolic pressure will mean less blood flow to the heart
- Reduced diastolic arterial pressure means less blood will flow to the heart
Clincal use of vasodilators
-Reduce cardiac preload \+Cardiac failure (CHF) \+Angina -Reduce cardiac after load- HTN -Local reductions in vascular resistance \+Prinzmetal's (variant) angina \+Peripheral vascular disease \+Raynauds disease
Pre-load reduction
- Relaxation of veins will decrease cardiac filling pressure (pre-load)
- Therefore use vasodilators with predominant venous action
- Useful in CHF and in angina- sudden reduction in preload and so cardiac work
Afterload reduction
- Relaxation of arterioles will decreased resistance and reduce BP (HTN). Afterload reduction also useful in Angina and HF
- Use vasodilators with predominant arterial action
- The sum forces opposing ventricular emptying. Hypertrophy is a physiological mechanism due to increased afterload
- Useful in cardiac failure to reduce cardiac work
Coronary flow
-Relacation of arteries will increase flow to an Organ if arteries are narrowed (angina) and decrease afterload by increasing compliance (Useful in HF)
Vasodilator drugs
Heterogenous Group: 2 major types
1) Directing acting: On vascular smooth muscle (VSM)- affect all constrictor agents
A- Drugs acting at ion channels
B-Drugs acting on NO systems
2) Indirectly acting or anti-vasoconstriction
A-Drugs acting on ion channels
1) Ca2+ channel blockers- inhibit voltage gated Ca2+ channels
2) K+ channel openers: Activates ATP dependant K+ channels
Muscle cell: cardiac or vascular
-Depolarisation, Ca2+ entry = contraction
-
Cardiac APs in general
- Rapid depolarisation
- Partial repolarisation (calcium shoulder, gives prolonged contraction)
- Plateau
- Depolarisation
- Pacemaker potential
Voltage gated calcium channels
- Present in all excitable cells- muscles and nerves
- Activated by cell depolarisation e.g. during cardiac AP
- Different subtypes: L; N; P/Q; T
- Different subtypes have different tissue distributions and functions
- It is L-type channels that mediate voltage dependant Ca2+ entry into the muscle
L-Type channel structure
- The a1C subunit of the L-type Ca2+ channel is the pore-forming unit
- Central function unit with similar structure to Na+ channels
- 4 homologous domains each with 6-a helices membrane spanning segments (S1-6)
- S4 contains +VE charged residues (voltage sensors)
- a1 subunit structure defines subtype and is the target subunit for antagonists and agonists
L-Type blockers act selectively on cardiovascular tissues- important for therapeutic use
-Neurons rely on N and P-type channels
-Skeletal muscle relies primary on [Ca]i
-Cardiac muscle requires Ca2+ influx through L-type Ca2+ channels
+Contraction (e.g. ventricular myocytes)
+Upstroke of AP (pacemaker)
-Vascular smooth muscle requires Ca2+ influx through L-type Ca2+ channels for contraction
CCBs- mechanism of action
- Increase the time that Ca2+ channels are closed
- Relaxation of there arterial smooth muscle but not much effect on venous smooth muscle
- Reduce calcium entry into vascular smooth muscle and so produce vasodilation
- Significant reduction in afterload BUT NOT preload
3 Modes of Ca2+ channel opening
Mode 0 -opening probability 0 -Favoured by DHP antagonists -% of time spent in this mode <1% Mode 1 -Opening probability low -% of time normally spent in this mode= 70% Mode 2 -Opening probability High -Favoured by DHP antagonists -% time open= 30%
-Weather not channel opens affects the binding of the drug
3 classes of calcium channel blocker
- Verapamil (phenylalkyamines)
- Diltiazem (benzodiazepine)
- Nifedipine (1,4-dihydropyridines)
The different drugs have different channel binding region properties
-Use-dependant binding (Target AP conducting cardiac cells)
+Verapamil binds to area of the channel that is only exposed once the channel is open
-Voltage-dependant binding (target smooth muscle)
+Amlodopine needs the channel to be inactive inorder to bind, because of the voltage of the Ca2+ channels (-30mV) the channels are normally closed
Phenylalkyamines (verapamil)
- Preferentially block channel;s in mode 1,2 so need opening
- Preferential effect on cardiac cells
- Use dependant, frequency dependant
- Affect working cells, reduce contraction, sinus rate and AV conduction
- Reduce myocardial contractility
- Reduce HR
- NB lots of interactions with other drugs
Dihydropyridines (Amlodopine
-Preferentially block channels in mode 0, dependant on cells holding potential
-Voltage dependant- selective for vascular smooth muscle cells (due to their membrane potentials) compared with cardiac cells
-Reduce afterload and so myocardial work
-Little or no direct chronotropic or inotropic actions (But indirect effects due to vasodilations)
NB- can worsen HF, dosing dependant on release profile
Hemodynamic effects of CCBs- Verapamil
- Peripheral vasodilation: +
- Coronary vasodilation: ++
- preload: 0
- Afterload: - -
- Contractility: - -
- HR: 0
- AV conduction: - -
Haemodynamic effects of CCBs- diltiazem
- peripheral vasodilation: +
- Coronary vasodilation: +++
- preload: 0
- Afterload: - -
- Contractility: 0
- HR: -
- AV conduction: -
Hemodynamic effects of CCB’s- amlodopine
- peripheral vasodilation: ++
- Coronary vasodilation: +++
- preload: 0
- Afterload: - - -
- Contractility:
- HR: 0 may increase barrow receptors
- AV conduction: 0
Use of Ca2+ channel blockers
- HTN
- Angina
- Treatment of supra ventricular arrhythmias (verapamil only)
- AF (diltiazem only)
K+ channel openers
- In excitable cells there are many K+ cells- important for setting and maintaining membrane potentials
- Opening of K channels cause hyper polarisation- this occurs when you have low [ATP]
Pharmacology on vascular smooth muscle
- Highly selective for arterial smooth muscle due to the distribution of ATP sensitive channels. Virtually no effect on venous smooth muscle
- Increase venous return due to increased flow in vascular beds. So increase in CO
- Reduce insulin release from pancreas
- Selectivity of action possible due to differential regulatory subunit expression
The K+ channel openers and uses
-Nicorandidil (N-(2-hydroxyethyl) nicotinamide nitrate
+Duality of action: nitro vasodilator and K channel opener
+Angina- Coronary artery dilation and reduce afterload
-Minoxidil
+HTN- arterial vasodilation
+Shampoo- for hair growth
-Diazoxide- chemically one of the thiazide type diuretics
+Chronic intractable hypoglycemia (i.e. reduce insulin release)
K+ channel opener side effects
- Edema- water and salt retention as result of baroreceptor reflex, can also give loop diuretics to help
- Hyperglycemia- due to effect on islet of Langerhans cells in pancreas, inhibiting insulin release
- Cutaneous vasodilation: flushing; dizziness; headache
K+ channel opener side effects
- Edema- water and salt retention as result of baroreceptor reflex, can also give loop diuretics to help
- Hyperglycemia- due to effect on islet of Langerhans cells in pancreas, inhibiting insulin release
- Cutaneous vasodilation: flushing; dizziness; headache
Directly acting vasodilators
B drugs acting on NO systems
- Agents that increase cyclic nucleotides: in VSM both cAMP and cGMP are associated with relaxation. Many agents act via production of nitric oxide (NO) (Nitric oxide donors, nitro vasodilators)
- Some agents inhibit breakdown (Phosphodiesterase)
Physiological production of nitric oxide
- Vascular smooth muscle cells are lined by endothelial cells and these mediated vasodilation
- Blood vessels with added ACh it dilates, if this is damaged then this doesn’t occur
- Blood flow causes shear stress on endothelial cells this causes an increase in Ca2+ in endothelial cells (NB- ACh and bradykinin also do this)
- Ca2+ increase activates nitric oxide synthase –> NO
- NO then diffuses into the muscle cell therefore this is a local action
- NO activates guanylate cyclase which increases cGMP
- cGMP associates with contractile proteins so inhibiting it causing relaxation
- Phosphodiesterase breaksdown cGMP so inhibiting vasodilation
Nitrates- Mode of action
- When nitrates are in the blood they produce NO
- Because NO is cell permeable it can cross lipid membrane through the endothelial cell into the smooth muscle cell
- We bypass the physiological NO production
- Short lived radical, activate soluble guanylate cyclase ….
Nitro-vasodilators- actions
- Vasodilator- preferential on venous muscle
- At low rises fall in venous return (Preload) and in left ventricular stress
- Higher doses fall in MAP (Afterload)
- Potent coronary vasodilators. Modest effects in ischaemic heart disease
- Improved sub-endocardial flow and collateral flow in partial coronary occlusion
- No affect upon contractile state
- Main effect is upon pre-load
Nitrates in coronary artery disease
- Atheromas usually block vessels so the resulting tissues then get reduced blood flow
- By giving nitrate you cause dilation which will act to increase blood flow through the collateral arteries which is another path to the ischemic area increasing blood flow
Nitrates Hemodynamic effects
1) Venous vasodilation
+Decreased pre-load causes
+Decrease pulmonary congestion
+Ventricular size reduction
+Decrease ventricular wall stress
+Decreased MVO2 (myocardial o2 consumption)
2)Coronary vasodilation causes increased myocardial perfusion
3)Arterial vasodilation causes decreased afterload
+Decreased CO
+Decreased BP
Clinical use of nitrates
- 1st agent was amyl nitrite
- Primary use in angina
- Sublingual glyceryl trinitrate peak plasma level in 1-2 min
- Isosorbide mononitrate and denigrate (orally active, long lasting) for prophylaxis
- Subject to tolerance due to exhaustion of enzymes (Guanylate cyclase) conversion to free NO
- Main therapeutic approach is to allow nitrate free period 8-12 hours per day
- Can cause hypotension, flushing and headaches
Sodium nitroprusside
-Acts equally on venous and arterial smooth muscle
-Metabolised in vivo to release NO
-Active only by IV infusion- very rapid onset and short duration
-Highly effective for short term use in specialist units
NB DANGER: cyanide metabolite (can kill)
Phosphodiesterase inhibition
- This is exploitation of physiological system
- By inhibiting phosphodiesterase this means that cGMP is not being broken down
- This vastly increases [cGMP] so increase in dilation
Phosphodiesterase inhibitors
- Many subtypes of phosphodiesterase which are differentially expressed, so there is a large potential for targeted action/prescription
- Phosphodiesterase inhibition leads to cGMP build up in VSM cell
- Cilostazol type II PDE inhibitor used for PVD (peripheral, vascular disease)
- Enoximone exerts most effect on the myocardi ; it has positive inotropic properties and vasodilator activity used in HF with reduced CO and filling pressures (Special inpatient units)
- Sildenafil- selective for type V PDE, found in corpus cavernosum
Hydralazine
-Directly acting vasodilator of unknown mode of action. seems to inhibit IP3, activation of Ca2+ release from sarcoplasmic reticulum
-Highly arterial selective. More effective on renal, coronary and cerebral circulation
-Used short term treatment of acute HTN in pregnancy and Intensive care settings
-HTN in renal failure
-HF in combination with nitrates
-But longer term high dose can lead to immune disorders
+Test for ANF and for proteinuria every 6 months
+Check acetylator status before increase dose above 100mg dd
2) Indirectly acting vasodilator drugs
-Agents act to block vasoconstrictor effects of signalling systems in the cardiovascular system
Vascular smooth muscle
- GPCR’s are expressed by muscle cells
- NA (alpha 1- GPCR)
- Angiotensin II (AT-1 receptors)
- NA release binds to GCPR and causes increase in IP3 leading to Ca2+ increase causing contraction
Alpha-1 antagonist
-Prazosin (doxasoin) Causes vasodilation and fall in arterial BP
-Sympathetic system controls bP on minute to minute basis therefore, antagonising alpha adrenoceptors is especially useful and therefore widely used in the treatment of HTN from step 3
-Also used for Benign prostatic hyperplasia (BPH)
NB: can cause dizziness and postural hypotension; can cause increase in urinary frequency
Angiotensin II
- Produced in response to reductions in BP
- Angiotensin II si an extremely potent vasoconstrictor via activation of AT-1 receptor
- Angiotensin II also increases NA release from sympathetic nerves
RAAS
- Sympathetic B1 stimulation or a drop in BP
- Kidney –> renin
- Angiotensinogen in plasma gets converted by renin into angiotensin I
- ACE( bradykinin breaks this down) converts Angiotensin I –> angiotensin II
- Angiotensin II causes fluid and salt retention; vasoconstriction and increase in TPR and afterload
Therapeutic targets
- ACEI- preferentially vasodilators kidneys, heart and brain
- AT1- receptor antagonists
- Renin inhibits
Vasodilator classification
Venous: Nitrates
Mixed: a-adrenergic blockers; ACEI; Angiotensin II inhibitor; K+ channel activators; nitroprusside
Arterial: Minoxidil; hydrazine
Use of vasodilators
HTN
-Selective dilators of arterioles (reduce peripheral resistance_
+Amlodopine
+Hydralazine
+Minoxidil
+Nitroprusside (Emergencies only)
Angina
-Reduce cardiac workload and improve coronary perfusion
+Nitrates- selective for veins and large arteries
+CCB’s- selective for arterioles and cardio-depressant: Benzothiazepines
+Nicorandil
Heart Failure
-Reduce preload and afterload
+Nitrates (reduced pre-load)
+Hydralazine
+PDE inhibitor- enoximone (where reduced CO and filling pressure)
Atrial Fibrillation
-Diltiazem
