2. Learning Objectives
– Classify vasodilators
– Describe the hemodynamic effects of VD
– List the adverse effects and
contraindication
– List the therapeutic uses
3. Classification of Vasodilators
(according to mechanism and Site of Action)
Classification based on MOA
• Directly acting Vasodilators
– Act directly on Vascular
smooth muscles
• Organic nitrates
• Drugs acting on K channels
• Calcium Channel Blockers,
• Indirectly acting
Vasodilators
– Inhibit action of
endogenous constrictors
• Those that inhibit sympathetically
mediated vasocontriction
• Those that inhibit renin-
angistensin system
General Classification
– Ca channel blockers: Inhibit
movement of Ca through L-type
channels (ie. Verapamil)
– Open K-channels: Minoxidil
(Rogaine), Diazoxide (acute HT)
– Direct vasodilator: mainly
arterioles, Hydralazine, may
inhibit calcium release
– Coupled to NO/cGMP: dilate veins
also, sodium nitroprusside,
nitroglycerin, nitrates etc
– Dopamine agonist: Fenoldopam
(Dopamine-1A subtype) for acute
hypertension
– Alpha-antagonists: Prazosin
(alpha1-), phenoxybenzamine
(irreversible)
3
5. 5
Effects of Vasodilators
• Vasodilators act:
– To increase total tissue blood flow
– To reduce arterial pressure
– To reduce central venous pressure
• Net effect:
– Reduction of cardiac preload (reduced
filling pressure) and after-load (reduced
vascular resistance), hence reduction in
cardiac work.
7. 7
Peripheral
Vasodilators
Ca2+ - channel blockers
Dihydropiridines
Verapamil
Diltiazem
Ca2+
NO
Activators of NO/guanylate cyclase pathway
Hydralazine ?
Nitroprusside
Nitroglycerin
K+ - channels activators
Minoxidile
Diazoxide
a1 – Adrenoreceptor
antagonists
Prazosin
K+
Ang II receptor
antagonists
Losartan
VSMCs
8. Nitric Oxide
– Discovered in the early 1980’s.
– A molecule that acts as a hormone by
being formed in response to a signal,
causing the smooth muscles
surrounding blood vessels to relax.
– Causes blood pressure to go down
– Mechanism of action not completely
understood
9.
10. NO Synthesis in Body
– Nitric oxide is formed by the oxidation of l-arginine
via an enzyme called nitric oxide synthase (NOS).
– The NOS enzyme uses NADPH and oxygen as
cosubstrates
• The NOS enzyme catalyzes a five-electron oxidation of Arginine
to NO and L-citrullline using NADH as the source of electrons.
• NOS produces NO in response to increased calcium ion
concentrations.
11. 11
Mechanism of action and pharmacologic
effects of Organic Nitrates
• Mechanism of Action:
– Relax smooth muscles by intracellular
conversion of nitrates to Nitric Oxide (NO)
– NO activates guanylate cyclase and increases
the cells’ cyclic GMP
– Elevated cGMP dephosphorylate myosin light
chain, resulting in vascular smooth muscle
relaxation
• Pharmacologic effects:
– Relieving coronary vasospasm
– redistributing myocardial blood flow to
ischaemic areas of the myocardium
– Tolerance can develop rapidly to the effects of
nitrate therapy
12.
13. 13
Common Adverse Drug Reactions of
organic nitrates
• Headache
– Increase dose slowly
• Hypotension
– GLYCERYL TRINITRATE causes syncope
14. 14
Peripheral Vasodilators
Vasodilators (for use in Hypertension)
Hydralazine
Minoxidil
Sodium Nitroprusside
Diazoxide
***
Vasodilators (for use in Angina)
GLYCERYL TRINITRATE (GTN),
ISOSORBIDE MONONITRATE
ISOSORBIDE DINITRATE
15. Sodium nitroprusside
• Sodium nitroprusside
– short-acting agent (few minutes)
administrated by infusion in
hypertensive emergencies
• (hypertensive encephalopathy, shock,
cardiac dysfunction) for max 24 hours (risk
of cumulation of cyanide toxicity)
– Releases NO
– the stock solution should be diluted
and covered with foil to prevent
photodeactivation
– adverse effects:
• too rapid reduction of BP, nausea,
palpitation, dizziness
• cyanide metabolite (thiocynanate)
accumulation – tachycardia,
hyperventilation, arrhythmias, acidosis
CN CN
CN CN
Fe
NO
CN
- -
-
-
++
-
+
17. 17
Hydralazine:
rapidly and fairly absorbed after oral administration
useful for hypertensive crisis during pregnancy
Adverse effects:
Na+ and water retention,
systemic lupus erythematosus –
Minoxidil:
”Last choice” for treatment of hypertension: therapy of severe
hypertension resistant to other drugs
prodrug its metabolite (minoxidil sulfate) is a potassium
channel opener ( repolarization + relaxation of vascular
smooth muscle)
• more effect on arterioles than on veins
• orally active
Adverse effects:
Na+ and water retention → coadministration with beta-vlocker and diuretic is
mandatory for this drug,
oedemas, hypertrichosis, breast tenderness, Headache, sweating
Topical minoxidil (Rogaine) used for correction of baldness.
Peripheral Vasodilators for
Hypertension….
18. 18
Nitrovasodilators for Angina
– GLYCERYL TRINITRATE
• (GTN or nitoglyceryl)
• Prodrug, must be denitrated to produce
active NO
• GTN is broken down into 1,2-glyceryl
dinitrate + Free NO
• Sublingual (To avoid first pass metabolism ),
buccal, transdermal
– ISOSORBIDE MONONITRATE
• Sustained release formulation, tablets
– ISOSORBIDE DINITRATE
(RISORDAN)
• Sustained release formulation, tablets
19. 19
Specific Uses of Nitrates
• GLYCERYL TRINITRATE (Nitriderm)
– Used for the rapid treatment of angina pain.
– To avoid first pass metabolism is given by
the sublingual route.
– May be used frequently and prophylactically
• Oral Nitrates
– Commonly given as a once a day sustained
release formulation
– Used for prophylaxis
20. 20
Vasodilators: K channels activators
• Cause vasodilation by activating K
channels
– Eg: Diazoxide
• given by rapid iv. injection (less than 30 seconds)* in
hypertensive emergencies
• -it is a potassium channel opener
• Adv effects:
– glucose intolerance due to reduced insulin secretion (used in
patients with inoperable insulinoma)
– Na+ and water retention, hyperglycaemia, hirsutism
• used for treating hypertensive emergencies
• but diazoxide may rarely be used if accurate infusion pumps
are not available and/or close monitoring of blood pressure is
not available
21. Why do we have to combine vasodilators with b-blockers and diuretics?
