Peripheral vasodilators
- Nitric oxide and nitrovasodilators
[Ref: SH(H)2:p359-374]
Used to treat HTN, hypertensive crisis, and facilitate forward LV stroke volume
Nitric oxide (NO)
- Endogenous gas
- Synthesized in endothelial cells
- Activates guanylate cyclase
--> Increase cGMP
--> Vasodilation
- Half-time <5 second
* Inactivated by Hb
* Localised effects
Physiological effect of NO
CVS
Regulation of systemic and pulmonary vascular resistance
Autoregulation of local circulation
* Endothelium-derived relaxing factor (EDRF)
Resp
Bronchodilation
V/Q matching
Platelets
Inhibits platelet activation
Nervous system
Neurotransmitter
* Excitatory in the CNS
May play a role in pain
Immune function
(???)
Effects of increased/decreased NO
Decreased NO
- Essential hypertension
- Platelet aggregation
- Pulmonary HTN
- Pyloric stenosis and achalasia
- Infection
Increased NO
- Hypotension
* e.g. in septic shock
- Hyperdynamic state
* e.g. in cirrhosis
- Epilepsy
- Inflammation
Clinical use
NO has been used clinically as an inhaled gas for treatment of pulmonary hypertension
May be useful in treatment of ARDS
Toxicity
- Increases MetHb as NO combines with Hb
- Rebound arterial hypoxaemia and pulmonary hypertension may occur after abrupt discontinuation
- ??? can cause ARDS in excess amount
Sodium nitroprusside (SNP)
Direct-acting, nonselective peripheral vasodilator
--> Relaxation of arterial and venous vascular smooth muscles
- Immediate onset
- Very short duration of action
--> Requires continuous infusion
- More effect on artery (as opposed to GTN, which act more on veins)
Mechanism of action
- SNP interacts with OxyHb
--> Transfer of an electron from the iron of OxyHb to SNP
--> MetHb + Unstable SNP radical
- Unstable SNP radical
--> NO + 5 CN- (cyanide)
- NO then mediates the direct vasodilation effect
NB:
One of the cyanide ions may also react with MetHb to form cyanomethaemoglobin (non-toxic)
Actions of SNP
CVS
Direct venous and arterial vasodilation
--> Decrease in systemic BP
Cardiac output tend to increase due to reflex tachycardia and decreased systemic vascular resistance
* Despite decreased venous return secondary to venodilation
Possible coronary steal effect
CNS
Increased cerebral blood flow and blood volume
--> Increased ICP
Resp
Controlled hypotension could lead to decreased PaO2
--> Hypoxic pulmonary vasoconstriction
Platelet aggregation
Increased NO
--> Increased intracellular cGMP
--> Inhibition of platelet aggregation
Infusion rate of SNP > 3 microgram/kg/min
--> Increased bleeding time
Clinical use
- Controlled hypotension
- Management of hypertensive emergency
* Temporary treatment, to be followed by longer-lasting therapy
- Management of patients with mitral or aortic regurgitation or CHF
- Attentuation of proximal hypertension (secondary to cross-clamping of the aorta) during aortic operation
- Cardiac surgery
--> SNP induced vasodilation helps in rewarming phase of the cardiopulmonary bypass
Toxicity
Cyanide toxicity
- Cyanide binds with tissue cytochrome oxidase
--> Prevents oxidative phosphorylation
- Increased cyanide concentration
--> Tissue anoxia, anaerobic metabolism, lactic acidosis
- Suspect cyanide toxicity when
* Tachyphylaxis in a previously responding patient
* Increased mixed venous pO2
* Metabolic acidosis
* Patient resistent to hypotensive effect despite maximal infusion rate (>2microgram/kg/min or 10microgram/kg/min for longer than 10 minutes) (???dosage correct)
Treatment of cyanide toxicity
- Immediate discontinuation of SNP
- Sodium bicarbonate
- Sodium thiosulfate
* Provides sulfer donor to convert cyanide (CN-) to thiocyanate (SCN)
Thiocyanate toxicity
Rare because thiocyanate is 100-fold less toxic than cyanide
Signs include:
* Hyperreflexia
* Confusion
* Psychosis
Methaemoglobinaemia
Requires doses of SNP exceeding 10mg/kg
--> Unlikely in clinical practice
Phototoxicity
After solution is prepared, must protect from light by aluminum foil
--> Can break down in vitro and form cyanide
Administration and dosage
- Initial dose of 0.3 to 0.5 microgram/kg/min IV
--> Titrate to effect
- Infusion need to be protected from light by aluminum foil
- Decrease risk of cyanide toxicity by combining SNP with another drug to decrease the dose of SNP needed
Nitroglycerin
Organic nitrate
Action
- Acts principally on venous capacitance vessels and large coronary arteries
- Also produce pulmonary vasodilation
- Mainly a venodilator
Mechanism of action
- Produces NO in presence of thio-containing compounds
Effects on organ systems
- Venous dilatation
- Relaxation of bronchial smooth muscles
- Relaxation of GIT smooth muscles (including sphincter of Oddi)
- Relaxation of esophageal and ureteral smooth muscle tone
- Cerebral vasodilation
--> Could increase ICP
CVS
- The hypotensive effect of nitroglycerin depends more on blood volume than SNP.
- Can trigger reflex tachycardia and increased myocardial contractility
- Increased coronary blood flow
* c.f. possible coronary steal with SNP
- Can prolong bleeding time
* Due to production of NO and decreased vascular tone
Clinical uses
Angina pectoris
Acute and chronic, due to atherosclerosis or coronary artery vasospasm
* Reduces myocardial oxygen requirement by reducing preload (mainly) and afterload
* May also stop vasospasm
Acute coronary syndrome
IV administration of nitroglycerin...
- May be beneficial in:
* Patients with persistent or recurrent angina pectoris after reperfusion
* Patients not receiving reperfusion therapy
- May not help in:
* Patients receiving early reperfusion therapy
- May be detrimental in:
* Patients with suspected right ventricular infarction (due to their dependence on preload)
--> May become acutely hypotensive with nitroglycerin
Other conditions
- Cardiac failure
- For controlled hypotension
- Relaxation of sphincter of Oddi
Route of administration
- Sublingal
--> Peak plasma concentration in 4 min
- Oral, buccal, transmucosal tablet
- Lingual spray
- Transdermal ointment or patch
NB:
Absorbed by PVC, thus GTN infusion requires special tubing
Pharmacokinetics
Elimination half-time of 1.5 min
Large volume of distribution
Complications
Methaemoglobinaemia
- Nitrite metabolite can oxidise iron in Hb and produce MetHb
--> Methaemoglobinaemia can occur
- Treat with methylene blue 1-2mg/kg IV over 5 minutes
--> Allows conversion of MetHb back to Hb
Tolerance
- Tolerance to the vasodilation effect occurs within 24 hours of sustained treatment
- Drug-free interval of 12-24 hours to reverse the tolerance
Side-effects
- Headache (dilation of meningeal vessels)
- Facial flushing
- Tolerance
- Decreased sensitivity to heparin
* Interferes with binding of heparin to antithrombin III
Other drugs
- Erectile dysfunction drugs
- Hydralazine
- Isosorbide dinitrate
- Papaverine
- Trimethaphan
Dipyridamole
- Often used in combination with warfarin in patients with prosthetic heart valve
--> thromboembolism prophylaxis
- Dipyridamole also inhibits platelet aggregation (like aspirin)
- Also used as prophylaxis against angina pectoris
Diazoxide
- Decreases blood pressure in 1-2 minutes
- Effect lasts 6-7 hours
- Inabililty to titrate to effect like SNP
- Causes significant increase in cardiac output and often increase in HR
- Not recommended for treatment of aortic dissection
Side effects of diazoxide
- Sodium and water retention
- Uterine relaxation
- Hyperglycaemia
- Catecholamine release
Adenosine
- Potent dilator of coronary artery
- Decreases myocardial oxygen requirement via anti-adrenergic and negative chronotropic effect
- Very brief elimination half-time
--> 0.6 to 1.5 second
Mechanism of action
Stimulation of potassium channels in supraventricular tissues
--> Hyperpolarisation of atrial myocytes
--> Decrease in diastolic depolarisation (phase 4) of the pacemaker cells in SA node
Ventricular myocytes do not have adenosine-sensitive potassium channels
Clinical use
Treatment of paroxysmal SVT and narrow complex tachyardia
- Alternative to verapamil
- Not effective in atrial flutter, atrial fibrillation, and VT
- Should not be used in 2nd or 3rd degree heart block or sick sinus syndrome
* Not without an artificial pacemaker
Controlled hypotension
- Tachyphylaxis does not occur
- Level used to induce hypotension will not alter cardiac automaticity or impulse conduction
- Not used so much for this purpose