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