VPT 311: General and Systemic Veterinary Pharmacology (2+1)

DIRECTLY ACTING VASODILATORS

• Directly acting vasodilators produce their action mainly by interfering with the availability of calcium for vasoconstriction.
• Calcium entry is prevented either by blocking voltage dependent Ca²⁺ channels or by causing hyperpolarization.
• Drugs produce vasodilator activity by altering Ca²⁺ release from the sarcoplasmic reticulum or reuptake into it and enzymes that determine Ca²⁺ sensitivity.
• These mechanisms are exemplified by calcium antagonists, potassium channel activators and drugs that influence cytoplasmic concentrations of cyclic neucleotides.

Nitrates

• Amyl nitrate, isosorbide dinitrate, glyceryl trinitrate ( nitroglycerine) are used as vasodilators.
• These are available as oral tablets, buccal tablets, sublingual tablets, inhalation preparations, topical patches (sustained release) and topical ointment.
• Nitroglycerine also helps to dilate coronary blood vessels.
• These drugs cause a direct relaxation of arterial and venous smooth muscles by acting as a source of nitric oxide which is released and causes direct relaxation.
• Toxicity includes hypotension, methemoglobinaemia and dermatitis.

Calcium channel blockers

• These drugs cause generalized vasodilatation, though individual agents differ in regional distribution of the effect by reducing intracellular availability of Calcium ions.
• Drugs under this category include verapamil, diltiazem, nifedipine, nimodipine and amlodipine.

Potassium channel activators

• These drugs relax smooth muscles by selectively increasing the membrane permeability to K⁺.
• This hyperpolarizes the membrane, switching off voltage dependent Ca²⁺ channels and inhibiting action potential generation.
• Drugs under this category include cromokalin, pinacidil, minoridil and diazoxide.

Agents that act by increasing cyclic nucleotide concentration

• Cyclase activation
  • Many drugs relax vascular smooth muscle by increasing the cellular concentration of either cGMP or cAMP.
  • Dopamine has mixed vasodilator and vasoconstrictor actions, but, is used therapeutically to dilate the renal vasculature where it increases the cAMP by activating adenylate cyclase.
• Nitroprusside
  • Is a very powerful vasodilator with little effects outside the vascular system.
  • It breaks down under physiological conditions to yield nitric oxide, which produces the vasodilatation effect.
  • Toxicity to nitroprusside includes excessive vasodilatation and accumulation of thiocyanate.
  • This drug also has a very short half life and must be administered by intravenous route as a freshly prepared solution.
• Natriuretic peptides cause vasodilatation by activating guanylate cyclase.
• Phosphodiesterase inhibitors like theophylline can also cause vasodilatation.

Vasodilators with unknown mechanism of action

• Hydralazine
  • Acts mainly on arteries and arterioles causing a fall of blood pressure accompanied by reflex tachycardia.
  • This drug produces an increase in the stroke volume and is useful in mitral insufficiency.
• Ethanol
  • Dilates cutaneous blood vessels causing the familiar drunkard’s flush.