NO-mimetic drugs
There are many possibilities to obtain an NO-mimetic effect.
- to increase endogenous synthesis of NO by administration of a precursor
- to give drugs which, in the body, liberate NO molecules from their own chemical structure; these drugs are called nitric oxide donors
- to enhance NO effects by inhibiting inactivation of cyclic GMP.
Increased biosynthesis
Arginine is the physiological precursor of NO, the diet supplies approximately 5 g of arginine per day.
Arginine has mild vasodilator and antihypertensive properties. It could inhibit development of atherosclerotic lesions and could have an antiplatelet effect.
Arginine stimulates the release of growth hormone by the pituitary gland and has been proposed for improving the growth of children. This effect does not seem linked to stimulation of NO synthesis.
Arginine has been also employed in the treatment of hyperammoniemia. It could improve immune function.
Pharmacological effects of arginine are obtained with high doses, going from 6 to 20 G per day.
Arginine is present in formulations for parenteral and oral administrations and also as a dietary supplement.
Nitric oxide donors
Drugs able to liberate in the body one or more NO molecules from their chemical structure are called nitric oxide donors. They are sodium nitroprusside, molsidomine and linsidomine, and organic nitrates.
Sodium nitroprusside
Sodium nitroprusside, Na2 [Fe (CN) 5 NO] 2 – is an unstable molecule given by intravenous infusion, which decomposes in the body in nitric oxide, NO, the active metabolite, and in cyanide, CN, which is toxic but is converted into thiocyanate. Nitroprusside is unstable in solutions which must be protected from light.
Sodium nitroprusside causes an immediate hypotension of short duration, blood pressure rises as soon as the infusion is discontinued. Because of these features, it is used:
- in treatment of hypertensive crises,
- to obtain a controlled arterial hypotension, during certain surgical operations,
- in cardiology, to treat acute congestive heart failures with peripheral vasocobstriction, resistant to other vasodilator treatments.
Adverse effects of nitroprusside are linked to its powerful vasodilator and hypotensive effects and the production of cyanide ions.
Cyanide released, in particular during overdoses and in individuals having a deficiency of the enzyme transforming cyanide into thiocyanate, can cause poisoning which has to be treated by hydroxocobalamin which inactivates cyanide by conversion into cyanocobalamine. This reaction is based on the high affinity of cyanide for metals such as cobalt. Hydroxocobalamin is given by infusion in high doses, from 30 to 100 mg.
Molsidomine and linsidomine
Molsidomine is metabolized in liver into linsidomine which, unstable in the biological environment, releases NO molecules. It is administered by oral route and is used in the preventive treatment of angina pectoris.
Linsidomine is administered by intracoronary route and has primarily a local effect. It is indicated in the treatment of coronary arterial spasm and as a coronary dilator during cardiovascular explorations.
It should be noticed that release of NO from linsidomine does not require the presence of any enzyme or compound with -SH group.
Principal adverse effects of molsidomine are hypotension and headache, especially at the beginning of treatment..
Organic nitrates
The term of organic nitrates indicates nitroglycerin which is often called glyceryl trinitrate, erythrityl tetranitrate, pentaerythrityle tetranitrate and isosorbide dinitrate which are NO donors. The first nitrate derivative, amyl nitrite, not generally used now, was introduced in therapeutics in 1870.
Degradation of nitrates with liberation of NO molecules in the body is not spontaneous. It requires the presence of molecules with sulfhydryl or thiol groups ( -SH) such as cysteine and glutathione.
R (ONO2) N + R' HS ¾® R (ONO2) n-1+ R' SNO + OH
R' SNO ¾® NO
This transformation is essential to the efficacy of nitrates. If tissues are depleted in molecules with sulfhydryl groups, organic nitrates lose their activity. This activity can be restored by administration of N-acetylcysteine. Exhaustion of HS groups occurs when the body is permanently impregnated with organic nitrates in high concentrations.
Effects
The essential property of nitrates is to relax vascular smooth muscles, but also intestinal and bronchial smooth muscles. This relaxation is induced by NO.
Nitrates induce arterial vasodilation which decreases peripheral resistances, but especially venodilation which decreases left ventricular diastolic volume and pressure. They also induce coronary vasodilation and inhibit coronary spasms. Vasodilation of cerebral vessels explains pulsatile headache and flushing of the face.
The efficacy of organic nitrates in angina pectoris and congestive heart failure is ascribed mainly to a decrease of cardiac work and oxygen requirements secondary to arterial and particularly venous dilation and possibly to coronary vasodilation.
Therapeutic uses
Efficacy of nitrates depends on formulations, routes of administration, indications and patient positions.
- In discontinuous administration by sublingual route or spray, glyceryl trinitrate has an obvious efficacy in the treatment of angina pectoris attacks. Its effect appears in one to three minutes and lasts ten to twenty minutes. The immediate relief from pain after intake of nitroglycerin is an argument in favour of the diagnosis of angina pectoris. This type of administration is also used for immediate prevention of an anginal attack, just before an effort known by the patient to be able to cause an attack.
- In continuous administration by digestive or transdermal routes, long-acting nitrates are used in treatment of stable angina and of congestive heart failure, indications where their efficacy is less obvious.
- Efficacy and side effects of nitrates are more marked when patients are upright than in lying positions because venodilation is more important.
- Intravenous administration is used in unstable angina, acute heart failure, myocardial infarction
Tolerance and withdrawal syndrome
Decrease of efficacy of organic nitrates when they are used in a continuous way has been recognized for a long time but there are individual differences: in certain patients tolerance does not seem to appear, whereas in others, it develops quickly.
Tolerance to organic nitrates is generally explained by depletion of tissue stores of molecules with a sulfhydryl group. A fall of nitrate concentration during a few hours, at least once every24 hours, would be necessary for the restoration of sulfhydryl stores. This point is in contradiction with the search for a stable steady state concentration. However explanations, other than that implicating sulfhydryl groups, have been proposed to explain this tolerance. It is possible that, according to patients, different mechanisms are involved in tolerance development.
In patients treated with organic nitrates, during nitrate-free intervals or at cessation of the treatmen, there could be an increased risk of anginal attacks. Dependance to organic nitrates was highlighted in workmen of ammunition factories (nitroglycerin and other nitrates like trinitrotoluene, TNT, are explosives): two to three days after discontinuing work (deprivation), some workmen presented angina pectoris attacks. This withdrawal syndrome in workmen suggests the possibility of similar effects in patients treated; one thus advises a progressive discontinuation of nitrates under monitoring.
Among nitrates, nicorandil occupies a special place. It is a derivative of nicotinic amide or PP vitamin which, in addition to its effect as a NO donor, is listed as an “opener” of potassium channels.
Adverse effects
Adverse effects of nitrates generally observed are dose dependant: headache, flushing of the face, aggravation of migraine, tachycardia, postural hypotension. Tolerance and withdrawal symptoms are difficult to assess.
Enhancers of NO effects, PDE-5 Inhibitors
A NO-mimetic effect can be obtained by direct stimulation of guanylate cyclase as obtained by NO itself, but also by inhibition of phosphodiesterases which inactivate cyclic GMP formed. The inhibition of this inactivation induces an increase of cGMP concentration and of its effects.
Phosphodiesterases of type 5, PDE5, are mainly present in cavernous bodies of the penis. Specific inhibitors of PDE5, PDE5 inhibitors, are sildenafil, vardenafil and tadalafil used in treatment of erectile dysfunction. Inhibition of PDE5 is reversible and disappears when the concentration of the drug or its active metabolite drops under its threshold level of activity.
Among these inhibitors, tadalafil inhibits more specifically PDE5 versus other PDE, in particular PDE6, than the two other inhibitors.
The mechanism of action of inhibitors of PDE5 is summarized below. Nitric oxide released by sexual stimulation induces formation of cyclic GMP which facilitates erection. Effects of cyclic GMP are limited by its hydrolysis by the PDE5 of cavernous bodies. Inhibition of PDE5 suppresses inactivation of cyclic GMP whose concentration increases inducing vasodilatation and erection. Duration of activity of the drug used depends on the duration of this inhibition.
The main difference between the three PDE5 inhibitors lies in the duration of their facilitator effect of erection after a single intake: that of tadalafil is the most sustained, more than 24 hours, in relationship with its long plasma half-life, 17 hours.
These 3 drugs are metabolized by cytochromes CYP3A4 and a certain number of interactions of pharmacokinetic type with other drugs are possible, see their respective notice. Intake of a PDE5 inhibitor which inhibits inactivation of cyclic GMP by a patient treated with a NO mimetic donor such as an organic nitrate which increases formation of cyclic GMP, is contraindicated because of the risk of severe hypotension. This is a pharmacodynamic potentiation.
Frequent adverse effects but without severe consequence of the PDE5 inhibitors are dyspepsia, headache, flushing, dizziness. When severe cardiovascular accidents occur in people having taken PDE5 inhibitors it is difficult to dissociate the direct responsibility of the drug of that of the other risk factors.
Sildenafil, and to a lesser degree vardefanil, can give transitory visual disturbances with alteration of the perception of colors, photophobia, blurred vision resulting probably of inhibition of retinal PDE6.
Sidenafil |
VIAGRA * |
Vardenafil |
LEVITRA * |
Tadalafil |
CIALIS * |
Note: phosphodiesterases
Phosphodiesterases, PDE, are enzymes which hydrolyze and inactivate cyclic AMP, and cyclic GMP. PDE are classified into 11 families called PDE1, PDE2… PDE11. PDE1, PDE2, PDE3, PDE4, PDE7 and PDE8 have as principal substrate cyclic AMP whereas PDE5, mainly present in cavernous bodies, act preferentially on cGMP. PDE6, present in retina, acts preferentially on cGMP. PDE10 and the PDE11 act on both cAMP and cGMP.
Note: dihydralazine
Hydralazine and dihydralazine relaxe small arteries, but their mechanism of action is not well understood. Some studies suggest that they could activate soluble guanylate cyclase directly and could increase the production of cGMP. Dihydralazine has been used as a hypotensive during many years. It also induces cardiac stimulation (tachycardia, increase in cardiac output), mainly elicited by a catecholamine release in reaction to vasodilation
|
