Nitrates pt.2 Flashcards
What is tolerance?
Marked attenuation in the magnitude of most of a drug’s pharmacological effects
Why does tolerance result with nitrates?
Two types:
- True vascular tolerance: may result from a reduced capacity of the vascular smooth muscle to convert nitroglycerin
to NO which can be due to cellular depletion of sulfhydryl groups, generation of free radicals (one is a reactive intermediate formed during the generation of NO from organic nitrates) that inactivate ALDH2, S-nitrosylation of soluble guanylyl cyclase (which desensitizes sGC and could explain cross-tolerance to different (nitro)vasodilators); enhanced response to vasoconstrictors such as angiotensin II, serotonin, and phenylephrine; or free radicals production that leads to endothelial dysfunction
- Pseudotolerance: Activation of mechanisms extraneous
to the vessel wall (common to different types of vasodilatory agents) including increase in sodium retention and volume expansion, neurohumoral activation which leads to increased sympathetic outflow and catecholamine release
What affects nitrate tolerance?
The magnitude of tolerance is a function of dosage and frequency of use.
What is the consequence of tolerance to nitrates? How can this be prevented? If the patient becomes resistant to nitrates, what are his symptoms called?
- Significant reduction in hemodynamic and anti-anginal activity
- The consequence of tolerance is that the risk of angina will increase during the intervals between doses (decreased angina threshold in the interval)
- Therapy should be designed to prevent tolerance. High doses should be avoided and therapy interrupted for 8–12 h daily, which allows the return of efficacy
- Resistance to nitrates classifies angina symptoms as “unstable”
Which drug is contraindicated with nitrates?
- PDE5 inhibitors (e.g. sildenafil, tadalafil) should not be prescribed to patients receiving any form of nitrate because they act synergistically to cause profound increases in cGMP and dramatic reductions in blood pressure (>25 mm Hg)
- A period of longer than 24 h may be needed following administration of a PDE5 inhibitor for safe use of nitrates, especially with tadalafil, due to its prolonged t1/2.
- Exposure to sympathomimetic agents (e.g., those in nasal decongestants and other sources) and serotonin receptor agonists used in the treatment of migraine (sumatriptan and similar) should be avoided
- The use of drugs that modify the perception of pain is a poor approach to the treatment of angina because the underlying myocardial ischemia is not relieved.
What are the therapeutic uses of organic nitrates?
- Stable angina pectoris (most important use)
- Variant (Prinzmetal) angina
- Congestive heart failure
- Unstable angina pectoris (ACS)
Side effects of organic nitrates
- Headache is common and can be severe, usually decreasing over a few days if treatment is continued and often controlled by decreasing the dose
- Transient episodes of dizziness, weakness, and other manifestations associated with postural hypotension may develop, particularly if the patient is standing immobile, and may progress occasionally to loss of consciousness, a reaction that appears to be accentuated by alcohol. It also may be seen with very low doses of nitrates in patients with autonomic dysfunction
- Even in severe nitrate syncope, positioning and other measures that facilitate venous return are the only therapeutic measures required
- All the organic nitrates occasionally can produce drug rash.
Ca+2 channel blockers vs nitrovasodilators for variant angina
- Whereas long-acting nitrates alone are occasionally efficacious in abolishing episodes of variant angina, additional therapy with Ca2+ channel blockers usually is required.
- Ca2+ channel blockers, but not nitrates, have been shown to influence mortality and the incidence
of MI favorably in variant angina; they should generally be included in
therapy.
Why can nitrovasodilators be used in congestive heart failure?
Relieve pulmonary congestion and increase cardiac output in congestive heart failure
What should be done alongside nitrovasodilators in stable angina
Should be used in stable angina pectoris as a part of a COMPREHENSIVE THERAPEUTIC PROGRAM with the primary goal being to prolong life which include LIFESTYLE CHANGES (such as quit smoking, lose weight and maintain a low-fat high-fiber diet), CORRECTION OF HYPERTENSION and HYPERLIPIDEMIA, PREVENTION OF THROMBOSIS
Forms that nitroglycerin comes in
Sublingual tablets,
sustained release capsules and tablets, sublingual powder, lingual spray, ointment, transdermal disc/pacth, IV, and aerosol
Onset of action of nitroglycerin and duration of effects
The onset of action is within 1–2 min (fastest with the spray), and the effects are undetectable by 1 h after administration
What onset forms do nitrates come in?
Short acting nitrates for standby therapy and long acting nitrates for the prophylaxis of angina
Absorption of nitroglycerin
Peak concentrations of GTN are found in plasma in less than 5 min of sublingual administration (even more rapid if delivered as a sublingual spray rather than as a sublingual tablet)
Half life of nitroglycerin
- 1–3 min
- Glyceryl dinitrate metabolites, which have about one-tenth the vasodilator potency, appear to have half lives
of about 40 min
