Regional and local vasodilators

Regional and local vasodilators.

Classification of drugs used in angina pectoris

I. Remedies that decrease the oxygen consumption and increase the oxygen delivery to the myocardium 

a)    Organic nitrates

-       nitroglycerin                            isosorbide dinitrat

-       sustac (mite, forte)                  isosorbide mononitrate

-       trinitrolong

-       nitrong

b)    Ca channel-blocking drugs

-       nifedipine                       diltiazem

-       verapamil                       mibefradil

c)    K channel activators

-       minoxidil                       pinacidil    

-       nicorandil                      diazoxid

d)    Various drugs

-       amiodarone  

II. Remedies that decrease the oxygen consumption:

a)    b-adrenoblockers                                  b) remedies that produce bradycardia

-       propranolol                                                   - alinidine

-       talinolol                                                       - falipamil

-       metoprolol

-       atenolol

III. Remedies that increase the oxygen delivery to the myocardium 

a)    myotropic coronarodilators

1.    phosphodiesterase inhibitors

-       aminophylline

-       xantinol nicotinates

-       carbocromen

2.    with adenosinic  mechanism

-       dipyridamol

-       lidoflazine

                3.NO donators

-       molsidomine

b)    Reflex coronarodilators

-       validol

Various esters of nitric acid (HNO3) and polyvalent alcohols relax vascular smooth muscle, e.g., nitroglycerin (glyceryltrinitrate) and isosorbide dinitrate.

The effect is more pronounced in venous than in arterial beds. These vasodilator effects produce hemodynamic consequences that can be put to therapeutic use. Due to a decrease in both venous return (preload) and arterial afterload, cardiac work is

decreased . As a result, the cardiac oxygen balance improves. Spasmodic

constriction of larger coronary vessels (coronary spasm) is prevented.

Nitroglycerin  (the active ingredient in dynamite) is the most important of the nitrates. It has duration of action from 10-20 min. (sublingual) and 8-10 hours (transdermal). Nitroglycerin is rapidly denitrated in the liver-first to the dinitrate, with retains a significant vasodilating effect, and more slowly to the mononitrate, with is much less active. Other nitrates are similar to nitroglycerine in their pharmacokinetics and pharmacodynamics. Isosorbide dinitrate is another commonly used nitrate: it is available in sublingual and oral forms. It is rapidly denitrated in the liver to isosorbide mononitrate with is also active. It is available as a separate drug for oral use. Several other nitrates are available for oral use and, like the oral nitroglycerin , have an intermediated duration of action (4-6 hours).

Mechanism of action: Denitration of the nitrates within smooth muscle cells release nitric oxide with stimulates guanylyl cyclase, causes an increase of the second messenger cGMP in smooth muscle. , probably by dephosphorylation of myosin. Also Nitroglycerin activates poteinkinase with contributes to the vasodilatation by Ca lost and. dephopsphorylation of myosin.

The reduction in vascular smooth muscle tone is presumably due to activation of guanylatecyclase and elevation of cyclic GMP levels. The causative agent is most likely nitric oxide (NO) generated from the organic nitrate. NO is a physiological messenger molecule that endothelial cells

release onto subjacent smooth muscle cells (“endothelium-derived relaxing factor,” EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The generation of NO within the smooth muscle cell depends on a supply of free sulfhydryl (-SH) groups; “nitrate-tolerance” has been attributed to a cellular exhaustion of SH-donors but this may be not the only reason.

Effects:  1.Nitroglycerin decreases afterload from arteriolar dilation

2. peripheral venodilation with results in reduced cardiac size and cardiac output through reduced preload

3. decreases pressure of ventricular wall in diastole

4. dilates the big coronary arterials

5. decreases peripheral vascular resistance. And blood pressure

6. ameliorates circulation in the ischemic areas

7.nitrates have no direct effects on myocardium, but a significant reflex tachycardia and increased force of contraction are predictable when nitroglycerin reduces the blood pressure.

8. other organs: nitrates relax the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract, but these effects are too small to be clinically useful.

Intravenous nitroglycerin (sometimes used in unstable angina) reduces platelet aggregation. There are no significant effects on other tissues.

Indications: all forms of angina pectoris ,myocardial infarction  to decrease the necroses area, hypertension in the small circulation. The standard form for treatment of acute anginal pain is the sublingual tablet, with has a duration of action of 4-6 hours. Oral normal-release nitroglycerin has a duration of action of –4-6 hours. Sustained-release oral forms have a longer duration of action.. other indication is the cardiac failure Transdermal formulations –24 hours.

Uses. Organic nitrates are used chiefly in angina pectori, less frequently in severe forms of chronic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachyphylactic). This “nitrate tolerance” can

be avoided if a daily “nitrate-free interval” is maintained, e.g., overnight.

At the start of therapy, unwanted reactions occur frequently in the form of a throbbing headache, probably caused by dilation of cephalic vessels. This effect also exhibits tolerance, even when daily “nitrate pauses” are kept. Excessive dosages give rise to hypotension, reflex tachycardia, and circulatory collapse.

Side effects: reflex  tachycardia, headache, vertigo, collapse, nausea, vomiting, met hemoglobinaemia, palpitations, severe effects: access of angina, ischemy, myocardial infarction .

Nitroglycerin (NTG) is distinguished by high membrane penetrability and very low stability. It is the drug of choice in the treatment of angina pectoris attacks. For this purpose, it is administered as a spray, or in sublingual or buccal tablets for transmucosal delivery. The onset of action is between 1 and 3 min. Due to a nearly complete presystemic elimination, it is poorly suited for oral administration. Transdermal delivery (nitroglycerin patch) also avoids presystemic elimination.

Isosorbide dinitrate (ISDN) penetrates well through membranes, is more stable than NTG, and is partly degraded into the weaker, but much longer acting, 5- isosorbide mononitrate (ISMN). ISDN can also be applied sublingually; however, it is mainly administered orally in order to achieve a prolonged effect. ISMN is not suitable for sublingual use because of its higher polarity and slower rate of absorption. Taken orally, it is absorbed and is not subject to first-pass elimination.

Molsidomine itself is inactive. After oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of "nitrate tolerance”.

Sodium nitroprusside contains a nitroso (-NO) group, but is not an ester. It dilates venous and arterial beds equally. It is administered by infusion to achieve controlled hypotension under continuous close monitoring. Cyanide ions liberated from nitroprusside can be inactivated with sodium thiosulfate (Na2S2O3)

Ca channel-blocking drugs:

Nifedipine: This drugs block –gated “L-type” calcium channels, the calcium channels most important in cardiac and smooth muscle. This drug reduces intracellular calcium concentration and muscle contractility.

Effects:   1. decreases the contractility

2.coronarodilation

3.decreases preload

4.decreases the myocardial needs in oxygen

5. increases subendocardial circulation

6.increases the collaterals circulation

7.decreases the automatism

8.dilates peripheral vessels

9.decrease afterlaod

10. decrease arterial pressure

11. reflex tachycardy

Other organs: Nifedipine relaxes the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract, reduces platelet aggregation., decreases insulin release

Drug interactions: with quinidine, procainamide, glycosides produces bradycardia.

Side effects: headache, vertigo, hypotension, edemas, bradycardia (verapamil) tachycardia (nifedipine), constipations, dyspeptic reactions, allergic reactions.

Various groups: amiodarone has antiarrhythmic action and it is effective in the coronary failure

 Mechanism of action it activates K channels and blocks ca channels.

Effects: decreases the myocardial needs of Oxygen,

Decreases the adrenergic influence,

Produces bradycardia, ameliorates coronary circulation, increases cardiac blood irrigation .

Side effects: bradycardia, atrioventricular block, retinopaphy, skin pigmentation, dysfunctions of thyroid gland, allergic reactions.

b-adrenoblockers:

These drugs block b-adrenoreceptors and decreases cardiac contractility. In this way, they decrease oxygen consumption. But these drugs don’t ameliorate coronary circulation.  

myotropic coronarodilators

phosphodiesterase inhibitors inhibit phosphodyesterase and increase the quantity of cAMP that inhibit Ca channels and finally produces vasodilatation.

Effects: coronarodilatation

Increase glucose utilization ,

Increase the quantity of intracellular K

Decrease the myocardial needs in oxygen

Side effects: tachycardia,  cardiac pains, vertigo, headache

 with adenosinic  mechanism

dipyridamol inhibits adenosindesaminase and increases the adenosine quantity. Adenosine has vasodilator effect.

Side effects: headache, dyspepsia, hypotension and Crash syndrome.( It dilates only healthy vessels but have no action on ischemic area.

Reflex coronarodilators

validol : Excites receptors from oral cavity and reflex ameliorates coronary circulation. If the pain persists after 2-3 minutes it is necessary changing the treatment. 

        The principles of treatment of myocardial infarction.

Myocardial infarction (MI or AMI for acute myocardial infarction), commonly known as a heart attack, occurs when the blood supply to part of the heart is interrupted. This is most commonly due to occlusion (blockage) of a coronary artery following the rupture of a vulnerable atherosclerotic plaque, which is an unstable collection of lipids (like cholesterol) and white blood cells (especially macrophages) in the wall of an artery. The resulting ischemia (restriction in blood supply) and oxygen shortage, if left untreated for a sufficient period, can cause damage and/or death (infarction) of heart muscle tissue (myocardium).

Classical symptoms of acute myocardial infarction include sudden chest pain (typically radiating to the left arm or left side of the neck), shortness of breath, nausea, vomiting, palpitations, sweating, and anxiety (often described as a sense of impending doom). Women may experience fewer typical symptoms than men, most commonly shortness of breath, weakness, a feeling of indigestion, and fatigue

Essentials

• If a person at risk of a myocardial infarction (MI) has an acute coronary syndrome lasting over 20 minutes, imminent MI must be suspected. Instead of chest pain, acute dyspnoea may be the primary symptom.
• An acute coronary syndrome without myocardial damage is often unstable angina, which calls for active treatment.
• The diagnosis should be made without delay since early therapy improves the prognosis decisively.
• Acute angioplasty (percutaneous transluminal coronary angioplasty [PTCA], percutaneous coronary intervention [PCI]) is the treatment of choice for reperfusion (Keeley, Boura, & Grines, 2003; Grines et al., 2003)  wherever it is available.
• Thrombolytic therapy is given as early as possible in all cases with a clinical picture of imminent MI and corresponding electrocardiogram (ECG) changes (See the Finnish Medical Society Duodecim guideline "Thrombolytic Therapy and Balloon Angioplasty in Acute ST Elevation Myocardial Infarction [STEMI]").
• If there are no contraindications, aspirin and a beta-blocker should be started for all patients and, for most patients, also an angiotensin-converting enzyme (ACE) inhibitor and a statin on the first days of treatment.
• Health care system should include a planned care pathway for coronary patients.

First line

Oxygen, aspirin, glyceryl trinitrate (nitroglycerin) and analgesia (usually morphine, although experts often argue this point), hence the popular mnemonic MONA, morphine, oxygen, nitro, aspirin) are administered as soon as possible. In many areas, first responders can be trained to administer these prior to arrival at the hospital. Morphine is classically the preferred pain relief drug due to its ability to dilate blood vessels, which aids in blood flow to the heart as well as its pain relief properties. However, morphine can also cause hypotension (usually in the setting of hypovolemia), and should be avoided in the case of right ventricular infarction. Moreover, the CRUSADE trial also demonstrated an increase in mortality with administering morphine in the setting of NSTEMI.

Of the first line agents, only aspirin has been proven to decrease mortality.

Once the diagnosis of myocardial infarction is confirmed, other pharmacologic agents are often given. These include beta blockers, anticoagulation (typically with heparin), and possibly additional antiplatelet agents such as clopidogrel. These agents are typically not started until the patient is evaluated by an emergency room physician or under the direction of a cardiologist. These agents can be used regardless of the reperfusion strategy that is to be employed. While these agents can decrease mortality in the setting of an acute myocardial infarction, they can lead to complications and potentially death if used in the wrong setting.

Drugs used in Miocardial infarction:

1.  Opioid drugs   (fentanyl, morphine, trimeperidine)

2. With anxiolitc purpose : tranqulisators (diazepam), neuroleptics.

Neurolepanalgesy  (fentanyl, droperidol or talamonal that contains fentanyl and droperidol)

3. Prevention of arrhythmias: antiarrhythmias (lidocaine)

4. For improvement of circulation

in the hypertonic state : hexamethonium, furasemide, triperium iodide)

in the hypotonic state : dopamine, norepinephrine, phenylehrine)

5. Prevention of thromboses: anticoagulators (heparin)

                                                antiagragants (fibrinolysine, aspirin) 

6. for acido-bases equilibrium: Na bicarbonate, Dextran 40, 70

7. for cardiac failure : cardiotonics (dopamine, glycosides)

8. for decrease the necroses area : nitroglycerine

9. for ameliorate the myocardial metabolism

a)    cardioprotectors: omopatrylate, trimethasidine

b)    antioxidants: coenzyme Q10

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Cerebral and peripheral vasodilators

Classification

A. Myotropic vasodilators:

1.     Alkaloids from Vinca minor: vincamine, vinpocetine, vincapan

2.     Xantines derivates: aminophylline, pentoxiphylline, xantinol nicotinate, coraldon

3.     Ca channel blockers.: nimodipine, cinnarizine

4.     antispastic drugs: papaverine, parasol, nicoverine, drotaverine

 B. Neurotropic vasodilators

             1.alkaloids from Ergot: ergotamine, dihydroergotamine, dihydroergotoxine

             2. a-adrenoblockers: nicergoline, tolasoline

             3. b-adrenomimetics: buphenine, isoxuprine

             4. antiserotoninics: cinnarizine, metysergide, lisurid

 C) Remedies that influence the metabolism

Nootrops, cerebrolisine, tanacan

1.Alkaloids from Vincaminor:

Effects: -the spasmolitic action and they dilate cerebral vessels, antiagregant effect, ameliorate the cerebral metabolism and circulation. Mechanism of action: It is proposed follow mechanism of action; These drug block Na channels. Indications: cerebral attack, chronic cerebral failure circulation., encephalopaphy, vestibular deregulations. Side effects: hypotension, tachycardia, allergy

2. Xantines derivates: pentoxiphylline: inhibits phosphodiesterase, increases cAMP, and produces vasodilation. Also it increases the quantity of adenosine, that produces vasodilatation. Indications: cerebral attack, chronic cerebral failure circulation., encephalopaphy, vestibular deregulations, peripheral deregylations of circulation.

3. Ca channel blockers: nimodipine blocks Ca channels in the brain., and decreases vessels tonus, ameliorates the cerebral circulation and increase the quantity of oxygen that are taken by the brain.  Indications: acute cerebral ischemia, subarahnoydal hemorrhages. Side effects: vertigo, hypotension, sedative effect.

4. Spasmolitics: papaverine inhibits phosphodiesterase and  increases the quantity of cAMP.  In this way it inhibits  Ca influx and produces vasodilatation.   

Indications: deregulation of cerebral and peripheral circulation, muscularly spasms

5. Derivates from Ergot inhibit a-adrenoreceptors., and inhibit reuptake of noradrenaline, but they posed also direct vasoconstrictors effect and can produce hypertention. Ergot alkaloids are obtained from Secale cornutum (ergot), the sclerotium of a fungus (Claviceps purpurea) parasitizing rye. Consumption of flour from contaminated grain was once the cause of epidemic poisonings (ergotism) characterized by gangrene of the extremities (St. Anthony’s fire) and CNS disturbances (hallucinations). Ergot alkaloids contain lysergic acid. They act on uterine and vascular muscle. Ergometrine particularly stimulates the uterus. It readily induces a tonic contraction of the myometrium (tetanus uteri). This jeopardizes placental blood flow and fetal O2 supply. The semisynthetic derivative methylergometrine is therefore used only after delivery for uterine contractions that are too weak.  Ergotamine, as well as the ergotoxine alkaloids (ergocristine, ergocryptine, ergocornine), have a predominantly vascular action. Depending on the initial caliber, constriction or dilation may be elicited. The mechanism of action is unclear; a mixed antagonism at "- adrenoceptors and agonism at 5-HT-receptors may be important. Ergotamine is used in the treatment of migraine . Its congener, dihydroergotamine, is furthermore employed in orthostatic complaints .

Other lysergic acid derivatives are the 5-HT antagonist methysergide, the dopamine agonists bromocriptine, pergolide, and cabergolide, and the hallucinogen lysergic acid diethylamide Indications: migraine, arterial hypotension.

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