Pharmacology for dentistry phần 40

Antihypertensive Agents opathy, peripheral vascular disorders, congestive heart failure, acute myocardial infarction, myocardial preservation during surgery, migraine, oesophageal spasm and exercise induced bronchial asthma AMLODIPINE Amlodipine is a long-acting calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle By inhibiting calcium ion influx it directly dilates vascular smooth muscle After oral administration of Samlodipine besylate, bioavailability is 6580% Approximately 93% drug is bound to plasma proteins It is extensively converted to inactive metabolites via hepatic metabolism It is excreted in urine as 10% parent drug and 60% of the metabolites Amlodipine is generally well tolerated The most commonly observed side effects are headache, edema, fatigue, flushing and dizziness Other side effects include nausea, abdominal pain, somnolence, palpitations, muscle cramps, frequency of micturition or nocturia, cough, breathlessness, epistaxis, impotence, nervousness and conjunctivitis It is indicated in the treatment of essential hypertension and angina pectoris DIRECT VASODILATORS HYDRALAZINE It acts directly on arteriolar smooth muscle to cause relaxation It decreases diastolic 183 pressure more than systolic blood pressure by lowering peripheral vascular resistance Due to preferential arteriolar dilatation, postural hypotension is uncommon It increases heart rate and cardiac output After oral administration its absorption is almost complete and rapid It is subject to significant first pass metabolism in liver Adverse effects include nausea, vomiting, tachycardia, dizziness, fatigue, weakness, palpitations, headache, paresthesia, tremor, constipation, anxiety, nasal congestion, lupus like syndrome and sleep disturbances It is indicated in hypertension (moderate or severe) and hypertension with renal involvement SODIUM NITROPRUSSIDE It has a brief duration of action It relaxes directly arteriolar and venous smooth muscle It decreases both preload and afterload thus both cardiac output and peripheral resistance are reduced It is given parenterally and onset of action occurs quickly (within minute) On stopping IV infusion, the effect dissipates rapidly It is converted to NO by endothelial cells and RBCs which relaxes vascular smooth muscle It is converted to thiocyanate in liver which is excreted slowly Adverse effects include nausea, vomiting, nervousness, palpitation, sweating, headache, disorientation, methaemoglobinaemia It is indicated in hypertensive crisis, congestive heart failure and acute mitral regurgitation This page intentionally left blank tterer p p a h CCh 4.3 1.4 Pharmacodynamics Antianginal Agents (Mode of Action of Drugs) Angina pectoris is a symptom of ischaemic heart disease It develops as a result of an imbalance between the oxygen supply and oxygen demand of the myocardium There is a paroxysmal chest pain which occurs when coronary blood flow is inadequate to supply required amount of oxygen to myocardium There is a characteristic radiating pain in distribution in left arm, chest, jaw and neck region This pain is mainly brought about by exertion/excitement when oxygen demand of heart increases and myocardial perfusion is decreased Decrease in myocardial perfusion is due to deposition of atherosclerotic plaques in blood vessels These plaques are due to accumulation of cholesterol and other lipid compounds which develop as patches on inner side of tunica intima of blood vessels i.e subintimal layer The drugs used in the treatment of angina pectoris are classified as in table 4.3.1 GLYCERYL TRINITRATE Glyceryl trinitrate (GTN) releases nitrite ion (NO2–) which is further metabolised to NO by enzymatic step involving reaction with tissue sulphydryl (–SH) groups in vascular smooth muscles NO released by GTN activates soluble, cytosolic form of guanylyl cyclase in vascular smooth muscles by interacting with haem group in the enzyme This converts GTP to cGMP cGMP dephosphorylates myosin light chain kinase and prevent myosin interaction with actin leading to relaxation Pharmacodynamics Action is almost exclusively on smooth muscle cells Effect on vascular smooth muscles: Both large arteries and veins relax in response to GTN But in small doses, marked venorelaxation is seen leading to reduced preload This causes decrease in stroke volume which is compensated with reflex tachycardia Arterioles relax less than venules because GTN evokes reflexes by baroreceptors which respond to decreased arterial pressure leading to reflex sympathetic discharge causing tachycardia and increased cardiac contractility 186 Section 4/ Drugs Acting on Cardiovascular & Urinary System Table 4.3.1: Classification of antianginal agents I Nitrates Glyceryl trinitrate (Nitroglycerine; ANGISED) 2.5-15 mg BD-TDS, 0.5 mg SL, 2.5-6.5 mg SR Amyl nitrate (VAPOROLE) 0.3 ml capsule inhalation Isosorbide dinitrate (SORBITRATE) 5-10 mg TDS-QID SL, 40-80 mg SR BD Isosorbide 5-mononitrate (MONOTRATE) 10-20 mg/day, 40 mg SR Erythrityl tetranitrate (CARDILATE) (30-60 mg/day oral, 5-10 mg SL) Pentaerythritol tetranitrate (PERITRATE) 30 mg/day II Beta blockers Propranolol, atenolol etc (For details see chapter on ‘Antihypertensive drugs’) III Calcium channel blockers Verapamil, nifedipine etc (For details see chapter on ‘Antihypertensive drugs’) IV Potassium channel openers Nicorandil, diazoxide etc (For details see chapter on ‘Antihypertensive drugs’) V Miscellaneous Dipyridamole (PERSANTIN) 25-100 mg TDS Nicotinyl xanthinate (COMPLAMINA) 300-600 mg TDS Effect on coronary blood of flow: Myocardial oxygen extraction is nearly maximum at rest, so, there is little reserve to meet increased demands So, increased myocardial demand for O2 can only be met by increased coronary blood flow which depends on diastolic pressure and duration of diastole because coronary blood flow is negligible during systole Pharmacokinetics They are administered through buccal, sublingual and parenteral routes Skin ointments are also available GTN is rapidly inactivated by hepatic first pass metabolism So, oral tablets which are swallowed are ineffective Excretion is primarily as glucuronide derivatives of the denitrated metabolite via kidney IV infusion has rapid onset of action but effects are quickly reversed on stopping the infusion So, it is used only in treatment of severe, recurrent angina at rest Adverse Effects Throbbing headache: It is due to arteriolar dilatation of meningeal arteries It usually decreases over a few days if treatment is continued and can be controlled by decreasing the dose Weakness and dizziness: It may arise due to postural hypotension especially if patient is standing in a single position for a while This is because, venodilatation results in ‘venous pooling’ i.e accumulation of blood in peripheral vessels leads to postural hypotension Flushing: It is due to arteriolar dilatation in face and neck region Sweating: Arteriolar dilatation in arteries beneath the skin tends to warm up and sweating is the body’s mechanism to dispel heat Tachycardia and palpitation: In small doses of GTN, arteriolar dilatation results in decreased arterial pressure This leads to reflex sympathetic dis- Antianginal Agents charge causing tachycardia and increased cardiac contractility So, palpitation are felt Methaemoglobinemia: Its a rare adverse effect Methaemoglobin has very low affinity for oxygen, so large doses of nitrites can result in pseudocyanosis (reduced O2 carrying capacity), tissue hypoxia and death Usually, even large doses of GTN and other organic nitrates not raise plasma levels of nitrite dangerously high Fainting: Venodilatation leads to increased capacity (venous pooling) leading to marked hypotension This can cause syncope/temporary loss of consciousness Indications Sublingual tablet: Angina pectoris Intravenous: Unstable angina, coronary vaso-spasm, left ventricular failure accompanying MI, hypertension and during cardiac surgery Ointment/transdermal patch: Prevention of angina pectoris ISOSORBIDE DINITRATE It can be given sublingually and orally for treatment of angina Mechanism of action is same as nitrates Adverse effects include throbbing headache, sweating, skin rash, palpitation, flushing, weakness and dizziness It is indicated in acute attacks (sublingually) and chronic prophylaxis (orally) of angina pectoris and coronary insufficiency In acute myocardial infarction, CHF and acute LVF 187 ISOSORBIDE-5-MONONITRATE It has a longer duration of action and mechanism of action is same as nitrates After oral administration hepatic first pass metabolism is less than isosorbide dinitrate, hence, systemic bioavailability is more It is indicated in pulmonary hypertension, prophylaxis of angina pectoris, post myocardial infarction therapy, CHF and acute LVF It is not recommended for acute attacks of angina ERYTHRITYL TETRANITRATE It is used for chronic prophylaxis of angina pectoris Tolerance may develop to pharmacological actions Adverse effects include flushing, headache, dizziness, methaemoglobinaemia and drug rash It is indicated in treatment and prophylaxis of exertional and vasospastic angina PENTAERYTHRITOL TETRANITRATE It is used for chronic prophylaxis of angina pectoris Tolerance may develop to pharmacological actions Beta blockers, calcium channel blockers and potassium channel openers detailed pharmacology is given in chapter ‘Antihypertensive drugs’ OTHER ANTIANGINAL DRUGS DIPYRIDAMOLE It is a coronary dilator and claimed to dilate coronary resistance vessels It probably ... inhalation Isosorbide dinitrate (SORBITRATE) 5-10 mg TDS-QID SL, 40- 80 mg SR BD Isosorbide 5-mononitrate (MONOTRATE) 10-20 mg/day, 40 mg SR Erythrityl tetranitrate (CARDILATE) (30-60 mg/day oral,... Beta blockers Propranolol, atenolol etc (For details see chapter on ‘Antihypertensive drugs’) III Calcium channel blockers Verapamil, nifedipine etc (For details see chapter on ‘Antihypertensive... myocardial infarction therapy, CHF and acute LVF It is not recommended for acute attacks of angina ERYTHRITYL TETRANITRATE It is used for chronic prophylaxis of angina pectoris Tolerance may develop