Treatment of hypertension part 2

 

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2) β-Adrenoceptor Blocking Agents
- All β-blockers are useful for lowering blood pressure in mild to moderate hypertension. In severe   hypertension, β-blockers are especially useful in preventing the reflex tachycardia that often results      from treatment with direct vasodilators. - β-blockers have been shown to reduce mortality after a myocardial infarction and some also reduce mortality in patients with heart failure. - Mechanism of action;           - They are block B-adrenoceptor in the heartà decrease cardiac outputà decrease BP.           - Propranolol inhibits renin release, and some of β-blockers may decrease peripheral vascular             resistance. - β-blockers precautions;      - The B-blockers must be tapered off gradually; Long-term treatment with a β-blocker à up-        regulation of the β-receptors. Sudden stop of B-blocker therapyàincreased receptors sensitivity        and can worsen angina or hypertension.      - Non-selective β-blockers used with caution in insulin-dependent diabetic patients (Mask        hypoglycemia symptoms).      - Non-selective β-blockers, are contraindicated in patients with COPD or asthma.      - β-blocker not used with non-dihydropyridines Ca2 channel blockers (Verapamil and Diltiazem) to        avoid heart block.      - Carvedilol > Metoprolol > Bisoprolol are only β-blockers may be used in CHF.
Propranolol (Inderal®)		Nadolol (Corgard®)
- Propranolol and Nadolol  are a non-selective β-blocker drugs, nadolol is more potent than    propranolol. Nadolol has a very long duration of action with low lipid solubility than propranolol. - Doses; - Propranolol: (orally) initial; 80 mg/day. Maintenance; 120-240 mg/day (increase if needed).                     -Nadolol: (orally) initial dose; 40 mg/day. Maintenance dose; 40-80 mg/day (increase if needed). dose:
Metoprolol (Lopressor®)	Atenolol (Tenormin®)		Esmolol (Brevibloc®)
Bisoprolol (Concor®)		Nebivolol (Nebilet®)
- Metoprolol, Atenolol, Esmolol , Bisoprolol and Nebivolol are selective β1-blockers (cardioselective). - Cardioselective drugs may be advantageous in treating hypertensive patients who also suffer from   asthma, diabetes, or peripheral vascular disease. - Carvedilol, Metoprolol and Bisoprolol are only β-blockers may be used in congestive heart failure. - Nebivolol induce releases of nitric oxide (endothelium-derived relaxing factor; EDRF) from   endothelial cells and causes vasodilation. - Esmolol is an ultra-short-acting, half-life (about 10 minutes). It is only available intravenously and it   is used during surgery or diagnostic procedures, some times for emergency care. - Doses; - Metoprolol: (orally) initial dose; 100 mg/day. Maintenance dose; 100-450 mg/day.                - Atenolol: (orally) 50 mg once daily, may be increased to 100 mg once daily.                - Esmolol: (IV) initial; 500 mcg/kg/min over 1 min, Maintenance; 50 mcg/kg/min for 4 min.                - Bisoprolol: (orally) initial dose; 5 mg once daily. Maintenance; 5 to 20 mg once daily.                - Nebivolol: (orally) initial dose; 5 mg once daily. Maintenance> 40 mg once daily.
Acebutolol (Sectral®)	Pindolol (Visken®)		Celiprolol (Selectol®)
Oxprenolol (Trasicor®)		Penbutolol (Levatol®)
- Acebutolol, Pindolol, Celiprolol ,Oxprenolol and Penbutolol  are partial agonists, i.e. β-blocker with     some intrinsic sympathomimetic activity (ISA), They lower blood pressure decreasing vascular   resistance and depress cardiac output or heart rate less than other β-blockers, this may be   particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease. - Doses; - Acebutolol: (orally) initial: 400 mg once or 200 mg twice. Maintenance: 400 - 800 mg/day.                 - Pindolol: (orally) initial dose: 5 mg twice daily. Maintenance dose: 10 to 60 mg/day.                 - Celiprolol: (orally) initial dose: 200 mg once daily. Maintenance dose: 400 mg/day.                 - Oxprenolol: (orally) 80-160 mg a day, 2 to 3 doses. The maximum daily dose is 320mg                 - Penbutolol: (orally) initial: 20 mg once daily. Maintenance dose: 20 to 40 mg once daily.
Labetalol (Trandate®)		Carvedilol (Dilatrend®)
- Labetalol and Carvedilol are a non-selective β-adrenergic blocker and selective α1-adrenergic   blocker. - Labetalol used in treatment of chronic or acute hypertension of pheochromocytoma and   hypertensive crisis. - Carvedilol reduces mortality in patients with heart failure (protective effect) and is therefore particularly useful in patients with both heart failure and hypertension. Doses; - Labetalol: (orally) initial: 100 mg twice daily. Maintenance: 200 to 400 mg twice daily.                (IV) 20-80 mg to treat hypertensive crisis.              - Carvedilol: (orally) initial: 6.25 mg twice daily with food. Maintenance: 6.25-25 mg twice

 

3) Angiotensin-Converting Enzyme Inhibitors (ACEIS)
Captopril (Capoten®)	Lisinopril (Zestril®)	Enalapril (Renitec®)
Fosinopril (Monopril®)	Perindopril (Coversyl®)	Ramipril (Tritace®)
Benazepril (Cibacen®)	Cilazapril (Zapritens®)	Imidapril (Tanatril®)
Zofenopril (Zofecard®)	Quinapril (Accupril®)	Trandolapril (Mavik®)
- The hypotensive activity of ACE inhibitors, due to;                   - Blocks the conversion of angiotensin I to angiotensin II.                   - Inhibits the degradation of bradykinin (vasodilator peptide, cause VD via NO release). - Cardiac output and heart rate are not significantly changed. - ACE inhibitors used alone or in combination. - ACE inhibitors are first-line drugs for hypertensive patients with diabetes, chronic kidney disease.   and patients at increased risk of coronary artery disease.   - ACEIS precautions;            - Hypotension may occur after initial dose.             - Avoid K+ supplements, diet rich in K+ and other drugs that increases K+ level in the blood e.g.               ARBS, Aliskiren and K+ sparing diuretics; may cause life-threatening hyperkalemia.             - ACEIS may develop dry persistence cough and angioedema; due to increase levels of               bradykinin and substance P, this effect resolves within a few days of discontinuation. Can be               treated by (two studies suggested);                           - Non-steroidal anti-inflammatory drugs; NSAIDS (e.g. aspirin 500 mg/day).                           - Iron supplements (e.g. ferrous sulfate) an inhibitor of NO synthase.             - ACEIS are contraindicated with pregnaney; increase risk of fetal malformation.

 

4) Angiotensin II Receptor Blockers (ARBS)
Losartan (Cozaar®)	Valsartan (Diovan®)	Candesartan (Atacand®)
Irbesartan (Aprovel®)	Eprosartan (Teveten®)	Telmisartan (Micardis®)
Olmesartan (Erastapex®)	Fimasartan (Kanarb®)	Azilsartan (Edarbi®)
- ARBS used alone or in combination. ARBS have a similar benefits to those of ACE inhibitors in   patients with hypertension, heart failure and chronic kidney disease. - ARBS have a similar precautions to ACE inhibitors, but less in cough and angioedema. - ARBS more selective blockers of angiotensin effect than ACE inhibitors.

 

5) Direct Renin Inhibitors

Aliskiren (Tekturna®)

- Aliskiren is the first and only drug available in a class of drugs called direct renin inhibitors (FDA   approval in 2007). - It is act by binding to active site of renin decreasing plasma renin activityà inhibiting conversion of   angiotensinogen to angiotensin I. - It is used in treatment of hypertension (alone or in combination with other antihypertensive agents). - It has long duration of action, used once daily. - Adverse effects: Diarrhea, GI symptoms and Rash.                                - Symptoms of hypotension e.g. headache and dizziness (after initiation treatment).                                - Angioedema and cough; but less common, than ACE inhibitors or ARBs.                                - May cause hyperkalemia. - Contraindication: Pregnancy; it can cause injury and death to the developing. - Drug interactions: with                - ARBS or ACEIS increase risk of renal impairment, hyperkalemia, and hypotension.                - K+ sparing diuretics or K+ supplements à increase hyperkalemia.                - NSAIDSà May reduce the hypotensive effects.                - LMEIS e.g. Erythromycinà decrease  metabolism of Aliskirenà ↑ it is effect.

 

6) α-Adrenoceptor Blocking Agents
Prazosin (Minipress®)	Doxazosin (Cardura®)		Terazosin (Hytrin®)
- Prazosin, Doxazosin and Terazosin are selective competitive α1 receptors blockers. - Acts by blocking postsynaptic α1-adrenoceptors on vascular smooth muscleà vasodilatation à   decrease total peripheral resistance decrease blood pressure. - The drugs are more effective when used in combination with other agents, such as a β-blockers and   a diuretic, than when used alone. - These drugs are used primarily in men with concurrent hypertension and benign prostatic   hyperplasia (BPH). - Doses; - Prazosin: (orally) initial: 1 mg 2-3 times daily. Maintenance: 6-15 mg/d in divided doses.                - Doxazosin: (orally) initial: 1 mg once daily. Maintenance: 1-16 mg once daily.                - Terazosin: (orally) initial: 1 mg once daily at bedtime. Maintenance: 1 to 5 mg once daily. - Most common side effects is first-dose orthostatic hypotension (initial syncope attack or first- dose                           phenomenon) this include headache, dizziness and palpitations à to overcome; the                           first dose must be minimized and giving at bed time.
Phenoxybenzamine (Dibenzyline®)		Phentolamine (Rogitine®)
Tolazoline (Priscoline®)
- Phenoxybenzamine, Phentolamine and Tolazoline are non-selective α-adrenoceptor blockers. - The drugs are useful in diagnosis and treatment of pheochromocytoma.

 

 

 

 

7) Calcium Channel Blockers (CCBS)
- They are at least five different types of calcium channels in Homo sapiens: L-, N-, P/Q-, R- and T-type,      with a number of classes of blockers, but almost all of them preferentially or exclusively block the L-   type voltage-gated calcium channel. - L-type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal     tissue (sinoatrial; SA and atrioventricular; AV nodes).  - These channels are responsible for regulating the influx of calcium into muscle cells, which in turn   stimulates smooth muscle contraction and cardiac myocyte contraction. - Therefore, blocking L-type calcium channels in the heart and in smooth muscle of the coronary and   peripheral arteriolar vasculature. This cause vasodilation, -ve inotropic, -ve chronotropic and -ve   dromotropic. N.B; CCBS do not dilate veins. - There are three classes of CCBS;         1) Dihydropyridines; mostly; selective for vascular smooth muscle.         2) Phenylalkylamines; mostly; selective for cardiac muscle.         3) Benzothiazepines; intermediate between phenylalkylamines and dihydropyridines. - CCBS are useful in the treatment of hypertensive patients who also have asthma, diabetes, and/or   peripheral vascular disease. - All CCBS are useful in the treatment of angina. In addition, non-dihydropyridines CCBS are used in   treatment of atrial fibrillation. -          Adverse effects: ·         First-degree atrioventricular block and constipation are common dose- dependent side effects of Verapamil.  ·         Verapamil and Diltiazem should be avoided in patients with heart failure or with atrioventricular block due to their -ve inotropic and -ve dromotropic effects.  ·         Dizziness, headache, and a feeling of fatigue caused by a decrease in blood pressure are more frequent with dihydropyridines.  ·         Peripheral edema is commonly reported with dihydropyridines.  ·         Nifedipine & other dihydropyridines may cause gingival hyperplasia.    - Generally; CCBS are commonly used during pregnancy and lactation to treat hypertension,   arrhythmia, and preeclampsia. - They have also been used as tocolytic agents to prevent premature labour and its complications. - CCBS is only recommended for use during pregnancy when benefit outweighs risk.
Dihydropyridines
Nifedipine (Adalat®)	Amlodipine (Norvasc®)	Felodipine (Plendil®)
Isradipine (DynaCirc®)	Lacidipine (Lacipil®)	Nicardipine (Cardene®)
Lercanidipine (Care dipine®)	Nitrendipine (Cardif®)	Nimodipine (Nimotop®)
- Nifedipine (is the prototype), Amlodipine , Felodipine, Isradipine, Lacidipine, Nicardipine, Lercanidipine, Nitrendipine and Nimodipine. This CCB class is easily identified by the suffix "-dipine". - All dihydropyridines have a much greater affinity for vascular calcium channels than for calcium channels in the heart; Show little interaction with other cardiovascular drugs, such as Digoxin. - Pharmacokinetics;     Most of these agents have short half-lives (3 to 8 hours) following an oral dose.     Sustained-release (SR) preparations are available and permit once-daily dosing.     Amlodipine has a very long half-life and does not require a sustained-release formulation.     Indication and dosage; Drug Indication Dosage Nifedipine Angina, Hypertension, Raynaud's phenomenon IV; 3-10 mcg/kg. Orally (not SR) 20-40 mg 3 times/d. Amlodipine Angina, Hypertension 5-10 mg orally once daily Felodipine Hypertension 5-10 mg orally once daily Isradipine Hypertension 2.5-10 orally twice daily Lacidipine Hypertension 2-6 mg orally once daily Nitrendipine Hypertension 20 mg orally once or twice daily Lercanidipine Angina, Hypertension 20-30 mg once daily at least 15 min before meals Nicardipine Angina, Hypertension, Cerebral vasospasm 20-40 mg orally 3 times daily Nimodipine Cerebral vasospasm, Subarachnoid Hemorrhage 60mg orally every 4 hours   - Nifedipine may be used for migraine prophylaxis or for premature labor. - Felodipine interact with grapefruit juice (grapefruit contains compounds known    furanocoumarins that block the CYP3A4 enzymes).   - Nimodipine and Nicardipine can pass BBB and is used to prevent cerebral vasospasm. - Clevidipine (Cleviprex®) is a newer agent that is formulated for IV use only.
Phenylalkylamines
Verapamil (Isoptin®)
- Verapamil a calcium channel blocker that is a class IV anti-arrhythmia agent. - It is the only member of this class that is available and the least selective of any CCBS. - It has significant effects on both cardiac and vascular smooth muscle. - It is the least effective of any CCBS on vascular smooth muscle. - It is used to treat hypertension, angina and supraventricular tachyarrhythmias and to prevent   migraine and cluster headaches. - Adult dose; Orally (Not SR) 80-160 mg orally 3 times daily. IV 75-150mcg/kg as bolus over at > 2 min. - Recent animal studies;           - Verapamil also inhibits thioredoxin-interacting protein, the protein that leads to the death of             pancreatic beta cells that produce insulin, and thus causes diabetes.           - Data accumulated indicates a verapamil-induced inhibition of the ability of resistant cells to             actively extrude chemotherapeutic agents.
Benzothiazepines
Diltiazem (Altiazem®)
- Diltiazem affects both cardiac and vascular smooth muscle, but it has a less pronounced   -ve inotropic effect on the heart compared to that of verapamil. - It is used in the treatment of hypertension, angina, and supraventricular tachyarrhythmias. - Topical diltiazem as a 2% cream or ointment effective in treatment chronic anal fissure, it cause   muscle relaxation and improve blood flow to facilitate healing. - Adult dose; Orally (Not SR) 30-80 mg orally 4 times daily. IV 75-150mcg/kg as bolus over at> 2 min.