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8) Centrally
Acting Sympathetic Inhibitors |
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Clonidine (Catapres®) |
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- Clonidine is an α2 agonist (centrally and
peripherally) that is used for the treatment of Hypertension. - It decreases blood pressure by; 1) Stimulate
presynaptic a2 receptors: - Decrease
Presynaptic Ca 2+ àdecrease
NE releaseà
decrease blood pressure. 2) Stimulate central α2
receptors: -Decrease
Sympathetic vasomotor centersà
decrease Sympathetic outflow àdecrease
NE release à
decrease renin releaseà
decrease blood pressure. 3) Stimulate I1
(Imidazoline) receptor: -
Sympatho-inhibitory action à
decrease blood pressure. - Adult dose; - Oral preparation
(Catapres®) → Must be given twice a day. - Initial
dose; 0.1 mg tablet twice daily (morning and bedtime). -
Maintenance dose; 0.2-0.6 mg per day given in divided doses. - Transdermal preparation
(Catapres-TTS®) given once every 7 days. - The most frequent adverse effects (dose-related) are: - Dry mouth,
drowsiness, dizziness, constipation and sedation. - Clonidine therapy should be gradually tapered off; - Clonidine
suppresses sympathetic outflow resulting in lower blood pressure, but sudden discontinuation
can cause rebound hypertension (life-threating hypertensive crisis) due to a rebound in
sympathetic outflow. (treated by α1 and ß blockers). |
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α-Methyldopa (Aldomet®) |
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- Methyldopa is an α2 agonist that has both central and
peripheral effects. Methyldopa has a dual mechanism of action 1) Methyldopa is converted into the false transmitter
(metabolite) called; alpha- methylnorepinephrine, in the CNS by dopamine
beta-hydroxylase (DBH) enzyme à
The false transmitter is central α2-agonistà
decrease sympathetic out flow à
decrease NE releaseà
decrease renin releaseà
decrease blood pressure. 2) It is a competitive inhibitor of dopa-decarboxylase enzyme
which converts L-dopa into dopamine. Dopamine is a precursor for norepinephrine and
subsequently epinephrine. - It is mainly used for management of hypertension in pregnancy (FDA
pregnancy category B). - Used with caution in lactating women (appears in breast milk). - Adult dose; - Initial dose; 250 mg
orally 2-3 times a day in the first 48 hours. - Maintenance dose; 500
mg to 2 g orally divided in 2 to 4 doses, up to a maximum of 3 g/day. - Hypertensive
emergency; 250 to 500 mg IV over 30 to 60 minutes every 6 hours up to a
maximum of 1 g every 6 hours or 4 g/day. |
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Selective Imidazoline Receptors Agonists |
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Rilmenidine (Hyperium®) |
Moxonidine (Cynt®) |
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- Used in mild to
moderate essential hypertension. - Moxonidine may
also promote sodium excretion, improve insulin resistance and glucose
tolerance & protect against hypertensive target
organ damage, such as kidney disease and cardiac hypertrophy. |
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9) Peripherally Acting Sympathetic
Inhibitors |
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Guanethidine (Ismelin®) |
|
- Guanethidine is an antihypertensive drug that reduces the release of
catecholamines, such as norepinephrine. - It acts by blocking the release of stored norepinephrine (NE)
(replacing NE in these vesicles) gradual depletion of NE stores
in the nerve endings gradual decrease in BP and HR. - It is used in the treatment of
moderate and severe hypertension and renal hypertension. - Side effects: Bradycardia, orthostatic
hypotension, failure of ejaculation and nasal congestion. |
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Reserpine (Hypoten®) |
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- Reserpine is a plant alkaloid from dried root of Rauwolfia
serpentina. - It acts by irreversibly blocks vesicular monoamine transporter (VMAT)
(block Mg2-/adenosine triphosphate-dependent
transport) of monoamine neurotransmitters (norepinephrine, dopamine, and serotonin) from storage
vesicles in the adrenergic nerve terminals in all body tissues. - It has a slow onset, a long duration of action. - After discontinuation The effects persist for many days. - It is used in the treatment of mild
hypertension. - Most common side effects: diarrhea,
hyperacidity, bradycardia and nasal congestion. |
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10) Ganglionic Blockers |
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Trimethaphan (Arfonad®) |
Mecamylamine
(Inversine®) |
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- Mono sulfonium (S+). - Don't pass BBB. - Ultra short duration of action (10 to 15 min.). - Not given orally (IV). - Treatment emergency hypertension. - Cause histamine release àFlushing.
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- Secondary
amine. - Pass BBB. - Longer
duration of action. - Given
orally. - Treatment
moderate hypertension. - Not cause
histamine release. |
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11) Vasodilators |
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- Vasodilators, are drugs or substances that cause vasodilation. - Classification of vasodilators drugs according to mechanism of
action; 1) Release of NO
from drug or endothelium; -
Sodium nitroprusside and Nitrates. 2) Reduction of
Ca2+ influx; -
Verapamil, Diltiazem and Nifedipine (and other dihydropyridines). 3)
Hyperpolarization of smooth muscle membrane through opening K+ channels; - Hydralazine, Minoxidil
and Diazoxide. 4) Activation of
dopamine receptors; -
Fenoldopam. - All the vasodilators that are useful in hypertension relax smooth
muscle of arterioles. - Sodium nitroprusside and the nitrates also relax veins. - Nitrates are used mainly in angina. |
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Hydralazine (Apresoline®) |
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- Hydralazine is a direct vasodilator, it dilates arterioles but not
veins. |
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Mechanism Of action |
- The
exact mechanism of action is not fully understood: - Hydralazine altering cellular
calcium metabolism, i.e. hydralazine causes smooth muscle hyperpolarization quite
likely through the opening of K- channels. It also may inhibit
IP3-induced release of calcium from the smooth muscle sarcoplasmic reticulum. - It also ↑
plasma renin concentrationà
sodium and water retention. |
|
Therapeutic uses |
- In Severe
essential hypertension when the drug cannot be given orally or when there is an urgent need to lower blood
pressure. - Commonly
used in combination with nitrates for the treatment of CHF in self- identified African American populations. - Oral
hydralazine is effective as monotherapy or as add-on therapy to methyldopa in the long term management of
chronic hypertension in pregnancy. - Adult dose;
- Oral dose. 10 mg orally 4 times a day
for the first 2 to 4 days. Increase to 25 mg orally 4 times a day for the balance of
the first week. For the second and subsequent weeks, increase dosage to 50
mg orally 4 times a day. - Hypertensive emergency, Usual dose: 20
to 40 mg IV or IM, repeated as necessary (patients with marked renal
damage may require a lower dose).
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Side effects |
- Most
common; Headache, nausea, anorexia, palpitation, sweating and flushing. - Up
to 20% of patients (how slowly acetylate the drug) who receive 400 mg/day or more mainly develop a systemic lupus
erythematosus syndrome. |
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Minoxidil (Loniten®) |
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- Minoxidil is a very efficacious orally active vasodilator. - Like hydralazine, minoxidil dilates arterioles but not veins. - Because of its greater potential antihypertensive effect, minoxidil
should replace hydralazine when maximal dose of the
hydralazine is not effective. - Minoxidil and hydralazine is almost always (should be) administered
in combination with a β- blockers (to balance the reflex
tachycardia) and a loop diuretics (to decrease sodium retention). - Uses; - Oral minoxidil; Treatment of severe hypertension. - Adult dose; 5 mg as a single daily dose, may be
increased to 10, 20 and then to 40 mg.
The effective dosage range is usually 10 to 40 mg per day. The maximum
recommended dosage is 100 mg/day. - Topical minoxidil
(Rogaine®); used in topical treatment (regrowth) of androgenic
alopecia in males and
females and stabilisation of hair loss in patients with
androgenic alopecia. - Vasodilator mechanism of action;
Minoxidil is a potassium channel opener, act by opening K+-
channels in smooth muscle membrane which closes voltage-
gated calcium channels and decreases intracellular calcium. - Most common side effects; Tachycardia,
angina and edema are observed when doses of B-
blockers and diuretics are inadequate.
- Headache, sweating and hypertrichosis. |
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Sodium Nitroprusside (Nipride®) |
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- Sodium Nitroprusside, is a powerful short acting parenterally
vasodilator that is used in treating hypertensive emergencies as
well as sever heart failure. - It is dilates both arterial and venous vessels. - Pharmacokinetics; - Chemically, is an
inorganic compound with the formula Na2[Fe(CN)5NO], It is rapidly metabolized by
uptake into red blood cells, with liberation of cyanide. Cyanide in turn is metabolized by the
mitochondrial enzyme in the presence of sulfur donor to the less toxic thiocyanate.
Thiocyanate is slowly eliminated by the kidney. - Duration of action; 1-10 minutes after infusion is stopped. - Dose; 0.5
mcg/kg/min, may be increased up to 10 mcg/kg/min. - Mechanism
of action; Sodium nitroprusside breaks down in circulation to release
nitric oxide (NO),
NO activates guanylate cyclase in vascular smooth muscle and increases
intracellular production of cGMP, the end result is vascular smooth
muscle relaxation. - Toxicity; The most serious toxicity is
related to accumulation of cyanide and may cause death. Administration
of sodium thiosulfate (sulfur donor) facilitates cyanide metabolism. Hydroxocobalamin
(vit. B12) combined with cyanide to form the non-toxic cyanocobalamin. |
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Diazoxide (Proglycem®) |
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- Diazoxide is a long acting arteriolar dilator that is used to treat hypertensive emergencies. - It is a potassium channel activator, which causes vascular smooth
muscle relaxation. - It is also inhibits the secretion of insulin from the pancreas, thus it
is used to counter hypoglycemia in disease states
such as insulinoma (a tumor producing insulin) or congenital hyperinsulinism. - FDA warning (2015) pulmonary hypertension has been reported in
infants and newborns treated with diazoxide. |
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Fenoldopam (Corlopam®) |
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- Fenoldopam is an agonist peripheral dopamine D1 receptors. - It is a racemic mixture and the R-isomer is the active component. - Routes of administration: for
continuous IV infusion onlyà
due to extensive first-pass metabolism and short half-life
elimination (10 minutes). - Period of administration: up to 48
hours in adults up to 4 hours in pediatric. - Mechanism of action: rapid-acting
vasodilator à
agonist of peripheral dopamine D1 receptors à
VD of renal blood vesselsà
diuresis. - Uses: treat severe hypertension in
hospitalized patients. - Dose: initial; 0.1 mcg/kg/min, the
dose is titrated upward every 15 or 20 min. to a maximum dose 1.6 mcg/kg/min. - Adverse effects: Headache, flushing,
dizziness, nausea and tachycardia (due to vasodilation). |
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12) Natural Antihypertensive Agents |
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- The following agents were identified: coenzyme Q10 (CoQ10),
ubiquinone, garlic, arginine, fish oil, hawthorn, olive oil, vitamin C,
vitamin E, skallcap, barberry, betel nut, bishop's weed, bitter melon, cat's claw, celery,
Eleutherococcus, gotu kola, guar gum, herbal diuretics, hibiscus, holly, jiaogulan, procaine,
lemongrass, mistletoe, morinda, Nigella sativa, oil of evening primrose, passion flower, periwinkle,
reishi mushroom, rhubarb, saffron, stevia, veratrum, white hellebore, willard water, withania, yellow
root, yohimbine, and yucca. - The degree of antihypertensive efficacy is rarely impressive when
compared with the blood Pressure reduction that can be
documented with the incorporation of lifestyle modifications (include DASH). |
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Hibiscus Tea (Hibiscus sabdariffa) |
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- Hibiscus tea is a herbal tea made as an infusion from crimson or deep
magenta-coloured calyces (sepals) of the roselle (Hibiscus
sabdariffa) flower (in Egypt called Karkade). - Studies has shown that drinking hibiscus tea may lower blood pressure in
people with type 2 diabetes, prehypertension or mild
hypertension. However, there is no reliable support recommending evidence hibiscus tea
in the treatment of primary hypertension. - Drinking 3 cups of hibiscus tea daily for 6 weeks reduced systolic blood
pressure by 7 mm Hg in prehypertensive and mildly
hypertensive. - Hibiscus flowers contain anthocyanins, which are believed to be the
active antihypertensive compounds, acting as ACE
inhibitors. - A study compared the effectiveness of hibiscus to the ACE-inhibiting
drug captopril (9.6 mg of total anthocyanins and captopril 50
mg/day); hibiscus worked as well as the drug captopril and not show significant differences relative
to hypotensive effect, antihypertensive effectiveness, and tolerability. - There is no difference between drinking hibiscus cold or hot. |
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Co-Enzyme Q10 |
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- Coenzyme Q-10 (CoQ-10) is a natural antioxidant (is a vitamin-like
substance) synthesized by the body, found in many foods &
available as a supplement, found in small amounts in meats & seafood. - COQ10 may play a role in treating heart and blood vessel conditions such
as CHF, angina and hypertension. - COQ10 may play a role in reducing the number and severity of migraine
headaches, and improving sperm motility in men. - There is no official daily value recommendation, but suggests at least
90 to 120 mg/day of supplemental COQ10 for any adult
with a family history of heart problems, or who is at increased risk for cardiovascular disease. - Researchers concluded that COQ10 has the potential to lower systolic
blood pressure by up to 17 mm Hg and diastolic blood
pressure by 10 mm Hg, without significant side effects. - Statins (class of lipid lowering drugs) are well-tolerated by most
people, they do have side effects, including muscle and joint aches
and a rare condition that causes muscle cells to break down. Some researchers have proposed that
taking a CoQ10 might reduce the risk of these side effects. - Some research has indicated therapeutic value in high doses to slow the
progression of Parkinson's disease. |
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ü Hypertensive Crises :- |
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- Hypertensive crisis; patients with blood pressures (BP) ≥
180/110 mm Hg. - This condition has been classified as hypertensive emergencies and
hypertensive urgencies: - Hypertensive
urgency; -
Elevations in BP (≥ 180/110 mm Hg) without progressive target-organ damage.
- May or
may not experience one or more of these symptoms: severe headache,
shortness of breath, nosebleeds and severe anxiety. - Hypertensive
emergency, -
Severe elevations in BP (≥ 180/110 mm Hg) with the presence of
acute or ongoing target
organ damage. - Acute
target-organ damage can include; hypertensive
encephalopathy, intracranial hemorrhage, acute
myocardial infarction, acute heart failure, pulmonary edema (shortness of
breath), aortic dissection, retinopathy or papilledema, decreased urine output or acute
renal failure and eclampsia. |
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Goals and treatment
options;
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Hypertensive Urgency |
Hypertensive
Emergency |
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- Managed by using oral
antihypertensive agents. - Treatment is
initiated with very low doses of
oral agents using incremental doses as needed
and avoiding large starting doses that may result
in excessive blood pressure reduction. - The initial goal is to reduce
blood pressure to
160/110 mm Hg over several hours to 2 days. - Mean arterial pressure (MAP)
should reduced
by no more than 25% within the first 24 hours. - All patients with hypertensive
urgency should
be reevaluated within 7 days. - Specific agents; - Captopril; 25 mg oral initially, followed
by 50- 100 mg time
90-120 minutes later, until the
target BP is achieved. - Nicardipine; 30 mg oral initially, repeated
every 8 hours until
the target is achieved. - Labetalol; 200 mg orally, repeated every
3-4 hours until the
target is achieved - Clonidine; 0.1-0.2 mg orally, followed by
0.05- 0.1 mg every 1
hour until target is achieved (max
dose of 0.7mg) - Nifedipine; 10-20 mg repeated every 6 to 8
hours until
target is achieved. |
- Managed by using IV
antihypertensive agents. - Patients are usually admitted
for intensive care unit (ICU) care and close follow-up. - Reducing the mean arterial
pressure (MAP) by no more than 25% or diastolic BP to
100-110 mm Hg within 30-60 minutes. - Specific agents (Agents are
chosen on the basis of
patient characteristics); - Sodium
Nitroprusside;
0.25-10 mcg/kg/min., maximum
3 mcg/kg/min. - Fenoldopam; 0.1 mcg/kg/min., maximum 1.6
mcg/kg/min. - Nitroglycerin; 5-10 mcg/min., maximum 100 - Enalaprilat; 0.625-125 mg every 4-6 hours, maximum 5 mg
every 6 hours, - Hydralazine; 5-10 mg every 4-6 hours. - Nicardipine; 5-15 mg/hour, max. 15 mg/hour. - Esmolol; 250-400-mcg/kg IV Bolus, then a 50- 100-mcg/kg/min.
infusion, maximum 300
mcg/kg/minute. - Labetalol; 20-80 mg IV Bolus every 15 minutes or 0.5-2
mg/min., max 300 mg/24 h. - Phentolamine; 5-15 mg IV bolus. |
Ø Preferred agents in
treatment of specific types of hypertensive emergencies;
|
Types of emergency |
Preferred agents |
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Cerebrovascular
accident (CVA) |
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Nitroglycerin or {Nitroprusside ±ACE inhibitor} |
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Methyldopa, Magnesium sulfate (do
not use with CCBS), Hydralazine |
Ø Special Populations:-
|
Preferred Agents |
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Thiazide, CCB |
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- Pregnancy |
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- Asthma and COPD |
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- Depression |
Centrally acting inhibitors, β-blockers, Reserpine |
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- Diabetes Mellitus |
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- Heart Failure
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- Hyperlipidemia |
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- Migraine |
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- Osteoporosis |
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β-blockers |
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