Antihypertensive renal vasodilator

Fenoldopam (76) is an antihypertensive renal vasodilator apparently operating through the dopamine system. It is conceptually similar to trepipam. Fenoldopam is superior to dopamine itself because of its oral activity and selectivity for dopamine D-1 receptors (D-2 receptors are as.sociated with emesis). It is synthesized by reduction of 3,4-dimethoxyphenylacetonitrile (70) to dimethoxyphenethylamine (71). Attack of diis last on 4-methoxystyrene oxide (72) leads to the product of attack on the epoxide on the less hindered side (73). Ring closure with strong acid leads to substituted benzazepine 74. O-Dealkylation is accomplished with boron tribromide and the catechol moiety is oxidized to the ortho-quinone 75. Treatment with 9NHC1 results in conjugate (1,6) chloride addition and the formation of fenoldopam (76) [20,21]. 

The required properties of such an agent Included (1) selectivity for peripheral vascular dopaminergic receptors versus < -and 6-adrenerglc receptors which could mediate pressor and cardiac effects, (2) absence of central dopaminergic and emetic effects, and (3) potent oral renal vasodilator effects. Dopamine has been associated with diuresis and natriuresls. Possible mechanisms include a direct tubular effect on sodium transport, indirect effects produced by changes in total or regional renal blood flow, or effects resulting from a dopamine Induced decrease in aldosterone release from the adrenal (9). Since diuretics play a key role in antihypertensive therapy, the addition of a natriuretic/diuretic component to the renal vasodilator profile would be valuable and appeared to be feasible. 

Most NSAIDs attenuate the antihypertensive effect of p-blockers (but not perhaps of atenolol), presumably due to inhibition of formation of renal vasodilator prostaglandins, leading to sodium retention. 

The antihypertensive effect of beta-blockers can be impaired by the concurrent administration of some nonsteroidal anti-inflammatory drugs (NSAIDs), possibly because of inhibition of the synthesis of renal vasodilator prostaglandins. This interaction is probably common to all beta-blockers, but may not occur with aU NSAIDs for example, sulindac appears to affect blood pressure less than indometacin (405-407). 

Hydralazine (Apresoline/ Others) [Antihypertensive/ Vasodilator] Uses Mod-severe HTN CHF (w/ Isordil) Action Peripheral vasodilator Dose Adults. Initial 10 mg PO qid, T to 25 mg qid 300 mg/d max Peds. 0.75-3 mg/kg/24 h POq6—12h -i in renal impair V CBC ANA before Caution [C, +] -1- Hqjatic Fxn CAD T tox w/ MAOI, indomethacin, BBs Contra Dissecting aortic aneurysm, mitral valveAheumatic heart Dz Disp Tabs, inj SE SLE-like synd w/ chronic high doses SVT following IM route, p ipheral neuropathy Interactions T Effects W/ antih5 pertensives, diazoxide, diuretics, MAOIs, nitrates. 

The hemodynamic effects of diazoxide are similar to those of hydralazine and minoxidil. It produces direct relaxation of arteriolar smooth muscle with little effect on capacitance beds. Since it does not impair cardiovascular reflexes, orthostasis is not a problem. Its administration is, however, associated with a reflex increase in cardiac output that partially counters its antihypertensive effects. Propranolol and other -blockers potentiate the vasodilating properties of the drug. Diazoxide has no direct action on the heart. Although renal blood flow and glomerular filtration may fall transiently, they generally return to predrug levels within an hour. 

Renal Decreased Na+ and HjO excretion, renal failure, decreased effectiveness of diuretics and antihypertensives PGE2- and PGb-induced vasodilation in juxtamedullary apparatus (increases renal blood flow, antagonizes renin, inhibits reabsorption of Na+ and HjO) cox-1 cox-2... 

Minoxidil is a very efficacious orally active vasodilator. The effect results from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. Increased potassium permeability stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine. 

Methyldopa [Aldomet) [Antihypertensive/Centrally Acting Antiadrenergic] Uses HTN Action Centrally acting antihypertensive Dose Adults. 250-500 mg PO bid-dd (max 2-3 g/d) or 250 mg-1 g IV q6-8h Peds. 10 mg/kg/24 h PO in 2-3 + doses (max 40 mg/kg/24 h - q6-l2h) or 5-10 mg/kg/dose IV q6-8h to total dose of 20—40 mg/kg/24 h i in renal insuff/elderly Caution [B (PO), C (IV), +] Contra Liver Dz MAOIs Disp Tabs, inj SE Discolors urine inidal transient sedadon/drowsiness frequent, edema, hemolydc anemia, hepadc disorders Interactions T Effects W/ anesthetics, diuredcs, levodopa, Li, methotrimeprazine, thioxanthenes, vasodilators, verapamil T effects OF haloperidol, Li, tolbutamide 1 effects W7amphetamines, Fe, phenothiazine, TCAs 1 effects OF ephedrine EMS Use diuredcs, verapamil, and sympathomimedcs w/ caudon may T risk hypotension, arrhythmias and pressors effects OD May cause profound hypotension, drowsiness, and impaired myocardial conduction activated charcoal may be effective... 

An antihypertensive substance is one which does not affect blood volume, blood viscosity, or the function of the heart it lowers blood pressure to normal levels in hypertensive states by generalized arteriolar dilatation, including those of the kidneys. Vasodilators (such as histamine), which lower arterial pressure at the expense of renal blood flow, are not antihypertensive. Furthermore, an ideal substance should affect the blood pressure in normal states to little or no extent. It can be predicted, however, that when true antihypertensive substances are found, they will not increase or maintain renal blood flow in the face of lowered arterial pressure when renal arterioles have lost the ability to dilate because of pathological changes (see Figure 3). 

Q5 Yes. Thiazide diuretic drugs are one of the treatments of choice for hypertension in elderly patients. Bendroflumethiazide, 2.5 mg daily, is commonly prescribed for hypertension in the United Kingdom. Although the thiazides have been in use for many years, their mechanism of action is not completely understood. They reduce renal reabsorption of sodium and water and so initially decrease blood volume they also dilate blood vessels and BP falls. However, blood volume may return to normal while the vasodilation and antihypertensive action remains. 

ADRENERGIC NEURONE BLOCKERS, ALPHA-BLOCKERS, CENTRALLY ACTING ANTIHYPERTENSIVES, VASODILATOR ANTIHYPERTENSIVES ASPIRIN 1 hypotensive effect not noted with low-dose aspirin Aspirin may cause sodium retention and vasoconstriction at possibly both renal and endothelial sites Monitor BP at least weekly until stable when high-dose aspirin is prescribed... 

Prostaglandin synthesis. Nonsteroidal anti-inflammatory drugs (NSAIDs), e.g. indomethacin, attenuate the antihypertensive effect of p-adrenoceptor blockers and of diuretics, perhaps by inhibiting the synthesis of vasodilator renal prostaglandins. This effect can also be important when a diuretic is used for severe left ventricular failure. 

Prostacyclin (epoprostenol) Inhibitor of platelet aggregation when blood contacts nonbiological systems, as in renal dialysis, as a pulmonary antihypertensive, and as a vasodilator... 

Prostaglandins as antihypertensives have so far not materialized as first hoped. PGs of the E and A series are potent vasodilators, as is PGI2 (see below). They decrease vascular resistance and systemic blood pressure. PGEs work directly on smooth muscle to produce this effect. PGA and PGA2 decrease pressure in essential hypertension to normal levels, increase cardiac output, and lower peripheral resistance. Renal circulation also improves. 

Terazosin produces vasodilation and reduces peripheral resistance but generally has little effect on cardiac output. Antihypertensive effect with chronic dosing is usually not accompanied by reflex tachycardia. There is little or no effect on renal blood flow or glomerular filtration rate. 

Hydralazine (apresoline) causes direct relaxation of arteriolar smooth muscle, possibly secondary to a fall in intracellular Ca concentrations. The drug does not dilate epicardial coronary arteries or relax venous smooth muscle. Hydralazine-induced vasodilation is associated with powerful stimulation of the sympathetic nervous system, likely due to baroreceptor-mediated reflexes, which results in increased heart rate and contractility, increased plasma renin activity, and fluid retention all of these effects counteract the antihypertensive effect of hydralazine. Although most of the sympathetic activity is due to a baroreceptor-mediated reflex, hydralazine may stimulate NE release from sympathetic nerve terminals and augment myocardial contractility directly. Most of hydralazine s effects are confined to the cardiovascular system the decrease in blood pressure after administration is associated with a selective decrease in vascular resistance in the coronary, cerebral, and renal circulations, with a smaller effect in skin and muscle. Because of preferential dilation of arterioles, postural hypotension is not common, and hydralazine lowers blood pressure equally in the supine and upright positions. 

---