Drug Inter:~Ctionsirivolving Vasodiiators A.Nu Aar,.~I~G-Narcnoccp60rch 1 .>I R: 1 Blocking Drugs

Home , Cyclandelate, Inositol nicotinate

Drug inter:~ctionsirivolving vasodiiators a.nu aAr,.~i~g-narcnoccp60rCh 1 .>I r: 1 blocking drugs

Vnsodil:~rors(Fig. 9.1) n~idal~)l~i~-:~drcr~occptor blocki~ig drug (Fig. 9.2) arc used in tour ~ilni~iarcas of CII.J~OV~~SCIII~~~IIICI.;IIIC\II~CS- II~I)C~~CIIS~OII, alljji~l;~l)cctoris, 1)cril)Ircral vascr~lilrdisc;rsc a~itlcol~gcslive Ilci~rCTailurc - ;III~wc 1i:lvc clnssilictl 'll~c~ii011 this hisis ('rablc Y .I ). 'l'lic ;~~~tillyl)crtcrlsivcgroup iacludcs tl~oseused in tllc Iiia~iagcnlcntufco~igcstivc llcart failure. It is ~iot1)ossiblc to classify 111cscdrugs Inorc r;~lio~i:~lly;IS lllcy arc a disp:~rarcgro1111, particularly tl~cdrugs i~scdit1 pcriplieral vascrllnr tliscasc. 17urtllcrmorc, tlic classilici~tion is 1101 comprd~c~isiveas therc is t~~cr~!io~ior other uasodilators a~rtlall~ha-adrcooccptor blockiug dr~~gsin tile liter- atorc,. but as tllesc arc not currently in clirli~l11sc tl~cyllavc bcen excluded. Tri- 11ia7.osiliand bi11azi11a1.e still bci~~gcvaI\tatcd, as is bupico~~lide,wllicll was inilii~lly i~itroduced:IS a doj);~~iiinebctn-llydroxy1:rse i~lliibitorbut possibly exerts its rn:.iiu I~yl)otc~lsivccKcctby direct vnsodil:tlioll (Vcl;lsco ct al., 1975).Tol1l1esoxideis aliorlier ticw vasodilator (Collicr cl al., 1978) \vliicll niay prove lo bc olvaluc ill hypertcnsio~l and co~~gcstiveIlcilrL krilurc but ns yct tllcrc is litrlc itlfurmation or1 tl~isdrug.

'l'lle ~)atlcrooTclTccl observcd wit11 this group depends ill part on tllc G-rdiovasc\~lar status prior to usc. For exe~iil~lc,~~riizosi~i reduccs preload aad al'tcrluatl in coogcslit~c l~cartTnilurc, wlicrcas in Ilyl)cr.tc~lsiooils III~I~IIacriori is arteriolar dilatio~r.I>iazoxidc., fig. 9.1. Struclural formvlae of representalive direct vasodilators.

, ~~,[HCJ . . I. , . .

,PRAZOSIN HYDROCHLORIDE Fig. 9.2. Structural fortnulae of representative alpha-adrenoceptor blocking drugs.

hydralazine and tninoxidil reduce resistance vessel tone and this is \!::if main haemodytiamic eKect in hypertension. At a cellular level the exact meclianisni of action is not ktAwn. 11~dralazirlcr.2' act by clielatiag lracc elements necessary for snlooth muscle contraction (K1x5- Weser, 1976a). Diazoxide arid minoxidil relax vascular smootli muscle prclkf..' --by-conipcting wit11 calcium (Wol~lel al., 1967; Rhodes and Suttcr, 1971 1. Sllr.* prusside irillibits either calcii~mrelease or the eflecl of calciuln on contractile protfl:.* (Cliidsey and Gottlieb, 1974). As with vasodilators, alpha-adrenoceptor blcxL*:f drugs also act by interfering wit11 calcium movernetit, probably by prevelltillf '2: entry of calciuni into the cell (Lcvitzki, 1976). - Prazosin was initially considered to be a direct vasodilator without ret.'cr!.': blocking activity (Constantine et al., 1973), but is now known to be a selecti\c P'"'

I . .

.# .#

. . I TkcraF\~ti~classilication or vi~sodilatorsand alpha-i~cl~.cnocc~,torblocking drugs -. -- Vasodilators Alpl~a-adrenoceptorblocking drugs f _..--- I \ntihyperlcn~iveS Diazoxide I'hc~~~xybcn;?arnir~e I lydralazine' Phc~~tolan~ine Minoxidil Pmzosi~~' Nitroprussidc'

lsosorbide dinitrate An~ylnitritc

I pcripllcral vascl~lardisease Cinnarizine Cyclandelatc Inositol nicotinate Isoxsuprine ' Nicotinic acid Nicotinyl tartrate , Tolazolincb

'\1w l~scdor under investigation in the managcmetlt of congestive llcari failure. ' \lit> h~sweak alpha-adrcnoccptor blocking cn'cct.

. synaptic alpha-adrenoceptor blocking drug (Cambridge ct al., 1977a). It does not blsk tlic prcsynaptic alpha-adrenoceptor and thus docs not interfere with the fccdbnck inhibition of noradrenaline release from the ncrw. ending (Cambridge et al., 1977b). Conscqucntly, prazosin does not cailse high lcvcls of circulating noradren- rlinc, a possible explanation for its haeniotlynamic advantages over conventional non-sclcctiue alpha-adrenoceptor blocking agents. Indeed the latter are of little value as arrtil~ypcrtensiveagents other than in the management of phaeochromocytoma and cv:n for this purpose thcy may be supcrcedcd by prazosin (Wallace and Gill, 1978) and lnbclalol (Rosei et al., 1976). 1)iazoxidc (Sellers and Icoch-Weser, 1969), hydralazine (O'Malley et al., 1975), : nlinoxidil (klchta et al., 1975), and prazosin (Brogdcn ct al., 1977) have a long dllralion of action in contrast with nitroprusside which has a transient action. In the ', Qcc of hydralazinc, minoxidil and prazosin the hppotcnsi~leeffect is longer than ai)uld bc expected on the basis of tllcir plasma half-livcs which are typically short tC;ottlicb et al., 1972; Lesser et al., 1974; Nobbs et al., 1975). Hydralazinc (hloore- Jones and Perry, 1966) and minoxidil (Pluss et al., 1972) are concentrated in the mucular ~vallsof the.arteries and this would explain the relatively long hypotensive cifccl. On the other hand, the half-life of diazoxide is about three times as long as its h!potensivc effcct and this may be related to its high allinity for protein binding sites lscllers and Koch-Weser, 1969). The transient hypotensive effect of ~iitroprusside due lo its rapid conversion in the body to thiocyanate. The relative contribution of coronary dilatation and peripheral dilatation to the antianginal eflects of rlicse drugs is slill a contentious matter. llcccnlly, Collier et al. (1978) dcnionstratctl lhat the pcriphcral dilatation is predominantly venodilatory. Dilatation of capacitaucc vcsscls rcduces prcload and systolic \vi1I1 tcnsion, a major determinant of rnyoc;trdial osygcli tlcnland, which ~vouldexplain tlic bencfit of thcse drugs in angina pcctoris (Nickerson, 1975). The time coursc of activity varies \\.idcly witliin this group. Amy1 nitrite, which of course is taken by i~il~alation,is almost ilnmcdiatc in onset of action and has a brief cluration of action. Isosorbidc tlinitrate is an cxaniplc of a longcr actirig nitrate which, after oral administration, has an onsct of action in 20 min and a duration ofaction of' 6 h (Dahany et a!., 1977). It lias bccn posti~latedtliat tlie nitrite is the active form of this group of drugs (Nickersou, 1975). Isosorbidc dinitrate is probably unique among organic nitrates in that conversion to nitrite does not'occur.

The value of thcsc tlrugs in the management of chronic all~crosclcroticvascular disease is highly clucstionablc. whcrcas in vasospastic discasc thcrc is a more'reason- ablc basis for thcir use. This is a l~ctcroge~ieousgroup of compouncls with varying modes of action. Cyclandelate is a \\leak phosphodiesterase inhibitor (Nickcrson, 1975). Nicotinic acid and nicotinyl alcohol, whicli is converted to nicotinic acid, have a dilatory effect on the cutancorls vcsscls in thc blush area, but are probably of placebo valuc in peripheral vascular discase (Nickcrson, 1975).'I'olazoline is a ~riilddirect vasodilator but also has alpha-adrcnoccptor blocking effects, which may not be significant in the doses used clinically. Tllymoxanlinc is an alpha-adrenoceptor blocking drug. t

3. ADVERSE DRUG IKTEKACTIONS

3.1. Diazoxide

Diazoxidc is a thiazitlc (Fig. 9.3); however, it lias no diuretic action. and in fact causes fluid retention frequently ncccssitati:ig concurrent administration of a diuretic (Hutcheon and Bnrthnlmus, 1962; Johnson, 1971). Diazoxide may interact with the following groups of drugs.

Fig. 9.3. Structural forniiilae of diazoxidc and chlorothiazidc. 3.1.1. Ilirirefic.~ 110th tlii;~zitlediurelics (Shapiro ct al.. 1961 ) and diazoxide (Okun ct al., 1964) may c;?cll cailsc liyl>crglyc:icmia. i-lypcrosmol:~rnon-lietotic corna (Charles and Danforth, 1971) and acute diabclic keloacidpsis (IJlxlike anti I-ln~~ington,1969) hilve been rcportcd with the use of intravenous tli:~zosidc lol lie. 1to\vcvcr, both of tlicse paticnts were uracmic and thc dccrcascd pl:~smaprotein binding ill uraemia (O'Malley et al., 1974) nlay explain tllc severity of tlicsc reactions. Dollcry et al. (1962) dcscribctl t\vo cascs of hypcrglycncmia in patients taking diazosi:lc ant1 tliiazidcs. Subscquct~tly,0k11n et al. (1963) rcported fivc pn.ticnts who dcvclopcd I~ypcrglycacniirtand acitlosis while on both drugs. They also notctl a higher incidcncc of hypcrgiycnernia wllcn botlr tlri~gswcre used than had previously becn atrributctl to diazoside Rlonc (Il~~tcl~cor~and Uarthallniis, 1962). A fi~rthcrstudy suggcsts that the scvcrity of I~ypcrglycacn~iawith dia7.oxide and thiazitlc is greater than with diazoxicle alone (Okun ct al., 1964). Seltzer and Allcn (1969) showcd that a combination of diazoside and a tllii17.id~co~~sistently ind~~ces a reversible hypcr- glycrlcmia. Concurrent usc of li-i~scmidcor etllacry~iicacid may also potentiate the hypcrglycac~iiic.cKcctsof diazoxidc (Kocll-Weser, 1976b). Okun et al. (1962) noted that the l~y~~erglgcacn~ic,interaction of oral diazoxide and ~hiazides occurred cspccially but not csclasively in pnlicnls with*diabetic glucose tolerance tests. The . increased Iiyperglyc:~cmic cll'cct seen wllc~illliazidcs and cliazoxide arc combined may be dr~cto conlpelition for protcin bincling siks (Sellers and Koch-Wcscr, 1969). 171c concurrcnt usc of thiazides, frl~scniitlcor ethacrynic acid may also potentiate the hypcruricaemic cn'ccts of diaxoxidc (Koch-Wescr. 1976b). Tlicse drugs cause hypcruricacmia by inllibition of tub~~larexcretion of uric acid (Johnson, 1971). * Tliiazitlc diuretics, by rcducing p!asmn volume, may cause postural hypotension when cornbincd with diazoxide (Koch-Wescr, 1976b). This reaction is rare with diazoxide alone. Diazoxide dccreascs the binding of fruse~nideto human albumin in vitro (Prandota and Pri~itt,1975) bur clinically signilicant eKccts l~avcnot becn documctlted.

3.1.2. A~lticoagltlnnts Warfarin is displaced from plasma protcin binding sites in vitro by diazoxidc (Sellers and ICocli-Wescr, 1970). While thc rclcvant studics have not been carried out in the ,clinical setting, thc possibility ofa potentiated anticoagulant response should be kept in tnind (see also Cliaptcr 10). '. 3.1.3. A~~ticorzc~lsnrlts Diazoxide has been rcported to reduce scruln phenytoi~ilevels in cliildrcn (Roe et al., 1975). In the two cascs reported diazoxidc and phenytoin were used to treat hypo- glycacmia and col~viilsionsrespcctivcly. Therapeutic serum phenytoin lcvcls were not achievcd while on diazoxide despite adequate doses of phenytoin. After diazoxide was discontinued serum phenytoin lcvcls returned to thcrapeulic lcvels but fell to undetectable levels within 4 days of reintroduction of diazoxide in one case. De- creased plasma protcin binding of phcnytoin was observed and may lead to increased clearance of the drug. I-Iowever, an increase in volume of distribution would also account for this decrease in plasrna levels. Pruitt et al. (1973) liave shown conversely that phenytoin does not significantly affect the binding of diazoxide to human albumin. On the other hand, anticonvulsants have been slio~vnto shorten the half-life of diazoxide. This may reflect induction of niicrosomal metal,olisni of diazoxide (Priiitt ct nl., 1973).The precise interaction with anticonvulsants is not clear but doses of these coml~oundsniay liave to be rnodified to achieve therapeutic effect in some patients.

3.1.4. Anril!lperretrsioes Vasodilators when given alone rarely cai~seexcessive lowering of blood pressure. This is probably due, at least in part, to intact homeostatic mechanisms. I-Iov~ever, the prior adlninistration of synlpatholytic drugs, e.g. adrenergic ncurone blockers or beta-adrenoccptor blockers. may in susceptible individuals augnlent the hypotensive effect of a bolus of diazoxide such that dangerous liypdtension results. The hypotcnsive effects of conlbi~~ingdiazoxide and hydralazine are discussed under liydralazine (see below).

3.1.5. Chlorrncfl~iazole Diazoxide crosses the placenta (Boulus et al., 1971) and may arrest labour when used in liypertc~isivecrises of eclampsia (Koch-Weser, 1976b). It has been suggested that a conibination of chlonncthiazolc and diazoxide acts synergistically to produce \ severe respiratory depression in the newborn, when used in mothers with eclampsia (Johnson, 1976). I-Iowever, the evidence presented is weak.

3.2.1. Ilypnorics In rats barbiturates have been shown to antagonise the hypotensive effects of liydralazine. Motvever, the interaction appeared to depend on {lie fi~nctionalstate of the circulation, the sclicdi~leof adlninistration and'the kind of barbiturate used (Czyzewska-Sjafran and \I1utkicwicz, 1977). They have also suggested from further experiments in rats that the haemodynaniic sequelac of hydralazine may alter the kinetics and pharmacological effects of hypnotics. There have been no sirnilar clinically significant interactions documented in vivo. . C 3.2.2. Diazoxide Profound hypotension, complicated by myocardial infarcts, cerebrovascular acci- dentsand renal failure, has been documented l'ollowing a combination ofhydralazine and diazoxide. These drugs are often used together in hypertensive e~nergenciesand severe supine hypotension has occurred if one is given shortly after the other, irre- spective of which is given first (Tnnscy et al., 1973; Hknrick et at., 1977; Romberg et al., 1977). In two cases severe hypoiension occurred followirig a combination of diazoxide and a single oral dose of hydmlazine (Kumar et al., 1976; Henrick et al., 1977), the dose of liydralazine in one case being only 25 mg. 3.3.1. JI~y)oterision The "first dose" phenonicnon is nzell clocun~ented(Rosendorf, 1976; Wood et al., 7 1976; Stokes ct al., 1977a) and may he severe enougli to cause loss of consciousncss (Gabriel et al., 1975). 'I'his response \volrld seem to bc dose-related rather than idio- syncratic in vie\!! of thc Inore marked en'ects of higl~doses (Wood ct al., 1976). It has bccn slio\vn tl~atthis response lilay be exasgeratcd in patients on a lo\v sodium diet 1vt1o are in addition receiving beta-adrenoceptor I~lockingdrugs and a diuretic (Graham et al., 1976).I!a thcse patients inarked falls in blood pressurc may accompany initial dosesas low as 0.25 mg (Simpson ct al., 1977). Stokes et al. (1977b) have sho\vn that orthostatic symptoms are less likely during a sodium intake of 250 mEq daily than during an intake of 100 mEq daily. Bolli and Simpson (1975) noted postural hypotension in nine paticnts taking a beta-adrenoceptor blocking agent, who were given a mean dose of 12.4 trig of prazosin. 13rogtlcn et al. (1977) have sugycstcd that'thc dose of l~razosinshould be reducctl when a thiazide or other hnlihypertcnsive agent is added. Si~bsequently,the prazosin dosage may be readjusted as necessary. Ti would also seem wise to exercise caution wlicn using prazosin concurrently with diuretics or beta-adrenoceptor blocking agents or in a patient who may be salt-depleted.

3.3.2. Clorliriinc .- Stuciics in rats on the interaction wit11 the central alpha-adrenoceptor agonist clonidine suggest that the hypotensive effect of clonidine is antagonised by prazosin in a dose-related fashion and the authors suggest that the combination should be avoided in clinical practice (Van Zkvieten et al., 1978). This antagonism has not been confirmed in clinical studies (Stokes ct al., 1977a). Studies in pithed rats have demonstrated that the pressor effect of clonidine is antagonised by low doses of prazosin (Van Zwieten et al., 1978). It has been suggested that prazosin may be usefully employed i,n the hypertensive crises of clonidine ivit11- drawal (Oates et al., 1978). These aspects of prazosin have not been adequately studied in vivo to make further colnlnent (see Chapter 8).

Serious adverse interactions with vasodilators and alpha-adrenoceptor blocking agents are rare. Many of the putative adverse interactions may be anticipated from a knowledge of the pharmacokinetic and pharmacod!.namic properties of these agents. particularly with regard to protein binding and antihypertensive and hyperglycaemic elfect. However, several of the interactions predicted lrom animal and in vitro studies have not been confirmed in vivo and appear to be of no practical importance. REFERENCES

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