Guanethidine and related drugs + Phenothiazines

Large doses of chlorpromazine may reduce or even abolish the antihypertensive effects of
gunethidine althoughin some patients the inherent hypotensive effects of the chlop[romazine
may possibly predominate.
Clinical evidence
Two severely hypertensive patients ,well controlled on 80 mg gunethidine daily, were
additionally given 200-300 mg chlorpromazine. The diastolic blood pressure of one rose over
10 days from 94 to 112 nnHg and continued to climb to 116 mmHg even when the
chlorpromazine was withdrawn. The diastolic pressure of the other rose from 105 to 127
mmHg, and then on to 150 mmHg even after the chlorpromazine had been withdrawn, other
reports similarly deecribe marked rises in blood pressure in patients on gunethidine when
given chlorpromazine (100-400 mg daily).
Mechanism
Chlorpromazine prevents the entry of guanethidine into the adrenergic neurons of the
sympathetic nervous system so that its blood pressure lowering effects are lost. This is
essentially the same mechanism of interaction as that seen with the tricyclic antidepressants.
Importance and management
Direct information is very limited but the interaction is established and can be clinically
important. It may take several days to develop. Not all patients may react to the same extent.
Monitor concurrent use and raise the guanethidine dosage if necessary.s
Guanethidine and related drugs + pizotifen
Abstract/summary
An isolated report describes the abolition of the anyihypertensive effects of debtisoquine by
pizotifen.
Clinical evidence, mechanism, importance and management
A man with severe focalglomerulonephritis and hypertension. Well controlled on debrisoquine
, 30 mg daily, timolol 10 mg and frusemide40 mg eight-hourly, was additionally given pizotifen
(sandomigran) as a prophylactic for migtaine. Over the next few weeks his blood pressure
climbed from 130/90 to 195/145 mm/Hg. It was found impossible to lower the pressure with
either dazoxide ar prazosin, but within 48 h of withdrawing the pizotifen thre pressure had
fallen to 105/82 mmHg and later stabilized at 140/90 mmHg. The reason is not known but
Sandoz, the manufactures of pizotifen. Suggest that as it is structurally similar to the tricyclic
antidepressants , it may possibly appose tha actions af debrisoquine in a smillar way blocking
the entry of the antihypertensive into adrenergic neurons of the sympathetic nervous system.

Information is limited to this report but it would be wise to check for this interaction in any
patient on debrisoquine or any other guanethidine-like hypertensive if pizotifen is given.
Guanethidine and Related drugs + Sympathomimetic amines (direcly-acting)
Abstract/summary
The pressor effects or noradrenaline (norepinephrine, levarterenol), phenylrphrine,
metaraminol and similar drugs can be increased two-to four-fold in the presence of
guanithidine and related drugs (bethanidine, debrisoquine, guanadrel, etg.). The mydriatic
effects are similarly enhanced and prolonged.
Clinical Evidance
(a) Pressor responses
A study in six noemal subjects,given 200 mg guanethidine on the first day of study and 100 mg
daily for the next two days. Showed that their pressor responses ( one third pulsr pressure +
dastolig pressure) when infused with noradrenaline in a range of doses were enhanced twoand-a-half to four times moreover cardiac arrhythmias apperead at lower doses of
noradrenaline ad with greater frequency than in the absence of guanethidine, and were more
serious in nature. There ara reports of this enhanced pressor response involving debrisoquine
with phenylrphrine , ( even when given orally) with bretylium and noreadrenaline, and
guanethidine with metaraminol. In the latter instance, 10 mg metaraminol given intravrnously
rapidly caused a blood pressure rise to 220/130 mmHg accompanied by severe headache and
extreme angina. An increased blood pressure (from 165/92 to 210/120 mmHg. Was also seen
in a patient on guanethidine who, prior to surgery, was treated with phenylephrine eye drops.

(b) Mydriatic responses

The mydriasis due to phenylrphrine administered as a 10% eyedrop solution was abserved to
be prolonged for up to 10 h in a patient concurrently receiving guanithidine for hypertension.
This enhanced mydriatic response has response has been described in other studies involving
guanithidine with adrenaline, phenylephrine or methoxamine and debrisoquine with
phenylephrine oe ephedrine.
Mechanism
If sympathetic nerves are cut surgically, the receptors which they normally stimulate become
hypersensitive. By preventing the release of noreadrenaline (norepinephrine ) fron adrenergic
neurones, guanethidine and other adrenergic neurone blockers cause a tempory drug induced
sympathectomy which is also accompanied by hypersensitivy af the receptors. Hence the
increased response to the stimulation of the receptors by diregly agting sympathomimetics.
Importance and management

An established, well-documented and potentally serios interaction. Since the pressor effects
are grossly exaggerated, dosages of directly-acting sympathomimetics (alpha-agonists) should
be reduced appropriately. The pressor effects of noreadrenaline (norepinephrine) are
increased two-tofour-fold, and of phenylephrine twofold. In addition it should be
remembered that the incidence and severity of heart arrhythmias is increased. Gonsiderable
care is required. Direct evidenge seems to be limited to noreadrenaline, phenylephrine and
metaraminol, but dopamine and methoxamine prosses direct sympathomimetic activity and
may be expected to interact similarly . No interaction would be expected with the beta-agonist
drugs used for the treatment of asthma (sucth as terbutaline, salbutamol). Bethanidine and
other guanethidine like drugs (guanoclor, gunoxan, gunadrel, etc.) are also expected to
behave like guanethidine. If as aresult of this interaction the blood pressure becomes groslly
elevated, it can be controlled by the administration of an alpha-adrenergic blocker such as
phentolamine, 10 mg oral nifedipine with water mayalso be effective. Phenilephrine is
contained in a number of over-the-counter cough and cold preparations, a few of which
contain up to 10 mg in a dose. This dose is only likely to cause a moderate blood pressure rise,
compared with the marked rise seen in subjects on debrisoquine given 0,75mg/kg (roughly 45
mg in a 10-stone individual). However this requires confirmation. An exaggerated pressor
response is clearly much more potentially serious than enhanced and prolonged mydriases,
but thr latter is also possible and undesirable. It can occur whether or not the guanethidinelike drugs has been given ryrtemycally ar topically. The same precautions apply about using
smaller amounts of the sympathomimetic drugs.

Guanethidine and relataed drugs+ Sympathomimetic amines (indirectly acting) and related
drugs
Abstract/summary
The antihypertensive effects of guanethidine-like drugs (bethanidine, debrisoquine, guanoclor,
etc.) can be reduced or abolished by the concurrent use of indirectly-acting sympathomimetics
and related drugs which are contained in cough, cold and influenza remedies or are used as
appetite suppressants (amphetamines, ephedrine, pseudoephedrine, phenylpropanolamine,
mazindol, methylphenidate, etg.). The blood pressure may even rise higher than before
treatment with the anthypertensive.
Clinacal evidence
When 16 hypertensive patients on 25-35 mg guanethidine daily were additionally given
dextroamphetamine (10 mg orally), ephedrine (90 mg orally), methamphetamine (30 mg IM)
or methylphenidate (20mg orally), the effects of the guanethidine were completely abolished
and in some instances the blood pressure rose higher than before treatment with the
guanethidine. Other reports describe the same interaction between gunethdine and

dextroamphetamine or methamphetamine , bethanidine and phenylpropanalamine or

mazindol; bretylium and amphetamine; debrisoquine and mazindol and an adrenergic blogker
and ephedrine.
Mechanism
Indirectly-acting sympathomimetic amines not prevent gunethidine-like drugs from entering
the adrenergic neurons of the sympathetic nervous system, but they can also displace the
anthypertensive drug already there. As a result the blood pressure lowering effects are lost. In
addition these amines release noradrenaline from the neurons which raises the blood
pressure. Thus the antihypertensive effects are not only opposed, but the pressure may even
be raised higher than before treatment. Mazindol is related to the tricyclic antidepressants and
probably interacts solely by blocking the entry of the gunethidine-like drugs into adrenergic
neurons.
Importance and management
Well document, well established and clinically important interactions. Patients taking
guanethidine and related drugs (bretylium, bethanidine, debrisoquine, gunoclor, gunacline,
gunadrel, etg.) . Should avoid indirectly-acting sympathomimetics (named above). Warn them
against the temptation to use proprietary over-the-counter nasal stuffiness commonly same
precautions apply to the sympathomimetics used appetite suppressants. However
disthylpropion appears not to interact with gunethidine or bethanidine,. Not every
guanethidine like antihypertensive-sympathomimetic combination has been investigated in
man, but from their well-understood pharmacology thay are expected to behave similarly.