Sympathomimetic drug interactions

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Sympathomimetic Drug Interactions

Sympathomimetic druginteractionsIntroduction

Norepinephrine (noradrenaline) is the principalneurotransmitter involved in the final link between nerveendings of the sympathetic nervous system and the adrenergicreceptors of the organs or tissues innervated. The effectsof stimulation of this system can be reproduced or mimickedby norepinephrine itself and by a number of other drugswhich can also cause stimulation of these receptors. Thedrugs which can behave in this way are described as‘sympathomimetics’ and act either directly on the adrenergicreceptors like norepinephrine itself or indirectly byreleasing stored norepinephrine from the nerve endings. Someof them do both.

We now know that the adrenergic receptors of the sympatheticsystem are not identical but can be subdivided into at leastfour main types, alpha-1, alpha-2, beta-1 and beta-2, and itis now possible broadly to categorise the sympathomimeticsinto groups according to their activity. The value of thiscategorisation is that individual sympathomimetic drugs canbe selected for their stimulant actions on particular organsor tissues. For example, salbutamol and terbutaline are so-called beta-agonists which selectively stimulate the beta-2receptors in bronchi causing bronchodilation. Thisrepresents a significant improvement on both isoprenaline(isoproterenol) which also stimulates beta-1 receptors inthe heart, and on ephedrine which stimulates alpha receptorsas well. Although the sympathomimetics are categorisedtogether in this chapter, it is important to appreciate thatthey have a very wide range of actions and uses. One shouldnot, therefore, extrapolate the interactions seen with onedrug to any other without fully taking into account theirdifferences and similarities. The Index should be consulted

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for a full listing of all interactions involving drugs withsympathomimetic activity.

Amphetamines and Related drugs + Chlorpromazine

The appetite suppressant and other effects ofamphetamines, chlorphentermine and phenmetrazine areopposed by chlorpromazine. The antipsychotic effects ofchlorpromazine can be opposed by amfetamine(amphetamine).

Clinical evidence

(a) Amphetamines + Phenothiazines

20 obese schizophrenic patients being treated withphenothiazines and other drugs (including chlorpromazine,thioridazine, imipramine and chlordiazepoxide) failed torespond to concurrent treatment with dexamfetamine(dextroamphetamine) for obesity, and the expected sleepdisturbance was not seen. Antagonism of the effects of

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amphetamines by chlorpromazine has been described in otherreports.

A study in a very large number of patients taking 200–600 mgchlorpromazine daily indicated that the addition of 10–40 mgamfetamine (amphetamine) had a detrimental effect on thecontrol of their schizophrenic symptoms.

(b) Chlorphentermine or Phenmetrazine + Chlorpromazine

Chlorpromazine was found in a double-blind controlled studyin patients to diminish the weight reducing effect ofphenmetrazine. The effects of both phenmetrazine andchlorphentermine on the control of obesity were found inanother study to be reduced by chlorpromazine.

Mechanism

Not understood. It is known that phenothiazines can inhibitthe uptake mechanism by which the amphetamines enterneurones. If this occurs at peripheral adrenergic neuronesand centrally at both adrenergic and dopaminergic neurones,some part of the antagonism of the amphetamines can beexplained.

Importance and management

Established interactions. These reports amply demonstratethat it is not desirable to attempt to treat patients withchlorpromazine and amphetamines, phenmetrazine orchlorphentermine concurrently. It is not clear whether thisinteraction takes place with phenothiazines other thanchlorpromazine, but it seems possible.

This interaction has been deliberately exploited, and withsuccess, in the treatment of 22 children poisoned withvarious amphetamines (dexamfetamine (dextroamphetamine),methamphetamine, phenmetrazine). 2 They were given 1 mg/kgchlorpromazine intramuscularly initially, followed byfurther doses as necessary.

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There seem to be no reports about interactions between otherdrugs related to dexamfetamine (e.g. benzphetamine,clortermine, fenproporex, phendimetrazine, phentermine,etc.) and chlorpromazine, but it would be prudent to bealert for these drugs to behave similarly.

Amphetamines + Lithium carbonate

The effects of the amphetamines can be opposed bylithium carbonate.

Clinical evidence, mechanism, importance and management

Two depressed patients spontaneously abandoned abusingamphetamines (methamphetamine with cannabis andphenmetrazine) because, while taking lithium carbonate, theywere unable to get ‘high’. Another patient complained of notfeeling any effects from amphetamines taken for weightreduction until lithium carbonate was withdrawn. 1 Acontrolled study in nine depressed patients confirmed thesefindings. 2 The reasons for these reactions are not known,but one suggestion is that amphetamines and lithium havemutually opposing pharmacological actions on norepinephrine(noradrenaline) uptake at adrenergic neurones. Informationis very limited, but be alert for evidence of reducedamfetamine (amphetamine) effects in the presence of lithium.

Amphetamines + Nasal decongestants

An isolated report describes the antagonism oflevamphetamine in a hyperactive child by nasaldecongestants containing phenylpropanolamine andchlorphenamine (chlorpheniramine).


Maintenance therapy with 42 mg levamphetamine succinatedaily in a 12-year-old hyperactive boy was found to beineffective on two occasions when he was concurrently

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treated with Contac and Allerest for colds. Both of theseproprietary nasal decongestants contain phenylpropanolamineand chlorphenamine (chlorpheniramine). 1 The reason is notunderstood. There is too little information to make anystatement about the general importance of this reaction.

Amphetamines + Urinary acidifiers or alkalinizers

The loss of amfetamine (amphetamine) in the urine isincreased by urinary acidifiers (ammonium chloride) andreduced by urinary alkalinizers (acetazolamide, sodiumbicarbonate).

Clinical evidence

A study in six normal subjects given 10–15 mg amfetamine(amphetamine) by mouth showed that when the urine was madealkaline (approximately pH 8) by giving sodium bicarbonate,only 3% of the original dose of amfetamine was excreted overa 16-h period compared with 54% when the urine was made acid(approximately pH 5) by taking ammonium chloride.

Similar results have been reported elsewhere. Psychosesresulting from amphetamine retention in patients withalkaline urine have been described.

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Mechanism

Amfetamine is a base which is excreted by the kidneys. Ifthe urine is alkaline most of the drug exists in theunionised form, which is readily reabsorbed by the kidneytubules so that little is lost. In acid urine, little of thedrug is in the unionised form so that little can bereabsorbed and much of it is lost. A more detailed andillustrated account of this interaction mechanism is givenin the introductory chapter.


A well established and well understood interaction butreports of clinical problems arising as a result are verysparse. The interaction can be usefully exploited to clearamfetamine (amphetamine) from the body more rapidly in casesof overdosage by acidifying the urine with ammoniumchloride. Conversely it can represent an undesirableinteraction if therapeutic doses of amfetamine are excretedtoo rapidly. Care is needed to ensure that amfetamineintoxication does not develop if the urine is made alkalinewith sodium bicarbonate or acetazolamide.

Beta-agonist bronchodilators + Potassium-depleting drugs

Beta-agonists (e.g. fenoterol, terbutaline, salbutamol(albuterol)) can cause hypokalaemia. This can be

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increased by other potassium-depleting drugs such asthe corticosteroids, diuretics (bumetanide, etacrynicacid (ethacrynic acid), furosemide (frusemide),thiazides, etc.) and theophylline. The risk of seriousheart arrhythmias in asthmatic patients may beincreased.

Clinical evidence

(a) Beta-agonist bronchodilators + Corticosteroids

24 normal healthy subjects showed a fall in serum potassiumlevels when given either 5 mg salbutamol (albuterol) or 5 mgfenoterol by nebuliser over 30 min. These falls wereincreased after taking 30 mg prednisone daily for a week.The greatest fall (from 3.75 to 2.78 mmol/l) was found90 min after fenoterol and prednisone. The ECG effectsobserved included ectopic beats and transient T waveinversion, but no significant interaction was noted for ECGdisturbances in these healthy subjects. 1 However, there isevidence that the risk of mortality may be increased incorticosteroid-dependent asthmatics who take beta-agonists.2

(b) Beta-agonist bronchodilators + Diuretics

The serum potassium levels of 15 normal subjects weremeasured after inhaling 5000 micrograms terbutaline whiletaking either a placebo, or 40 mg furosemide (frusemide)daily, or 40 mg furosemide + 50 mg triamterene daily forfour days. With terbutaline alone the levels fell from 3.88to 3.35 mmol/l; after taking furosemide as well they fell to3.13 mmol/l; and after furosemide and triamterene they fellto only 3.29 mmol/l. These falls were reflected in some ECG(T wave) changes.

After seven days’ treatment with 5 mg bendroflumethiazide(bendrofluazide) daily for a week the serum potassium levelsof 10 normal subjects had fallen from 3.78 to 3.07 mmol/l.

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After taking 100–2000 micrograms inhaled salbutamol(albuterol) as well, the levels fell to 2.72 mmol/l. ECGchanges consistent with hypokalaemia and hypomagnesaemiawere also seen.

Other diuretics which can cause potassium loss includebumetanide, furosemide, etacrynic acid (ethacrynic acid),the thiazides, and many other related diuretics. See Table14.2.

Table 14.2 Potassium-depleting diuretics

Carbonicanhydraseinhibitors

Acetazolamide, diclofenamide(dichlorphenamide), disulfamide(disulphamide), ethoxzolamide, methazolamide

Loopdiuretics

Azosemide, bumetanide, etacrynic acid(ethacrynic acid), etozolin, furosemide(frusemide), muzolimine, piretanide,torasemide

Organomercurials Chlormerodrin, meraluride, mercaptomerin

Thiazides andrelateddiuretics

Althiazide, ambuside, bemetizide,bendroflumethiazide (bendrofluazide),benzthiazide, benzylhydrochlorothiazide,buthiazide, chlorothiazide, chlortalidone(chlorthalidone), clopamide, clorexolone,cyclopenthiazide, cyclothiazide,epithiazide, ethiazide, fenquizone,hydrobentizide, hydrochlorothiazide,hydroflumethiazide, indapamide, mebutizide,

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mefruside, methylclothiazide, meticrane,metolazone, polythiazide, quinethazone,teclothiazide, trichlormethiazide, xipamide

(c) Beta-agonist bronchodilators + Theophylline

The concurrent use of salbutamol (albuterol) or terbutalineand theophylline can cause a fall in serum potassium levels.There is a theoretical risk with other beta-agonists. Seedetails under ‘Theophylline + Beta-agonist bronchodilators’(refer to Index).

Mechanism

Additive potassium-losing effects.


Established interactions. The CSM in the UK 5 give thefollowing advice: “Potentially serious hypokalaemia mayresult from beta2-adrenoceptor stimulant therapy. Particularcaution is required in severe asthma, as this effect may bepotentiated by concomitant treatment with theophylline andits derivatives, corticosteroids, and diuretics, andhypoxia. Plasma potassium concentrations should therefore bemonitored in severe asthma”. Hypokalaemia may result inheart arrhythmias in patients with ischaemic heart diseaseand may also affect the response of patients to drugs suchas the digitalis glycosides and antiarrhythmics.

Dobutamine or Amrinone + Calcium chloride

Calcium chloride infusion reduces the cardiotoniceffects of dobutamine but not those of amrinone.

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An experimental study of the mode of action of dobutamine in22 patients recovering from aortocoronary bypass surgeryfound that an infusion of calcium chloride (1 mg/kg/mininitially, later 0.25 mg/kg/min) reduced by 30% the increasein cardiac output produced by dobutamine (an infusion of2.5–5.0 micrograms/kg/min). The cardiotonic actions ofamrinone (a phosphodiesterase inhibitor) in a group of 24similar patients were unaffected by the calcium infusion.Just how the calcium alters the dobutamine effects is notknown but since dobutamine is a beta-receptor agonist it isreasonable to postulate that it interferes with the signaltransduction through the beta-adrenergic receptor complex.The clinical importance of these findings is uncertain.

Dobutamine + Cimetidine

An isolated report describes an exaggeratedhypertensive response to dobutamine in a patient oncimetidine while undergoing anaesthetic inductionbefore surgery.


A patient developed unexpectedly marked hypertension(210/100 mmHg) in response to the infusion of dobutamine (5micrograms/kg/min) during induction of anaesthesia (withmidazolam, fentanyl, vecuronium and oxygen) for coronaryartery bypass grafting. The infusion was stopped and overthe next 15 min the blood pressure fell to 90/59 mmHg. A newinfusion had just the same hypertensive effect, and hisblood pressure was subsequently controlled at 120/80 mmHgwith only 1 micrograms/kg/min of dobutamine.

The authors of the report suggest that this exaggeratedresponse to dobutamine may have been due to the 1 g

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cimetidine which the patient was taking daily. Theypostulate that the cimetidine may possibly have inhibitedthe metabolism and clearance of the dobutamine by the liver,thereby increasing its effects. This is an isolated case andits general importance is not known, but it would now seemprudent to reduce the dosage of dobutamine initially inpatients taking cimetidine.

Dobutamine + Dipyridamole

The addition of dipyridamole to dobutamine forechocardiography can cause potentially hazardoushypotension.


Ten patients with a low probability of coronary arterydisease underwent dobutamine echocardiography. Five weregiven dobutamine alone, while the other 5 had a low dose ofdipyridamole added to the maximal dose of dobutamine to seewhether the sensitivity of the test could be improved. Fourof the patients given both drugs experienced severehypotension while no hypotension was seen in the controlgroup. The conclusion was reached that this combination ofdrugs can be hazardous and should not be used in patientssuspected of coronary heart disease.

Dobutamine + Theophylline

A man on theophylline about to undergo surgery,developed marked tachycardia when treated withdobutamine.

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An asthmatic patient taking 150 mg theophylline twice daily,digoxin and spironolactone was anaesthetised for aorticvalve replacement with fentanyl, midazolam and pipecuronium.Following induction, intubation and ventilation with 100%oxygen, his systolic blood pressure fell from 120 to80 mmHg, and his heart slowed from 70 to 50 bpm. Dobutaminewas then infused at 5 micrograms/kg/min, whereupon 2–3 minlater his heart rate rose to 150 bpm and his systolicpressure rose to 190 mmHg. The authors of the report 1

attribute the tachycardia to a dobutamine/theophyllineinteraction resulting from a synergistic increase in cyclicAMP levels in cardiac muscle. They advise the carefultitration of dobutamine in any asthmatic takingtheophylline, particularly if a slow-release preparation isbeing used. More study of this apparent interaction isneeded.

Dopamine + Ergometrine (Ergonovine)

A single report attributes the development of gangrenein a patient to the infusion of dopamine afterergometrine.

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Gangrene of the hands and feet has been described in onepatient who was given an infusion of dopamine following theadministration of ergometrine. 1 This would seem to haveresulted from the additive peripheral vasoconstrictoreffects of both drugs which reduced the circulation to suchan extent that infection became unchecked. It would seemprudent to avoid concurrent use or monitor the outcomeextremely closely.

Dopamine + Phenytoin

There is some limited evidence that patients needingdopamine to support their blood pressure can becomeseverely hypotensive if phenytoin is added to theirtreatment.


Five critically ill patients with a variety of conditionsand under treatment with a number of different drugs weregiven dopamine hydrochloride to maintain an adequate bloodpressure. When seizures developed they were additionallygiven phenytoin at an infusion rate of 10–25 mg/min.Coincidentally their hitherto stable blood pressures fellrapidly and one patient died from cardiorespiratory arrest.A similar reaction was demonstrated in dogs madehypovolaemic and hypotensive by bleeding. However anotherstudy in dogs was unable to find evidence of this seriousadverse interaction, and no evidence of marked hypotensionoccurred in a patient with cardiogenic shock on dopamine anddobutamine when a phenytoin infusion was added.

The documentation of this adverse interaction is limited tothis single report so that it is not fully established, butthere is enough evidence to suggest that phenytoin shouldonly be used with great caution in those requiring dopamineto maintain their blood pressure. More study is needed.

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Dopamine + Tolazoline

Acute and eventually fatal hypotension occurred in apatient given dopamine and tolazoline concurrently.

Clinical evidence

A patient who had undergone surgery three days before wasgiven dopamine to maintain his cardiac index at about3.5 l/min/m2. Pulmonary arterial pressure had been steadilyrising since the surgery so that on day 4 he was given aslow bolus of tolazoline (2 mg/kg) to reduce the afterloadof the right ventricle. Systemic arterial pressureimmediately fell to 50/30 mmHg whereupon the dopamineinfusion was increased, but the arterial pressure then felleven further to 38/15 mmHg. The dopamine was stopped andephedrine, methoxamine and fresh frozen plasma were given.Two hours later his blood pressure was 70/40 mmHg. Twofurther attempts were made to infuse dopamine, but thearterial pressure fell to 40/15 mmHg on the first occasion,and to 38/20 mmHg on the second. The patient died of cardiacarrest.

Mechanism

Not fully understood. Dopamine has both alpha(vasoconstrictor) and beta (vasodilator) activity. With thealpha effects on the systemic circulation competitivelyblocked by the tolazoline, its vasodilatory actions wouldpredominate, resulting in paradoxical hypotension.

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Information is limited but this interaction would appear tobe established. The authors of this report warn thatinfusion of dopamine should not be considered forseveral hours after giving even a single small dose oftolazoline. They point out that impaired renal functionoften accompanies severe respiratory failure which maysignificantly prolong the half-life of tolazoline and itseffects.

Ecstasy (3,4-Methylenedioxymethamphetamine, MDMA) +Citalopram

The psychological effects of 3,4-Methylenedioxymethamphetamine (MDMA, ‘Ecstasy’) aremarkedly reduced by the concurrent use of citalopram.It seems likely that other SSRIs will also reduce orblock the effects of MDMA. An isolated report describesa neurotoxic reaction in a man on citalopram when hetook unknown amounts of MDMA.

Clinical evidence

(a) Reduced MDMA effects

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A double-blind placebo-controlled psychometric study in 16normal subjects found that 3,4-Methylenedioxymethamphetamine(MDMA) - ‘Ecstasy’ produced an emotional state withheightened mood, increased self-confidence and extroversion,moderate derealisation and an intensification of perception.1 Most of these effects were found to be markedly reduced bypretreatment with citalopram (40 mg intravenous).

(b) Neurotoxic reaction

When a man on 60 mg citalopram daily additionally tookunknown amounts of MDMA he became aggressive, agitated,severely grandiose, restless and performed peculiarcompulsive movements (“. . . in a peculiar and joylessdancelike manner.”). He lacked normal movement control andsaid he could see little bugs. He was treated withhaloperidol and chlordiazepoxide, and improved within 2 daysof replacing the citalopram by promazine. This appears to bethe first and only report of this reaction.

Mechanism

The psychological effects of MDMA are believed to be due tothe release of serotonin (5-HT) and dopamine within thebrain, which is blocked by 5-HT uptake inhibitors such ascitalopram. The neurotoxic reaction is not understood.


This MDMA/citalopram study was primarily undertaken to findout how MDMA works, but on the basis of these results andanimal studies it seems likely that patients already takingcitalopram may not be able to get ‘high’ on usual doses of‘Ecstasy’. And if the proposed mechanism of interaction iscorrect, the same is also likely to be true if they aretaking any other SSRI (such as fluoxetine, fluvoxamine,paroxetine, sertraline). The neurotoxic reaction cited seemsto be an isolated case but it illustrates some of the risksattached to using ‘recreational’ drugs by patients already

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taking other medications, particularly antidepressant andpsychotropic drugs which affect the same receptors in theCNS.

Ephedrines + Adsorbents, Antacids, Urinary acidifiers andalkalinizers

Alkalinization of the urine by sodium bicarbonate orother urinary alkalinizers causes retention ofephedrine and pseudoephedrine in the body, leading tothe possible development of toxicity (tremors, anxiety,insomnia, tachycardia). Acidification of the urine withammonium chloride has the opposite effect because theloss is increased. Kaolin does not appear to interactsignificantly with pseudoephedrine but aluminiumhydroxide may possibly cause a more rapid onset ofactivity.

Clinical evidence

(a) Ephedrine + Urinary acidifiers & alkalinizers

The excretion of ephedrine in the urine of three normalsubjects, made acidic (about pH 5) with ammonium chloride,was two to fourfold higher than when the urine was madealkaline (about pH 8) with 3 g oral sodium bicarbonate. 1

(b) Pseudoephedrine + Antacids or Urinary acidifiers & alkalinizers

Prompted by the observation of a patient with renal tubularacidosis and persistently alkaline urine who developedunexpected toxicity when given ordinary doses ofpseudoephedrine, a study was made on eight adult and childsubjects of the possible effects of changing the urinary pHon the loss or retention of pseudoephedrine by the body.When the urinary pH was made alkaline with sodiumbicarbonate, the half-life of a single 0.5 mg/kg dose ofpseudoephedrine increased from 1.9 to 21 h.

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This confirms an earlier study in which it was found thatwhen the urinary pH of three subjects was made about 8(using sodium bicarbonate), the half-lives ofpseudoephedrine were 16, 9.2 and 15 h respectively. When thepH was made about 5 (using ammonium chloride), the half-lives were 4.8, 3.0 and 6.4 respectively.

Another study found that 5 g sodium bicarbonate increasedthe absorption rate at 2–4 h of a single 60-mg dose ofpseudoephedrine. The same study also found that 30 mlaluminium hydroxide gel did not affect the total amount ofpseudoephedrine absorbed over 24 h but the rate ofabsorption was briefly increased.

(c) Pseudoephedrine + Kaolin

30 ml of a 30% suspension of kaolin was found in a study in6 normal subjects to cause a small decrease (about 10%) inthe absorption of a single 60-mg dose of pseudoephedrine.The rate of absorption was also decreased.

Mechanism

The ephedrines are basic drugs mainly excreted unchanged inthe urine. In acid urine, most of the drug is ionised in thetubular filtrate and unable to diffuse passively back intothe circulation, and is therefore lost in the urine. Inalkaline urine, it mostly exists in the lipid-soluble formwhich is retained. As a result they are lost much moreslowly and accumulate. The increased rate of absorption ofpseudoephedrine in the gut seen with sodium bicarbonate andaluminium hydroxide is probably also due to pH rises whichfavour the formation of the lipid-soluble absorbable form ofpseudoephedrine. The reduced absorption with kaolin isprobably due to adsorption of the pseudoephedrine onto thesurface of the kaolin.

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The ephedrines/urinary alkalinizer interaction isestablished but reports of adverse reactions in patientsappear to be rare. Monitor the outcome of alkalinizing theurine for any evidence of toxicity due to drug retention(tremor, anxiety, insomnia, tachycardia, etc.), reducing thedosage if necessary. Acetazolamide makes the urine alkalineand would be expected to interact with the ephedrines in thesame way as sodium bicarbonate. Acidification of the urinewith ammonium chloride increases the loss of the ephedrinesin the urine and could be exploited in cases of drugoverdosage. Aluminium hydroxide may possibly cause a morerapid onset of pseudoephedrine activity (but this needsconfirmation) whereas the effects of kaolin on absorptionare small and unlikely to be clinically important.

Methylphenidate + Clonidine

Much publicised fears about the serious consequences ofusing methylphenidate with clonidine appear to beunfounded. There is evidence that concurrent can beboth safe and effective.


The current summary of product characteristics formethylphenidate in the UK 1 carries the following statement.“Serious adverse events have been reported in concomitantuse with clonidine, although no causality for thecombination has been established. The safety of usingmethylphenidate in combination with clonidine or othercentrally acting alpha-2 agonists has not beensystematically evaluated.” Similar statements are alsoincluded in the US product information.

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A thumb-nail sketch of the background to this somewhatambivalent statement is that rumours began to circulate inthe US in 1995, fuelled by national radio broadcasts andnewspaper reports about the deaths of 3 children who weretaking methylphenidate and clonidine. One died fromventricular fibrillation due to cardiac abnormalities, onefrom cardiac arrest attributed to an overdose of fluoxetine,and the third death is unexplained. Studies of these 3 casesand one other failed to establish any link between the useof the methylphenidate/clonidine combination and thesedeaths, the final broad conclusion being that the event waslargely a media-inspired scare story built on inconclusiveevidence. 2,3 A small scale pilot study in 24 patientssuggested that the combination is both safe and effectivefor the treatment of attention deficit hyperactivitydisorder 4, and the makers of one formulation ofmethylphenidate 5 say that they are “. . . not aware of anyreports describing adverse events when using Concerta XL(methylphenidate) in combination with clonidine.”

Phenmetrazine + Amobarbital (Amylobarbitone)

The CNS side effects and the weight-reducing effects ofphenmetrazine are reduced by amobarbital(amylobarbitone).


A comparative study in 50 overweight adults of the effectsof either 75 mg phenmetrazine daily or 50 mg phenmetrazineplus 30 mg amobarbital (amylobarbitone) daily found thatalthough the adverse CNS side-effects, particularlyinsomnia, headache and nervousness, were decreased by thepresence of the barbiturate, the weight reducing effectswere also decreased (by 65%). 1

Phentermine + Fluoxetine

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An isolated report describes phentermine toxicity in awoman shortly after stopping fluoxetine.


A woman of 22 who had successfully and uneventfully taken20 mg fluoxetine daily for 3 months, stopped the fluoxetineand then 8 days later took a single 30-mg tablet ofphentermine. Within a few hours she experienced racingthoughts, stomach cramps, palpitations (pulse 84), tremors,dry eyes and diffuse hyperreflexia. The problems had allresolved the following day after taking 1.5 mg lorazepam.The authors of this report interpreted what happened as aninteraction between the phentermine and the residualinhibitory effects of the fluoxetine on liver cytochromeP450 enzymes, which (they postulated) lead to elevatedphentermine serum levels with the resultant sympathetichyperstimulation. It is known that fluoxetine and its activemetabolite are only cleared from the body slowly and canpersist for weeks. The authors also alternativelytentatively wondered whether some of the symptoms might havefitted the serotonin syndrome. 1

This is an isolated case and its general importance isunknown, but the authors of the report draw attention to thepossible risks of taking SSRIs and sympathomimetic drugsused for controlling diet.

Phenylephrine + Atropine

The hypertensive and other serious adverse effects ofphenylephrine absorbed from eye drops can be markedlyincreased by atropine.

Clinical evidence

A brief report describes seven cases of a “pseudo-phaeochromocytoma” with severe rises in blood pressure and

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tachycardia in young adults and children undergoing eyeoperations when treated with 10% phenylephrine eye drops andatropine. Only two of them had any pre-existingcardiovascular illness (moderate hypertension). All wereunder general anaesthesia with propofol, phenoperidine andvecuronium, and premedicated with intramuscular atropine,and some were later given more intravenous atropine becauseof the bradycardia when the oculomotor muscles werestretched. The total atropine doses were less than0.01 mg/kg in adults and 0.02 mg/kg in the children. Atleast 0.4 ml of 10% phenylephrine was used. In three casesleft ventricular failure occurred with pulmonary oedema thatneeded monitoring in intensive care. 1

In a study of this interaction, six normal subjects weregiven a phenylephrine infusion (0.42 micrograms/kg/min)before and after being given three intravenous doses ofatropine (0.02, 0.01, 0.01 mg/kg) at 90, 120 and 150 min. Itwas found that a dose of phenylephrine which raised thediastolic and systolic blood pressures by 4 mmHg beforeusing atropine, raised the pressures by 17 mmHg whenatropine was present. For safety reasons the increases inblood pressure were limited to 30 mmHg above the base line.2

Mechanism

Phenylephrine causes vasoconstriction which can raise theblood pressure. Normally this would be limited by abaroreflex mediated by the vagus nerve, but if thischolinergic mechanism is blocked by atropine, the rise inblood pressure is then largely uncontrolled. Severehypertension may occur, and other adverse cardiac eventssuch as acute heart failure may follow.


A surprisingly large amount of phenylephrine can be absorbedfrom eye drops, and the potential adverse effects of this

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(severe hypertension, cardiac arrhythmias, myocardialinfarction) are now well documented. 3-5 The reports citedhere are good evidence that these risks are increased by thepresence of atropine, and this interaction is established.It is clearly potentially serious. The authors of the reportcited 1 suggest that the risks can be reduced by reducingthe concentrations of phenylephrine used, swabbing tominimise the amounts which drain into the nasolachrimal ductto the nasal mucosa where rapid absorption occurs, andreducing the drop size by using a thin-walled cannula. 6

Other suggestions for reducing systemic absorption arepunctal plugging, nasolachrimal duct compression, and lidclosure after instillation of the eye drop. 6

Phenylpropanolamine + Caffeine

Phenylpropanolamine can raise blood pressure and thismay be further increased by caffeine.Phenylpropanolamine can also markedly raise serumcaffeine levels. Combined use may result in ahypertensive crisis in a few particularly susceptibleindividuals and increase the risk of intracranialhaemorrhage. Manic psychosis has also been seen.

Clinical evidence

After taking 75 mg phenylpropanolamine or 400 mg caffeinealone, or both together, the blood pressures of 16 normalsubjects rose from 137/85 mmHg to 148/97 mmHg, and after150 mg phenylpropanolamine alone they rose to 173/103 mmHg.One of the subjects had a hypertensive crisis after 150 mgphenylpropanolamine and again 2 h after 400 mg caffeine.This needed antihypertensive treatment. 1 The same group ofworkers describe a similar study in which the AUC ofcaffeine increased more than 20–fold (from 0.8 to18.5 micrograms h/ml) when taken with 75 mgphenylpropanolamine, and the peak serum caffeine levelincreased almost fourfold (from 2.1 to 8.0 micrograms/ml). 2

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Additive effects on blood pressure are described in anotherreport. 3 Mania with psychotic delusions occurred in ahealthy woman (who normally drank 8–10 cups of coffee daily)within 4 days of starting to take a phenylpropanolamine-containing decongestant. She recovered within a week ofstopping both the coffee and the phenylpropanolamine. 4

Mechanism

Uncertain. Simple additive hypertensive effects would seemto be part of the explanation.


Established interactions. These studies illustrate thepotential hazards of these drugs, even in normal healthyindividuals, but it has to be said that there seem to be noother reports of adverse reactions, which is perhapssurprising bearing in mind that coffee is very widely usedand phenylpropanolamine is also widely available over thecounter. The authors of one report 1 advise that likelyusers of phenylpropanolamine (those with allergies, oroverweight, or postpartum women) and those particularlyvulnerable (elderly or hypertensive) should be warned abouttaking more than the recommended doses, and of takingcaffeine at the same time, because of the possible risk ofintracranial haemorrhage. The effects of high levels ofcaffeine (insomnia, jitteriness, nervousness, agitation) areundesirable and unpleasant.

Phenylpropanolamine + Indometacin (Indomethacin)

An isolated case report describes a patient onphenylpropanolamine who developed serious hypertension

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after taking a single dose of indometacin(indomethacin), but a controlled study in othersubjects failed to find any evidence of an adverseinteraction.

Clinical evidence

A woman who had been taking one Trimolet (85 mg D-phenylpropanolamine) daily for several months as an appetitesuppressant, developed a severe bifrontal headache within15 min of taking 25 mg indometacin (indomethacin).Thirty min later her systolic blood pressure was 210 mmHgand the diastolic was unrecordable. A later study on herconfirmed that neither drug on its own caused this response,but when taken together the blood pressure rose to a maximumof 200/150 mmHg within half an hour of taking theindometacin, and was associated with bradycardia. The bloodpressure was rapidly reduced by phentolamine. 1

In contrast, a controlled study, carried out to investigatethis possible interaction, failed to find any evidence thatthe concurrent use of 75 mg indometacin twice daily and75 mg slow release phenylpropanolamine daily in 14 healthyyoung women caused a rise in blood pressure. 2

Mechanism

Not understood.


Direct information seems to be limited to these reports.They suggest that an adverse hypertensive response is veryunlikely in most normal individuals given these doses, butit should be borne in mind that phenylpropanolamine, even onits own, can sometimes cause severe hypertension. 3-5

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Ritodrine + Miscellaneous drugs

Supraventricular tachycardia developed in a woman onritodrine when given glycopyrrolate (glycopyrronium).The abuse of cocaine does not appear to increase theincidence of side effects in patients given ritodrine.


Premature labour in a 39-year-old who was 28 weeks pregnantwas arrested with an intravenous infusion of ritodrinehydrochloride. Two weeks later while on the maximum dose ofritodrine (0.3 mg.min–1) her uterine contractions beganagain and she was scheduled for emergency caesarian section.It was noted in the operating room that she had copious oralsecretions so she was given 100% oxygen by mask and 0.2 mgglycopyrrolate (glycopyrronium) intravenously. Shortlyafterwards she developed superventricular tachycardia (arise from 80 to 170–180 bpm) which was converted to sinustachycardia (130 bpm) with 0.5 mg propranolol intravenouslyin divided doses. 1

The reason for this reaction is not understood. Ritodrinealone has been responsible for tachyarrhythmias and onepossible explanation for this interaction is that theeffects of these two drugs were additive. Two other cases oftachyarrhythmia have been described in patients premedicatedwith atropine who were given ritodrine as a singleintravenous bolus. 2 Information is very limited and the

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interaction is not well established but some caution isclearly appropriate if both drugs are used. The authors ofthe first report advise avoidance.

A study in patients found no evidence of an increase inadverse side-effects in pregnant patients given ritodrinefor premature labour who had been abusing cocaine.

Sympathomimetics (directly and indirectly-acting) +Clonidine

Experimental studies in patients show that pretreatmentwith clonidine can increase the blood pressureresponses to ephedrine and phenylephrine, but not thoseof norepinephrine (noradrenaline). In the context ofadverse reactions these increases appear to be oflittle clinical importance.

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A study in 75 patients (38 premedicated with 5 micrograms/kgclonidine with 20 mg famotidine, and a control group of 39given only famotidine and 90 min later anaesthetised withthiamylal) found that the pressor response to phenylephrine(2 micrograms/kg as an intravenous bolus) was augmented butnot the response to norepinephrine (noradrenaline) (0.5micrograms/kg). The reasons are not understood. There wereno significant differences between the groups in terms ofhypertension, arrhythmia or bradycardia. 1 A similar andrelated study by the same group of workers using enfluraneand nitrous oxide for anaesthesia found that the meanmaximal blood pressure increases in the clonidine group whengiven phenylephrine (2 micrograms/kg as an intravenousbolus) were +26% and +32% respectively for awake andanaesthetised subjects, and +13% and +18% respectively inthe control group. 2 The authors of the first report 1 saidthat “. . . the degree of pressor augmentation after bothagents (phenylephrine and norepinephrine) may be of littleclinical importance.” The findings of these studies are inline with those of other studies with patients who showed ablood pressure augmentation when given intravenous ephedrine0.1 mg/kg after pretreatment with clonidine.

Sympathomimetics (directly and indirectly-acting) + Lithiumcarbonate

The effects of norepinephrine (noradrenaline) andphenylephrine on blood pressure are slightly reduced bylithium carbonate. Tyramine does not interact.


A study in 8 patients with manic depression found that aftertaking lithium carbonate for 7–10 days (serum level range0.72–1.62 mmol/l) the dosage of norepinephrine(noradrenaline) had to be increased by 1.8 micrograms in 7of the 8 to raise the blood pressure by 25 mmHg. The pressor

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effect of the norepinephrine (noradrenaline) was reduced 22%by the lithium. 1 Another study in 17 depressed patientswith serum lithium levels in the range 0.8–1.2 mmol/l foundthat 12% more norepinephrine (noradrenaline) was needed toraise the blood pressure by 30 mmHg, and 31% morephenylephrine. 2 The reasons are not known. In both of thesestudies the pressor effects of tyramine were found to beunaffected by the presence of the lithium. 1,2

These decreases in the pressor response to norepinephrine(noradrenaline) and to phenylephrine in the presence oflithium carbonate are both relatively small and it seemsunlikely that they will present any problems in practice.

Sympathomimetics (directly and indirectly-acting) +Rauwolfia alkaloids

The pressor and other effects of directly actingsympathomimetics (epinephrine (adrenaline),norepinephrine (noradrenaline), phenylephrine, etc.)are slightly increased in the presence of the rauwolfiaalkaloids. The effects of indirectly actingsympathomimetics or those with mixed activity(amphetamines, mephentermine, ephedrine,phenylpropanolamine, etc.) may be reduced or abolished.

Clinical evidence

After taking 0.25–1.0 mg reserpine daily for two weeks thepressor responses of seven normal subjects to norepinephrine(noradrenaline) were slightly increased (20–40%) but theirresponses to tyramine (an indirectly acting amine) werereduced about 75%. 1 A man on reserpine who becamehypotensive while undergoing surgery failed to respond to anintravenous injection of ephedrine, but did so after 30 mintreatment with norepinephrine, presumably because the storesof norepinephrine at adrenergic neurones had becomereplenished. 2 A child who had accidentally taken reserpine

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(thought to be about 6.5 mg) also failed to respond to anintramuscular injection of ephedrine (16 mg). 3 Themydriatic effects of ephedrine in man were shown to beantagonised by pretreatment with reserpine, 4 but a numberof patients on reserpine were found to have increased bloodpressures (+30/+13 mmHg) during surgery if pretreated withphenylephrine eye drops. 5

Experiments with dogs have demonstrated that epinephrine(adrenaline), norepinephrine and phenylephrine — all withdirect actions — remain effective vasopressors aftertreatment with reserpine and their actions are enhanced tosome extent, whereas the vasopressor actions of ephedrine,amfetamine (amphetamine), methamphetamine, tyramine andmephentermine — all with indirect actions — are reduced orabolished by reserpine. 6-8

Mechanism

The rauwolfia alkaloids cause adrenergic neurones to losetheir stores of norepinephrine, so that they can no longerstimulate adrenergic receptors and transmission ceases.Indirectly acting sympathomimetics (which depend on theirability to stimulate the release of stored noradrenaline)may therefore be expected to become ineffective, whereas theeffects of directly acting sympathomimetics should remainunchanged or possibly even enhanced because of thesupersensitivity of the receptors which occurs when they aredeprived of stimulation by norepinephrine for any length oftime. Drugs with mixed direct and indirect actions, such asephedrine, should fall somewhere between the two, althoughthe reports cited seem to indicate that ephedrine haspredominantly indirect activity in man. 2-4


These are established interactions, but the paucity ofclinical information suggests that in practice theseinteractions do not present many problems. If a pressor drug

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is required, a directly acting drug such as norepinephrine(noradrenaline) or phenylephrine may be expected to beeffective. Metaraminol has also been successfully used as apressor drug in reserpine-treated patients. 9 The receptorsmay show some supersensitivity so that a dosage reductionmay be required. Somewhat surprisingly in the light of theother evidence, one report claims that 25 mg ephedrine givenorally or intramuscularly, once or twice a day, proved to bean effective treatment for reserpine-induced hypotension andbradycardia in schizophrenic patients. 10

Terbutaline + Magnesium sulphate

Terbutaline and parenteral magnesium sulphate appearnot to interact adversely.


Eight normal healthy adults were given two doses of 0.25 mgterbutaline subcutaneously 30 min apart, with and without4 g magnesium sulphate intravenously in 250 ml saline overthe same 30-min period. 1 The effects of the terbutalinewere found to be moderately increased (RR interval + 0.09 s;QTc + 0.01 s; diastolic pressure + 8 mmHg; systolic pressurereduced; serum calcium + 0.13 mg/dl; glucose + 9 mg/dl) butthe size of all of the changes was only small. Theconclusion was reached that there appear to be no goodreasons for avoiding their concurrent use, for example inthe emergency treatment of asthma and other conditions.

Tyramine-rich foods + Cimetidine

A woman on cimetidine experienced a severe headachewith hypertension when she drank Bovril and ate somecheese.

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A woman of 77 with hiatus hernia, on 400 mg cimetidine fourtimes daily for three years, experienced a severe frontalheadache and hypertension which appeared to be related tothe ingestion of a cup of Bovril and some English cheddarcheese, both of which can contain substantial amounts oftyramine. 1 Although the authors point out the similaritybetween this reaction and that which is seen in patients onMAOI who eat tyramine-rich foods (see ‘MAOIs + Tyramine-richfoods’), there is no satisfactory explanation for whatoccurred. This is an isolated report and there is no reasonwhy patients in general on cimetidine should avoid tyramine-rich foods.

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Sympathomimetic drug interactions

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