Pharmacy Blog – Dr Vibore

Blood pressure may fall sharply when calcium-channel blockersare first given to patients already taking alpha blockers (particularly prazosin and terazosin),and vice versa. In a small study,tamsulosin did not have any clinically relevant effects on bloodpressure well controlled by nifedipine. Verapamil may increasethe AUC of prazosin and terazosin. Alpha blockers and calcium-channel blockers may be combined for additional blood pressurelowering in patients with hypertension.

1. Doxazosin. Although there was a tendency for first-dose hypotension no serious adverse events or postural symptoms were seen in 6 normotensive subjects given nifedipine 20mg twice daily for 20 days, with doxazosin 2mg once daily for last 10 days. The same results were noted in 6 other normotensive subjects given drugs in opposite order. No pharmacokinetic interactions were found.(See reference number 1) However, US manufacturers note a study in which slight (less than 20%) alterations were found in pharmacokinetics of nifedipine and doxazosin when they were given concurrently. As would be expected,blood pressures were lower when both drugs were given.(See reference number 2)

Prazosin. In a placebo-controlled,crossover study 12 hypertensive subjects were given nifedipine 20 mg and prazosin 2 mg, separated by one hour. Concurrent use reduced blood pressure more than either drug alone,but when prazosin was given after nifedipine its effects were delayed (See reference number 3). Two patients with severe hypertension given prazosin 4 or 5mg experienced a sharp fall in blood pressure shortly after being given nifedipine sublingually. One of them complained of dizziness and had a reduction in standing blood pressure from 232/124 to 88/48 mmHg about 20 minutes after taking nifedipine 10 mg. However, in a further 8 patients with hypertension taking prazosin, reduction in blood pressure 20 minutes after addition of sublingual nifedipine was smaller (mean reduction of 25/12 mmHg when lying and 24/17 mmHg when standing) (See reference number 4). It is not clear what contribution prazosin had to effect seen with sub-lingual nifedipine, since experiment was not repeated using a prazosin placebo, but blood pressure in these patients had earlier remained unchanged 1 hour after taking prazosin alone. Note that sublingual nifedipine alone may cause a dangerous drop in blood pressure.

Tamsulosin. In a placebo-controlled study in 8 hypertensive men with blood pressure well controlled by nifedipine, addition of tamsulosin 400 micrograms daily for 7 days then 800 micrograms daily for a further 7 days had no clinically relevant effect on blood pressure (assessed after 6 and 14 days of tamsulosin). In addition, no first-dose hypotension was seen on first day of tamsulosin, or when tamsulosin dose was increased (See reference number 5).

Terazosin. Retrospective analysis of a large multinational study in patients given terazosin 5 or 10mg daily found that terazosin only affected blood pressure of patients taking calcium-channel blockers (amlodipine, felodipine, flunarizine, isradipine and nifedipine) if blood pressure was uncontrolled. No change in blood pressure was seen in those with normal blood pressure (i.e. those without hypertension and those with hypertension controlled by calcium-channel blockers). The most common adverse effect in 10-week terazosin phase was dizziness, and incidence of this appeared to be lower in those taking antihypertensives (13 to 16%) than those not taking antihypertensives (21 to 25%) (See reference number 6).

The US manufacturers note that when diltiazem 240mg daily was given with alfuzosin 2.5mg three times daily maximum serum levels and AUC of alfuzosin were raised by 50 % and 30%, respectively, and maximum serum levels and AUC of diltiazem were raised by 40%. However,no changes in blood pressure were seen (See reference number 7).

Prazosin. A study in 8 normotensive subjects given a single 1mg dose of prazosin found that peak serum prazosin levels were raised by 85 % (from 5.2 to 9.6 nanograms/mL) and prazosin AUC was increased by 62 % when it was given with a single 160mg dose of verapamil. The standing blood pressure,which was unchanged after verapamil alone, fell from 114/82 to 99/81 mmHg with prazosin alone, and was further reduced to 89/68 mmHg when both drugs were given together (See reference number 8). A similar pharmacokinetic interaction was noted in another study in hypertensive patients (See reference number 9). In this study, first 1mg dose of prazosin alone caused a 23 mmHg fall in standing systolic blood pressure, and half patients (3 of 6) experienced symptomatic postural hypotension. A similar fall in blood pressure occurred when first 1mg dose of prazosin was given to 6 patients who had been taking verapamil for 5 days, and 2 patients experienced symptomatic postural hypotension (See reference number 9).

Tamsulosin. A study into safety of tamsulosin, with particular regard to use of other medications, found that concurrent use of verapamil increased risk of adverse events related to tamsulosin treatment by threefold. The use of other calcium-channel blockers (not specified) did not appear to increase adverse effects,although there was a trend towards an increase (See reference number 10).

Terazosin. When verapamil 120mg twice daily was added to terazosin 5mg daily in 12 hypertensive patients, peak plasma levels and AUC of terazosin were increased by about 25%. In contrast, in another 12 patients taking verapamil 120mg twice daily, addition of terazosin

(1 mg increased to 5mg daily) had no effect on verapamil pharmacokinetics (See reference number 11). Both groups of patients had significant falls in standing blood pressure when they first started taking both drugs. Symptomatic orthostatic hypotension (which lessened within about 3 weeks) occurred in 4 patients when verapamil was first added to terazosin,and in 2 patients when terazosin was first added to verapamil (See reference number 11).

Not fully understood. It would seem that vasodilatory effects of alpha blockers and calcium-channel blockers can be additive or synergistic, particularly after first dose (See reference number 1,12). The fall in blood pressure seen with prazosin and verapamil may, in part, result from a pharmacokinetic interaction,(See reference number 12)as does interaction between alfuzosin and diltiazem. Tamsulosin possibly has less effect on blood pressure since it has some selectivity for alpha receptors in prostate (see Alpha blockers,).

The interaction between calcium-channel blockers and alpha blockers would appear to be established and of clinical importance, although documentation is limited. Marked additive hypotensive effects can occur when concurrent use is first started,particularly with alfuzosin, bunazosin, prazosin and terazosin; but see also Alpha blockers, . It is recommended that patients already taking calcium-channel blockers should have their dose of calcium-channel blocker reduced and begin with a low-dose of alpha blocker, with first dose taken just before going to bed. Caution should also be exercised when calcium-channel blockers are added to established treatment with an alpha blocker. Patients should be warned about possibilities of exaggerated hypotension, and told what to do if they feel faint and dizzy. There is limited evidence that terazosin and tamsulosin may not cause an additional hypotensive effect in longer term in patients with BPH who have hypertension already well-controlled with calcium-channel blockers. Nevertheless, caution should be exercised in this situation, and a dose reduction of calcium-channel blocker may be required. It seems likely that any pharmacokinetic interaction will be accounted for by this dose titration.

1.

Donnelly R,Elliott HL, Meredith PA, Howie CA, Reid JL. The pharmacodynamics and pharmacokinetics of the combination of nifedipine and doxazosin. Eur J Clin Pharmacol (1993) 44, 279–82.

2.

Adalat CC (Nifedipine). Bayer HealthCare. US Prescribing information,August 2005.

3.

Kiss I,Farsang C. Nifedipine-prazosin interaction in patients with essential hypertension.Cardiovasc Drugs Ther (1989) 3, 413–15.

4.

Jee LD,Opie LH. Acute hypotensive response to nifedipine added to prazosin in treatment ofhypertension. BMJ (1983) 287, 1514.

5.

Starkey LP,Yasukawa K, Trenga C, Miyazawa Y, Ito Y. Study of possible pharmacodynamicinteraction between tamsulosin and nifedipine in subjects with essential hypertension. J Clin Pharmacol (1994) 34, 1019.

6.

Kirby RS. Terazosin in benign prostatic hyperplasia: effects on blood pressure in normotensive and hypertensive men. Br J Urol (1998) 82,373–9.

7.

Uroxatral (Alfuzosin hydrochloride extended-release tablets). Sanofi-Aventis US LLC. USPrescribing information,March 2007.

8.

Pasanisi F,Elliott HL, Meredith PA, McSharry DR, Reid JL. Combined alpha adrenoceptorantagonism and calcium channel blockade in normal subjects. Clin Pharmacol Ther (1984) 36, 716–23.

9.

Elliott HL,Meredith PA, Campbell L, Reid JL. The combination of prazosin and verapamilin the treatment of essential hypertension. Clin Pharmacol Ther (1988) 43, 554–60.

Michel MC,Bressel H-U, Goepel M, Rübben H. A 6-month large-scale study into the safetyof tamsulosin. Br J Clin Pharmacol (2001) 51, 609–14.

Lenz ML,Pool JL, Laddu AR, Varghese A, Johnston W, Taylor AA. Combined terazosin andverapamil therapy in essential hypertension. Hemodynamic and pharmacodynamic interactions. Am J Hypertens (1995) 8, 133–45.

Meredith PA,Elliott HL. An additive or synergistic drug interaction: application of concentration-effect modeling. Clin Pharmacol Ther (1992) 51, 708–14.

Trazodone can make driving or handling other dangerous machinery more hazardous, particularly during first few days oftreatment, and further impairment may occur with alcohol.

Clinical evidence,mechanism, importance and management

A study in 6 healthy subjects comparing effects of single-doses of amitriptyline 50mg and trazodone 100mg found that both drugs impaired performance of a number of psychomotor tests, causing drowsiness and reducing clearheadedness to approximately same extent. Only manual dexterity was further impaired when subjects taking trazodone were given sufficient alcohol to give blood levels of about 40 mg% (See reference number 1).

Another study similarly found that impairment of psychomotor performance by trazodone was increased by alcohol.(See reference number 2) This appears to be due to a simple additive depression of CNS. This is an established interaction,and of practical importance. Patients should be warned that their ability to drive,handle dangerous machinery or to do other tasks needing complex psychomotor skills might be impaired by trazodone, and further worsened by alcohol.

Warrington SJ,Ankier SI, Turner P. Evaluation of possible interactions between ethanol andtrazodone or amitriptyline. Neuropsychobiology (1986) 15 (Suppl 1), 31–7.

Tiller JWG. Antidepressants,alcohol and psychomotor performance. Acta Psychiatr Scand (1990) (Suppl 360), 13–17.

1. Li J,Jiang Q-G, Zhong W-D. Persistent ethanol drinking increases liver injury induced by trinitrotoluene exposure: an in-plant case-control study. Hum Exp Toxicol (1991) 10, 405–9.

Some individuals exposed to xylene vapour,who subsequentlydrink alcohol, may experience dizziness and nausea. A flushingskin reaction has also been seen.

Clinical evidence,mechanism, importance and management

0.8 g/kg of alcohol found that about 10 to 20 % experienced dizziness and nausea (See reference number 1,2). One subject exposed to 300 ppm of m-xylene vapour developed a conspicuous dermal flush on his face,neck, chest and back. He also showed some erythema with alcohol alone (See reference number 3). A study using a population-based pharmacokinetic and pharmacodynamic model predicted that probability of experiencing CNS effects following exposure to xylene at current UK occupational exposure standard (100 ppm time-weighted average over 8 hours) increased markedly and non-linearly with alcohol dose (See reference number 4).

The reasons for these reactions are not fully understood, but it is possible that xylene plasma levels are increased because alcohol impairs its metabolic clearance by cytochrome P450 isoenzyme CYP2E1 (See reference number 4). After alcohol intake,blood xylene levels have been reported to rise about 1.5- to 2-fold;(See reference number 2) acetaldehyde levels may also be transiently increased (See reference number 2).

Alcoholic beverages are quite often consumed during lunchtime or after work, and since excretion of xylene is delayed by its high solubility and storage in lipid-rich tissues, simultaneous presence of xylene and alcohol in body is probably not uncommon and could result in enhancement of toxicity of xylene (See reference number 5).

Savolainen K,Riihimäki V, Vaheri E, Linnoila M. Effects of xylene and alcohol on vestibularand visual functions in man. Scand J Work Environ Health (1980) 6, 94–103.

Riihimäki V,Savolainen K, Pfäffli P, Pekari K, Sippel HW, Laine A. Metabolic interaction between m-xylene and ethanol. Arch Toxicol (1982) 49, 253–63.

Riihimäki V,Laine A, Savolainen K, Sippel H. Acute solvent-ethanol interactions with specialreference to xylene. Scand J Work Environ Health (1982) 8, 77–9.

MacDonald AJ,Rostami-Hodjegan A, Tucker GT, Linkens DA. Analysis of solvent centralnervous system toxicity and ethanol interactions using a human population physiologicallybased kinetic and dynamic model. Regul Toxicol Pharmacol (2002) 35, 165–76.

Lieber CS. Microsomal ethanol-oxidizing system. Enzyme (1987) 37,45–56.

The selective and non-selective alpha blockers are categorised and listed in table 1 below,(see below). The principal interactions of alpha blockers are those relating to enhanced hypotensive effects. Early after introduction of selective alpha blockers it was discovered that, in some individuals, they can cause a rapid reduction in blood pressure on starting treatment (also called first-dose effect or first-dose hypotension). The risk of this may be higher in patients already taking other antihypertensive drugs. The first-dose effect has been minimised by starting with a very low dose of alpha blocker, and then escalating dose slowly over a couple of weeks. A similar hypotensive effect can occur when dose of alpha blocker is increased, or if treatment is interrupted for a few days and then re-introduced. Some manufacturers recommend giving first dose on retiring to bed, or if not, avoiding tasks that are potentially hazardous if syncope occurs (such as driving) for first 12 hours. If symptoms such as dizziness,fatigue or sweating develop, patients should be warned to lie down, and to remain lying flat until they abate completely.

It is unclear whether there are any real differences between alpha blockers in their propensity to cause this first-dose effect. With exception of indoramin, postural hypotension, syncope, and dizziness are listed as adverse effects of alpha blockers available in UK and for most it is recommended that they should be started with a low dose and titrated as required. Tamsulosin is reported to have some selectivity for alpha receptor 1A subtype, which are found mostly in prostate, and therefore have less effect on blood pressure: an initial titration of dose is therefore not considered to be necessary. Nevertheless, it would be prudent to exercise caution with all drugs in this class.

Alpha blockers are also used to increase urinary flow-rate and improve obstructive symptoms in benign prostatic hyperplasia. In this setting,their effects on blood pressure are more of an adverse effect, and their additive hypotensive effect with other antihypertensives may not be beneficial.

Table 1 Alpha blockers
Drug	Principal indications
Selective alpha1 blockers (Alpha blockers)
Alfuzosin	BPH
Bunazosin	Hypertension
Doxazosin	BPH; Hypertension
Indoramin	BPH; Hypertension; Migraine
Prazosin	BPH; Heart failure; Hypertension; Raynaud’s syndrome
Tamsulosin	BPH
Terazosin	BPH; Hypertension
Other drugs with alpha-blocking actions
Moxisylate	Peripheral vascular disease; Erectile dysfunction
Phenoxybenzamine	Hypertensive episodes in phaeochromocytoma; Neurogenic bladder; Shock
Phentolamine	Erectile dysfunction; Hypertensive episodes in phaeochromocytoma
Urapidil	Hypertension

One report describes 5 patients taking procarbazine whose faces became very red and hot for a short time after drinking wine (See reference number 1). Another says that flushing occurred in 3 patients taking procarbazine after they drank beer (See reference number 2). Two out of 40 patients taking procarbazine in a third study complained of facial flushing after taking a small alcoholic drink, and one patient thought that effects of alcohol were markedly increased (See reference number 3). Yet another study describes a flush syndrome in 3 out of 50 patients who drank alcohol while taking procarbazine (See reference number 4).

Unknown, but it seems possible that in man, as in rats,(See reference number 5) procarbazine inhibits acetaldehyde dehydrogenase in liver causing a disulfiram-like reaction (see Alcohol + Disulfiram interaction).

An established interaction but of uncertain incidence. It seems to be more embarrassing,possibly frightening, than serious and if it occurs it is unlikely to require treatment, however patients should be warned. The manufacturers say it is best to avoid alcohol (See reference number 6). Procarbazine is also a weak MAOI and therefore interactions with certain foodstuffs,including alcoholic drinks, especially heavy red wines, although very rare, must be borne in mind (see Procarbazine + Sympathomimetics interaction).

Mathé G,Berumen L, Schweisguth O, Brule G, Schneider M, Cattan A, Amiel JL, Schwarzenberg L. Methyl-hydrazine in the treatment of Hodgkin’s disease and various forms of haematosarcoma and leukaemia. Lancet (1963) ii, 1077–80.

Dawson WB. Ibenzmethyzin in the management of late Hodgkin’s disease. In Natulan,Ibenzmethyzin. Report of the proceedings of a symposium, Downing College, Cambridge, June1965. Jelliffe AM and Marks J (Eds). Bristol: John Wright; 1965. P. 31–4.

Todd IDH. Natulan in management of late Hodgkin’s disease,other lymphoreticular neoplasms, and malignant melanoma. BMJ (1965) 1, 628–31.

Brulé G,Schlumberger JR, Griscelli C. N-isopropyl-:5.5pt; font-weight:normal; color:#000000″>α-(2-methylhydrazino)-p-toluamide, hydrochloride (NSC-77213) in treatment of solid tumors. Cancer Chemother Rep (1965) 44, 31–

8.

Vasiliou V,Malamas M, Marselos M. The mechanism of alcohol intolerance produced by various therapeutic agents. Acta Pharmacol Toxicol (Copenh) (1986) 58, 305–10.

Matulane (Procarbazine hydrochloride). Sigma-tau Pharmaceuticals,Inc. US Prescribing Information, February 2004.

Alcohol may modestly increase clearance of procainamide

Clinical evidence,mechanism, importance and management

In 11 healthy subjects alcohol 0.73 g/kg,followed by alcohol 0.11 g/kg every hour increased clearance and decreased elimination half-life of a single 10-mg/kg oral dose of procainamide by 34 % and 25%, respectively. This was due to increased acetylation of procainamide to its active metabolite N-acetylprocainamide.(See reference number 1) The clinical relevance of these modest changes is probably small.

1. Olsen H,Mørland J. Ethanol-induced increase in procainamide acetylation in man. Br J Clin Pharmacol (1982) 13, 203–8.

Clinical evidence,mechanism, importance and management

The manufacturer says that patients taking olanzapine have shown an increased heart rate and accentuated postural hypotension when given a single-dose of alcohol (See reference number 1). In a study,9 of 11 subjects experienced orthostatic hypotension when they drank alcohol one hour after taking olanzapine 10mg (See reference number 2). No pharmacokinetic interaction has been seen (See reference number 1-3). In practical terms this means that patients should be warned of risk of faintness and dizziness if they stand up quickly. The manufacturers also say that drowsiness is a common adverse effect of olanzapine,and they warn about taking other products that can cause CNS depression, including alcohol (See reference number 3,4). The US manufacturer(See reference number 3) says that patients should not drink alcohol with olanzapine because of potential drowsiness that would result.

Zyprexa (Olanzapine). Eli Lilly. Clinical and Laboratory Experience A Comprehensive Monograph,August 1996.

Callaghan JT,Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet (1999) 37, 177–93.

Zyprexa (Olanzapine). Eli Lilly and Company. US Prescribing information,November 2006.

Zyprexa (Olanzapine). Eli Lilly and Company Ltd. UK Summary of product characteristics,September 2006.

Alcohol may possibly increase adverse effects of niclosamide

Clinical evidence,mechanism, importance and management

The manufacturer of niclosamide advises avoiding alcohol while taking niclosamide. The reasoning behind this is that while niclosamide is virtually insoluble in water, it is slightly soluble in alcohol, which might possibly increase its absorption by gut, resulting in an increase in its adverse effects. There are no formal reports of this but manufacturer says that they have some anecdotal information that is consistent with this suggestion (See reference number 1).

1. Bayer. Personal communication,July 1992.

The detrimental effects of drinking alcohol and smoking cannabismay be additive on some aspects of driving performance. However, there is some evidence that regular cannabis use per se does not potentiate effects of alcohol. Smoking cannabis may alter thebioavailability of alcohol.

Simultaneous use of alcohol and oral :8.7pt; font-weight:normal; color:#000000″>Δ(See reference number 9)-tetrahydrocannabinol (THC, major active ingredient of cannabis) reduced performance of psychomotor tests, suggesting that those who use both drugs together should expect deleterious effects to be additive (See reference number 1). In a further placebo-controlled study,subjects smoked cannabis containing 100 or 200 micrograms/kg of :8.7pt; font-weight:normal; color:#000000″>Δ(See reference number 9)-tetrahydrocannabinol and drank alcohol (to achieve an initial blood level of 70 mg%,with further drinks taken to maintain levels at 40 mg%) 30 minutes before driving. They found that cannabis,even in low to moderate doses, negatively affected driving performance in real traffic situations. Further, effect of combining moderate doses of both alcohol and cannabis resulted in dramatic performance impairment as great as that observed with blood-alcohol levels of 140 mg% alone (See reference number 2,3).

One study in 14 regular cannabis users (long-term daily use) and 14 infrequent cannabis users found that regular use reduced disruptive effects of alcohol on some psychomotor skills relevant to driving, whereas infrequent use did not have this effect. In this study, neither group had smoked any cannabis in 12 hrs before alcohol test (See reference number 4). Another study found that moderate doses of alcohol and cannabis, consumed either alone or in combination, did not produce significant behavioural or subjective impairment following day (See reference number 5).

A study in 12 healthy subjects who regularly used both cannabis and alcohol found that alcohol 0.5 g/kg significantly increased break latency without affecting body sway,whereas cannabis given as a cigarette containing tetrahydrocannabinol 3.33%,increased body sway but did not affect brake latency. There were no significant additive effects on brake latency, body sway, or mood when two drugs were used together (See reference number 6). A population-based study of 2,777 drivers involved in fatal road crashes, who drank alcohol and/or used cannabis, found that although both cannabis and alcohol increased risk of being responsible for a fatal crash, no statistically significant interaction was observed between two drugs (See reference number 7).

Fifteen healthy subjects given alcohol 0.7 g/kg developed peak plasma alcohol levels of 78.25 mg% at 50 minutes, but if they smoked a cannabis cigarette 30 minutes after drink, their peak plasma alcohol levels were only 54.8 mg% and they occurred 55 minutes later. In addition, their subjective experience of drugs decreased when used together (See reference number 8). However,another study found that smoking cannabis 10 minutes before alcohol consumption did not affect blood-alcohol levels (See reference number 5). A further study found that blood-alcohol levels were not affected by :8.7pt; font-weight:normal; color:#000000″>Δ(See reference number 9)-tetrahydrocannabinol given orally one hour before alcohol (See reference number 1).

Several studies have found that cannabis and alcohol produce additive detrimental effects on driving performance,but other studies have failed to show any potentiation. This is probably due to variety of simulated driving tests used and possibly time lag between administration of alcohol and cannabis; behavioural impairment after cannabis has been reported to peak within 30 minutes of smoking (See reference number 5). Nevertheless, both drugs have been shown to affect some aspects of driving performance and increase risk of fatal car accidents. Concurrent use of cannabis and alcohol before driving should therefore be avoided.

Bird KD,Boleyn T, Chesher GB, Jackson DM, Starmer GA, Teo RKC. Intercannabinoid andcannabinoid-ethanol interactions and their effects on human performance. Psychopharmacology (Berl) (1980) 71, 181–8.

National Highway Traffic Safety Administration. Marijuana and alcohol combined severelyimpede driving performance. Ann Emerg Med (2000) 35,398–9.

Jolly BT. Commentary: drugged driving—different spin on an old problem. Ann Emerg Med (2000) 35,399–400.

Wright KA,Terry P. Modulation of the effects of alcohol on driving-related psychomotor skillsby chronic exposure to cannabis. Psychopharmacology (Berl) (2002) 160, 213–19.

Chait LD,Perry JL. Acute and residual effects of alcohol and marijuana, alone and in combination, on mood and performance. Psychopharmacology (Berl) (1994) 115, 340–9.

Liguori A,Gatto CP, Jarrett DB. Separate and combined effects of marijuana and alcohol onmood, equilibrium and simulated driving. Psychopharmacology (Berl) (2002) 163, 399–405.

Laumon B,Gadeqbeku B, Martin J-L, Biecheler M-B; the SAM Group. Cannabis intoxicationand fatal road crashes in France: population based case-control study. BMJ (2005) 331, 1371–

6. Correction. ibid. (2006) 332,1298.

8. Lukas SE,Benedikt R, Mendelson JH, Kouri E, Sholar M, Amass L. Marihuana attenuates the rise in plasma ethanol levels in human subjects. Neuropsychopharmacology (1992) 7, 77–81.