risk/benefit assessment of antihypertensive drugs in pregnancy
TRANSCRIPT
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important. The response to treatment should be assessed individually as intrinsic patient variability may give rise to differences in adverse effects between the various agents. Although twice daily timolol is probably most effective in lowering lOP, if there is a history of respiratory disease, timolol (and the other nonselective agents) should be avoided; betaxolol should only be used with extreme caution in this situation. However, in the absence of a history of respiratory disease, betaxolol may be the agent of first choice (because of the lower risk of precipitating systemic adverse effects), although it may cause more stinging on instillation. 1
All patients receiving B-blockers should be carefully assessed with regard to both lOP and adverse effects. Ocular B-blockers can be used concomitantly with other
antiglaucoma medications (e.g. miotics and carbonic anhydrase inhibitors), but their combined action with adrenaline (epinephrine) is suspect, particularly in the case of nonselective agents. 1 The use of systemic B-blockers together with ocular B-blockers is perhaps best avoided, particularly as they may decrease retinal perfusion. Concomitant use of calcium antagonists may result in serious bradycardia, particularly in the case of verapami1.6
References I. Brooks AMV, Gillies WE. Drugs and Aging 2: 208-221, 1992 2. HurvitzLM,et al. Drugs 41: 514-532, 1991 3. Akingbehin T, Villada JR. Brit J Ophth 75: 519-523, !991 4. Allen Re, et al. Am J Ophth 101: 535-541,1986 5. Berry DP, et al. Arch Ophth 102: 42-45, 1984 6. Gerber SL, et al. Survey a/Ophthalmology 35: 205-218, 1990
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RisklBenefit Assessment of Antihypertensive Drugs in Pregnancy
Many drugs are available for the treatment of hypertension in pregnancy, but caution is required as treatment involves consideration of both the mother and fetus.!
Definitions and Pathophysiology Hypertension during pregnancy can be categorised as
pregnancy-induced hypertension (PIH), a condition specific to pregnancy, or chronic hypertension.2 However, many terms exist to classify these disorders, and some
.. ........ -.
classification systems are fairly complex. PIH has been defined according to the following criteria:2
Blood pressure> 140/90mm Hg, or a rise in diastolic blood pressure of > 25mm Hg from that of early pregnancy. Present in a primigravida. Onset after 20 weeks' gestation.
• No history of hypertension or renal disease. Blood pressure returns to normal by 3 months postpartum.
Pre-eclampsia is regarded as PIH with proteinuria, oedema, or both. The hypertension in pre-eclampsia is due to vasospasm and increased peripheral resistance. 3,4 The cause of the vasospasm is unknown, but vascular sensitivity to angiotensin II and other pressor agents is known to be
Table 1. Risks and benefits of drugs used in the short term management of severe hypertension in pregnancy [data from Kyle & Redman,1 unless otherwise stated]
Drug Dosage
Hydralazinet Smg IV bolus then S· 1 Omg every 20·30 min3
labetalol SO- 1 OOmg IV every 20-30 min, up to 200mg
Nifedipine S-20mg orally I as capsu les)
Diozoxide 30-60mg IV minibolus doses every 1 0-l S min
Sodium ntrate to achieve nitroprusside desired effect
o One report.
Maternal (M) and fetal (F) risks
Headache, Hushing, palpitations, nausea, vomiting 1M); passible lupus-like reactian 1M + F)O, bradycardia (F)
Flushing, tremulousness (M)3
Faciol Rushing, headache, palpitations 1M)
Unpredictoble effects on BP, leading to cerebrol ischaemia 1M) and fetal distress; fetal and neanatal hyperbilirubinaemia and thrombocytopenia
possible cyanide paisoning and metabolic acidosis 1M + F)
t Availoble in Germany os dihydrolazine ! dosage: 6.2S-12.Smg IV).
Vol. 1, No.1; January 25, 1993
Effective; has been used for nearly 40 years
Relotively free of moternol adverse effects and appears to be safe for the fetus
Rapid onset of action, apparent lock of fetal odverse effects
Comments
Onset of action is within 20-30 min. Degree of BP reduction can be variable
Not as much experience with its use as hydralazine
lock of data from controlled trials; tocolytic potential; concurrent treatment with mognesium may have a synergistic effect
Reserve for women with severe hypertension unresponsive to other agents
Use only in extreme emergencies
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. ....... -. Table 2. Risks and benefits of drugs used in the long term management of hypertension in pregnancy1
Drug Dosage Maternal (M) and fetal (F) risks Benefits Comments
Methyldopa 250mg 3 times doily, Sedation, depression, Effective M.ethyldopo is the only anti-increased up to dizziness (M) hypertensive drug which has 2-3 g/day been evaluated and shown
to be sofe for the developing child
f3.-Adrenoceptor eNS effects (especially propranolol), Effective, few maternal Avoid long tenn use due to bkx:kers risk of bron~sm in patients with adverse effects possible limiting effect on fetal
asthma (M); bradycardia, growth growth retordotion (F)
Lobetolol l00mg 3 or 4 times Scalp tin~ling, tremulousness, Effective No long tenn paediatric doily, increased up to postural ypotension, headache, studies are available 1200 mg/ day (maximum) increase in platelet count (M)a
Prazosin Storting dose: 0.5 mg/day Effective Reports of prazosin use in (preferably at night); pregnancy are limited i ncrea se as necessary up to 2Omg/ day (maximum)
Nifedipine IOmg twice do:t;ncreased Effective, well tolerated Promising results require ufo to 120 mg/ (as con~rmotion in controlled trials sow-release toblets)
Diuretics Potential for intrauterine growth Use only in cases of pulmonary relar~ due to decrease in plasma oedema and carclioc disorderS volume, raised serum urate, hypokaioemia, hyponotroemia (M)
a Reported but not confirmed_ b Has not been reported with diuretic use.
increased in patients with pre-eclampsia. It has been hypothesised that the vasospasm is due to an imbalance of vasoconstrictor and vasodilating prostaglandins. Another theory is that endothelial cell function is disturbed, perhaps via an immune-mediated mechanism, leading to increased platelet activation and intravascular coagulation. The incidence of pre-eclampsia is about 7%, and is most common in young primigravidae. Risk factors for its development include:3
• Nulliparity • A mother or sister with a history of the disorder
Presence of hypertension or renal disease • Multiple pregnancy.
Treatment Aims It is important to recognise that pre-eclampsia is
primarily a placental disorder, and treatment is probably only palliative. As hypertension in pregnancy occurs for only a short period, the aims of treatment are different to those in non-obstetric practice. These aims are:
To prevent maternal morbidity and mortality. To improve maternal and perinatal outcome by preventing or ameliorating pre-eclampsia and its resultant complications.
It is necessary to treat severe hypertension (~ 1701110mm Hg) because of the risk of cerebral haemorrhage in women who develop pre-eclampsia or eclampsia. However, the indications for treatment of mild to moderate hypertension (140 to 169/90 to 109mm Hg) are less clear, and there is no consensus regarding treatment at present.
Short Term Management of Severe Hypertension Drugs that have been used in this setting are described
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in table 1. Most experience has been with hydralazine, given either intravenously or intramuscularly; however, the onset of action is slower (30 to 40 min) with the latter route of administration. Labetalol is a combined (X- and B-adrenoceptor blocker, affecting (X- and B-receptors in the ratio of 1 : 7. It is also given intravenously; the dose required to lower blood pressure may vary considerably. Calcium antagonists are increasingly being used in obstetric practice because of their ease of administration and rapid onset of action. 1 Most experience has been with nifedipine, but information on the safety of this drug remains incomplete until large, controlled follow-up studies are performed.
Diazoxide should only be used for the occasional case of hypertension unresponsive to other therapy, and sodium nitroprusside should be reserved for extreme emergencies only.
Long Term Management of Hypertension The risks and benefits of drugs used in this setting are
summarised in table 2. Methyldopa, a central (X2-
adrenoceptor agonist, has an excellent maternal and fetal safety record, and is the only antihypertensive drug that has been shown to be safe for the developing child. It can therefore be regarded as first-line therapy.
Prospective controlled trials of B-adrenoceptor blockers have shown varying and sometimes conflicting results for mother and fetus. 1 Their long term use should be avoided because of possible effects on fetal growth.
Labetalol is effective when given orally in this situation, and appears to be as safe as methyldopa with regard to the fetus, but long term paediatric studies have not been performed. Reports of the use of (X]-adrenoceptor antagonists (e.g. prazosin) in pregnancy are limited, but neonatal outcome appears to be normal. Results with long term nifedipine are encouraging, but data from controlled trials are lacking.
Vol. I, No.1; January 25,1993
. ....... -. Table 2. Risks and benefits of drugs used in the long term management of hypertension in pregnancy1
Drug Dosage Maternal (M) and fetal (F) risks Benefits Comments
Methyldopa 250mg 3 times doily, Sedation, depression, Effective M.ethyldopo is the only anti-increased up to dizziness (M) hypertensive drug which has 2-3 g/day been evaluated and shown
to be sofe for the developing child
f3.-Adrenoceptor eNS effects (especially propranolol), Effective, few maternal Avoid long tenn use due to bkx:kers risk of bron~sm in patients with adverse effects possible limiting effect on fetal
asthma (M); bradycardia, growth growth retordotion (F)
Lobetolol l00mg 3 or 4 times Scalp tin~ling, tremulousness, Effective No long tenn paediatric doily, increased up to postural ypotension, headache, studies are available 1200 mg/ day (maximum) increase in platelet count (M)a
Prazosin Storting dose: 0.5 mg/day Effective Reports of prazosin use in (preferably at night); pregnancy are limited i ncrea se as necessary up to 2Omg/ day (maximum)
Nifedipine IOmg twice do:t;ncreased Effective, well tolerated Promising results require ufo to 120 mg/ (as con~rmotion in controlled trials sow-release toblets)
Diuretics Potential for intrauterine growth Use only in cases of pulmonary relar~ due to decrease in plasma oedema and carclioc disorderS volume, raised serum urate, hypokaioemia, hyponotroemia (M)
a Reported but not confirmed_ b Has not been reported with diuretic use.
increased in patients with pre-eclampsia. It has been hypothesised that the vasospasm is due to an imbalance of vasoconstrictor and vasodilating prostaglandins. Another theory is that endothelial cell function is disturbed, perhaps via an immune-mediated mechanism, leading to increased platelet activation and intravascular coagulation. The incidence of pre-eclampsia is about 7%, and is most common in young primigravidae. Risk factors for its development include:3
• Nulliparity • A mother or sister with a history of the disorder
Presence of hypertension or renal disease • Multiple pregnancy.
Treatment Aims It is important to recognise that pre-eclampsia is
primarily a placental disorder, and treatment is probably only palliative. As hypertension in pregnancy occurs for only a short period, the aims of treatment are different to those in non-obstetric practice. These aims are:
To prevent maternal morbidity and mortality. To improve maternal and perinatal outcome by preventing or ameliorating pre-eclampsia and its resultant complications.
It is necessary to treat severe hypertension (~ 1701110mm Hg) because of the risk of cerebral haemorrhage in women who develop pre-eclampsia or eclampsia. However, the indications for treatment of mild to moderate hypertension (140 to 169/90 to 109mm Hg) are less clear, and there is no consensus regarding treatment at present.
Short Term Management of Severe Hypertension Drugs that have been used in this setting are described
ISSN 1172-0360/93/0125-013/$1.00 ©Adis International lid
in table 1. Most experience has been with hydralazine, given either intravenously or intramuscularly; however, the onset of action is slower (30 to 40 min) with the latter route of administration. Labetalol is a combined (X- and B-adrenoceptor blocker, affecting (X- and B-receptors in the ratio of 1 : 7. It is also given intravenously; the dose required to lower blood pressure may vary considerably. Calcium antagonists are increasingly being used in obstetric practice because of their ease of administration and rapid onset of action. 1 Most experience has been with nifedipine, but information on the safety of this drug remains incomplete until large, controlled follow-up studies are performed.
Diazoxide should only be used for the occasional case of hypertension unresponsive to other therapy, and sodium nitroprusside should be reserved for extreme emergencies only.
Long Term Management of Hypertension The risks and benefits of drugs used in this setting are
summarised in table 2. Methyldopa, a central (X2-
adrenoceptor agonist, has an excellent maternal and fetal safety record, and is the only antihypertensive drug that has been shown to be safe for the developing child. It can therefore be regarded as first-line therapy.
Prospective controlled trials of B-adrenoceptor blockers have shown varying and sometimes conflicting results for mother and fetus. 1 Their long term use should be avoided because of possible effects on fetal growth.
Labetalol is effective when given orally in this situation, and appears to be as safe as methyldopa with regard to the fetus, but long term paediatric studies have not been performed. Reports of the use of (X]-adrenoceptor antagonists (e.g. prazosin) in pregnancy are limited, but neonatal outcome appears to be normal. Results with long term nifedipine are encouraging, but data from controlled trials are lacking.
Vol. I, No.1; January 25,1993
--Antihypertensive drugs of choice in the second and third trimesters 1
Long term administration
• Methyldopa
Short term administration • Intravenous hydralazine; ar • Oral nifedipine
Drugs to Avoid in Pregnancy ACE inhibitors are contraindicated in pregnancy as they
may cause severe fetal disturbances. Diuretics should be avoided except in cases of pulmonary oedema or cardiac disturbances. B-B10ckers are probably safe for short term control of blood pressure in the latter part of pregnancy but should not be administered long term as they can adversely affect fetal growth. 1
References 1. Kyle PM, Redman CWG. Drug Safety 7: 223-224, 1992 2. Brown MA. Aust NZ J Med 21: 257-273, 1991 3. McCombs J. Clinical Pharmacy 11: 236-245,1992 4. Cunningham FG, et al. N Engl J Med 326: 927-932, 1992
Drug Interactions with the Macrolide Antibiotics
The macrolides are widely used in the treatment of patients with community-acquired respiratory tract and skin and soft tissue infections, and are generally well tolerated. However, such patients are often treated with concomitant medications for a variety of reasons and there exists a potential for pharmacokinetic drug interactions.
Interaction Potential of Individual Macrolides
Since the introduction of the original macrolide erythromycin in the 1950s, a number of reports have incriminated these drugs as a potential source of clinically important drug interactions. Such interactions are thought to principally occur through inhibition of hepatic drug metabolism and the formation of inactive microsomal enzyme complexes. However, the various analogues of this class differ in their potential to induce such reactions and may be classified into 3 groups accordingly (table l).t
Troleandomycin (triacetyloleandomycin) and erythromycin are prone to inactivate cytochrome P450 complex and have a high interaction potential. Newer agents such as clarithromycin, flurithromycin, josamycin, midecamycin, miocamycin and roxithromycin form complexes to a lesser extent and are rarely associated with drug interactions. Azithromycin, dirithromycin, rokitamycin and spiramycin do not inactivate cytochrome P450 and do
t Several of the newer macrolides discussed in this review are not yet generally available.
Vol. 1, No.1; January 25,1993
not appear to modify the pharmacokinetic profile of other drugs. 1
Clinically Important Pharmacokinetic Interactions
Although erythromycin is a less potent inhibitor of microsomal metabolism than troleandomycin, both these drugs have been associated with major clinically significant interactions (table 2). Indeed, troleandomycin and erythromycin may cause ergotism when administered concomitantly with ergot alkaloids and may decrease the clearance and/or increase serum concentrations of concomitantly administered carbamazepine, theophylline, or triazolam with possible consequent increased or toxic effects.2-7 Erythromycin may also reduce the clearance and/or increase serum concentrations of bromocriptine, cyclosporin, digoxin, warfarin, and the nonsedating antihistamines terfenadine and astemizole, which again may result in increased effects or toxicity of these drugs. 1,9-11
Troleandomycin has been reported to cause cholestatic jaundice when administered with oral contraceptive steroids, 1 ,8 an effect that has been attributed to inhibition of steroid metabolism. Thus, concurrent administration of erythromycin or troleandomycin with drugs that have been implicated in such pharmacokinetic interactions should be avoided (or considered only with close patient monitoring), especially as other macrolides with less interaction potential are available.
Josamycin, midecamycin and possibly the related compounds, clarithromycin, flurithromycin and miocamycin, may cause a clinically significant interaction with carbamazepine and cyclosporin requiring close monitoring. I Patient monitoring also appears prudent when clarithromycin and theophylline are given together, although the interaction between roxithromycin and drugs such as theophylline or cyclosporin does not seem to require dosage adjustment. No pharmacokinetic interactions have been reported with azithromycin, dirithromycin, rokitamycin or spiramycin. 1
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Table 1. Potential af macralide antibiotics ta cause clinically important pharmacokinetic interactions with other drugs
Interaction potential
High (frequently cause drug interactions)O
Law (seldom cause drug interactians)b
Minimal (nat incriminated in causing drug interactions)
Macrolides
Erythromycin T roleondomycin
Clarithromycin Flurithramycin Josamycin Midecamycin Miocamycin Roxithromycin
Azithromycin Dirithramycin Rakitamycin Spiramycin
a Avoid concurrent use with drugs whose metabolism is known to be offected (see table 2) or undertake with caution (with appropriate patient monitoring).
b Undertake concomitant administration with certain drugs (see table 2) with caution (roxithromycin excepted).
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--Antihypertensive drugs of choice in the second and third trimesters 1
Long term administration
• Methyldopa
Short term administration • Intravenous hydralazine; ar • Oral nifedipine
Drugs to Avoid in Pregnancy ACE inhibitors are contraindicated in pregnancy as they
may cause severe fetal disturbances. Diuretics should be avoided except in cases of pulmonary oedema or cardiac disturbances. B-B10ckers are probably safe for short term control of blood pressure in the latter part of pregnancy but should not be administered long term as they can adversely affect fetal growth. 1
References 1. Kyle PM, Redman CWG. Drug Safety 7: 223-224, 1992 2. Brown MA. Aust NZ J Med 21: 257-273, 1991 3. McCombs J. Clinical Pharmacy 11: 236-245,1992 4. Cunningham FG, et al. N Engl J Med 326: 927-932, 1992
Drug Interactions with the Macrolide Antibiotics
The macrolides are widely used in the treatment of patients with community-acquired respiratory tract and skin and soft tissue infections, and are generally well tolerated. However, such patients are often treated with concomitant medications for a variety of reasons and there exists a potential for pharmacokinetic drug interactions.
Interaction Potential of Individual Macrolides
Since the introduction of the original macrolide erythromycin in the 1950s, a number of reports have incriminated these drugs as a potential source of clinically important drug interactions. Such interactions are thought to principally occur through inhibition of hepatic drug metabolism and the formation of inactive microsomal enzyme complexes. However, the various analogues of this class differ in their potential to induce such reactions and may be classified into 3 groups accordingly (table l).t
Troleandomycin (triacetyloleandomycin) and erythromycin are prone to inactivate cytochrome P450 complex and have a high interaction potential. Newer agents such as clarithromycin, flurithromycin, josamycin, midecamycin, miocamycin and roxithromycin form complexes to a lesser extent and are rarely associated with drug interactions. Azithromycin, dirithromycin, rokitamycin and spiramycin do not inactivate cytochrome P450 and do
t Several of the newer macrolides discussed in this review are not yet generally available.
Vol. 1, No.1; January 25,1993
not appear to modify the pharmacokinetic profile of other drugs. 1
Clinically Important Pharmacokinetic Interactions
Although erythromycin is a less potent inhibitor of microsomal metabolism than troleandomycin, both these drugs have been associated with major clinically significant interactions (table 2). Indeed, troleandomycin and erythromycin may cause ergotism when administered concomitantly with ergot alkaloids and may decrease the clearance and/or increase serum concentrations of concomitantly administered carbamazepine, theophylline, or triazolam with possible consequent increased or toxic effects.2-7 Erythromycin may also reduce the clearance and/or increase serum concentrations of bromocriptine, cyclosporin, digoxin, warfarin, and the nonsedating antihistamines terfenadine and astemizole, which again may result in increased effects or toxicity of these drugs. 1,9-11
Troleandomycin has been reported to cause cholestatic jaundice when administered with oral contraceptive steroids, 1 ,8 an effect that has been attributed to inhibition of steroid metabolism. Thus, concurrent administration of erythromycin or troleandomycin with drugs that have been implicated in such pharmacokinetic interactions should be avoided (or considered only with close patient monitoring), especially as other macrolides with less interaction potential are available.
Josamycin, midecamycin and possibly the related compounds, clarithromycin, flurithromycin and miocamycin, may cause a clinically significant interaction with carbamazepine and cyclosporin requiring close monitoring. I Patient monitoring also appears prudent when clarithromycin and theophylline are given together, although the interaction between roxithromycin and drugs such as theophylline or cyclosporin does not seem to require dosage adjustment. No pharmacokinetic interactions have been reported with azithromycin, dirithromycin, rokitamycin or spiramycin. 1
.. ......... .-.
Table 1. Potential af macralide antibiotics ta cause clinically important pharmacokinetic interactions with other drugs
Interaction potential
High (frequently cause drug interactions)O
Law (seldom cause drug interactians)b
Minimal (nat incriminated in causing drug interactions)
Macrolides
Erythromycin T roleondomycin
Clarithromycin Flurithramycin Josamycin Midecamycin Miocamycin Roxithromycin
Azithromycin Dirithramycin Rakitamycin Spiramycin
a Avoid concurrent use with drugs whose metabolism is known to be offected (see table 2) or undertake with caution (with appropriate patient monitoring).
b Undertake concomitant administration with certain drugs (see table 2) with caution (roxithromycin excepted).
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