- ACRONYMS AND DEFINITIONS
- AHA - American Heart Association
- BP - Blood pressure
- HCTZ - Hydrochlorothiazide
- HTN - Hypertension
- RCT - Randomized controlled trial
- SBP - Systolic blood pressure
- DRUGS IN CLASS
- Alpha-2 agonists
- Clonidine (Catapres®)
- Clonidine patch (Catapres-TTS®)
- Dexmedetomidine (Igalmi®) - approved for agitation in bipolar and schizophrenia [Igalmi® PI]
- Methyldopa (Aldomet®)
- Tizanidine (Zanaflex®) - approved as a muscle relaxer
- Clonidine (Kapvay®) - approved to treat ADHD
- Guanfacine (Intuniv®) - approved to treat ADHD
- Lofexidine (Lucemyra™) - approved to treat opiate withdrawal
- Combination products
- Aldoril® (HCTZ + methyldopa)
- MECHANISM OF ACTION
- Alpha-2 agonists, also called alpha-2-adrenergic agonists, stimulate alpha-2 receptors in the brain stem, which reduces sympathetic outflow and leads to decreased vascular resistance, lower blood pressure, and slower heart rate [8]
- HYPERTENSION | Clonidine
- Overview
- Clonidine was FDA-approved in 1974 and studies evaluating its effects in hypertension are older. Two trials where clonidine was compared to other antihypertensives and placebo are detailed below.
- A small crossover study published in 1977 enrolled 32 patients with hypertension
Main inclusion criteria
- DBP 105 - 129 mmHg on at least 3 separate occasions over a month
- Hypertension that was previously untreated or uncontrolled on meds
Main exclusion criteria
- Renal failure
- Heart failure
- MI in the previous year
Baseline characteristics
- Median age 54 years
- Average SBP ∼ 187 mmHg, DBP ∼ 116 mmHg
- Median duration of hypertension - 2 years
- Previous treatment with BP meds - 63%
Randomized treatment groups
- Group 1 - Clonidine titrated to effect. Average dose at the end of 12 weeks was 0.540 mg/day.
- Group 2 - Propranolol titrated to effect. Average dose at the end of 12 weeks was 576 mg/day.
- Group 3 - Placebo
- Patients received each therapy for 12 weeks with a 2-week washout period between each regimen
Primary outcome: average blood pressure at the end of the 12-week treatment period
Results
Duration: 12 weeks on each regimen | ||||
Outcome | Clonidine | Propranolol | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome (average BP) | 167/101 | 168/101 | 185/114 | 1 and 2 vs 3 p<0.01 | 1 vs 2 p>0.05 |
Average pulse | 74 | 66 | 80 | 1 and 2 vs 3 p<0.05 | 1 vs 2 p<0.01 |
|
Findings: Clonidine and propranolol were equipotent in reducing blood pressure, but clonidine has more initial side-effects than propranolol
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
- Male veteran
- DBP 95 - 109 mmHg off medications
Baseline characteristics
- Average age 59 years
- Average BP 152/99 mmHg
- Black race - 48%
- Current smoker - 32%
Randomized treatment groups
- Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
- Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
- Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
- Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
- Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
- Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
- Group 2 (186 patients) - Placebo
- There was a washout period of 4 - 8 weeks before randomization
- Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results
Average BP reduction at the end of the titration phase (SBP/DBP mmHg) | ||||||
---|---|---|---|---|---|---|
HCTZ | Atenolol | Captopril | Clonidine | Diltiazem | Prazosin | Placebo |
14 / 10 | 11 / 12 | 9 / 10 | 16 / 12 | 13 / 14 | 12 / 11 | 3 / 5 |
|
Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
- Methyldopa
- Methyldopa has been in used since the 1960s and studies evaluating its effects in hypertension are small and older. Results from a Cochrane meta-analysis that included 6 trials are provided below.
- STUDY
- A Cochrane meta-analysis evaluated trials where methyldopa was used to treat hypertension
- Included studies were small and older (1970s-1990s)
- Doses of methyldopa ranged from 500 - 2250 mg/day
- An analysis of 6 trials found the following effects:
- Methyldopa lowered the average systolic blood pressure by 13 mmHg compared to placebo
- Methyldopa lowered the average diastolic blood pressure by 8.4 mmHg compared to placebo [5]
- Findings: Methyldopa lowers blood pressure to varying degrees compared to placebo for patients with primary hypertension. Its effect on clinical outcomes, however, remains uncertain.
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- Summary
- Clonidine and methyldopa are effective at lowering blood pressure. Clonidine can have significant side effects, so it is primarily used as a fourth- or fifth-line agent in resistant hypertension.
- Methyldopa is one of the few medications that has been rated safe in pregnancy, which is where it is mostly used
- HYPERTENSIVE URGENCY
- Clonidine has a quick onset of action, with blood pressure effects occurring 30 - 60 minutes after a dose. Because it acts quickly, it is often given in ERs and clinics to lower blood pressure in patients with very high readings (SBP ≥ 180 mmHg, DBP ≥ 120 mmHg).
- See hypertensive urgency for recommendations on treating these patients
- SIDE EFFECTS
- Clonidine (Catapres®)
- Drowsiness/fatigue
- Clonidine suppresses sympathetic outflow, which can cause drowsiness and fatigue. In studies, up to 66% of patients were affected. Symptoms tend to diminish with continued treatment. [1,3,4]
- Dry mouth
- Up to two-thirds of clonidine-treated patients report dry mouth, which often improves with continued use [1,3,4]
- Dry eyes
- Clonidine can cause or worsen dry eyes, which may irritate contact wearers and people with chronic dry eyes
- Constipation
- Decreased sympathetic outflow can lead to constipation
- In studies, up to 10% of patients on clonidine have experienced constipation [1]
- Dizziness
- In studies, up to 16% of patients on clonidine have experienced dizziness [1,3]
- Slow heart rate (bradycardia)
- Clonidine can slow the heart rate and cause bradycardia. In one small study, the average resting heart rate decreased by 7 beats per minute in clonidine-treated patients. Caution should be used when combining clonidine with other cardiac-suppressing meds (see drug interactions below), [1,3]
- Clonidine patch (Catapres-TTS®)
- These side effects are in addition to those seen with clonidine (see clonidine above)
- Skin reactions
- Skin reactions to the patch are common, with up to 50% of users experiencing redness or itching. Contact dermatitis requiring discontinuation has been seen in up to 20% of patients. [8]
- MRI reactions
- The clonidine patch should be removed before an MRI because it contains aluminum, which can cause burns. [8]
- Electrical cardioversion
- The clonidine patch should be removed before electrical cardioversion because it can increase the risk of arcing [8]
- Methyldopa (Aldomet®)
- The frequency of methyldopa side effects is not well-defined
- Drowsiness / fatigue
- Methyldopa decreases sympathetic outflow and this can cause drowsiness and fatigue [2]
- Positive direct Coombs test / hemolytic anemia
- In certain conditions, autoantibodies can form against red blood cells (RBCs), causing them to hemolyze. The direct Coombs test detects autoantibodies and complement components attached to RBCs.
- 10 - 20% of patients on methyldopa will develop a positive direct Coombs test after 6 - 12 months of therapy, and 0.5% - 1% will experience hemolytic anemia
- The manufacturer recommends a CBC be performed before therapy and periodically thereafter. It also states that "it may be useful" to do a direct Coombs test prior to therapy and after 6 to 12 months of treatment.
- If Coombs-positive hemolytic anemia occurs, stopping methyldopa typically halts the process [2,12]
- Hepatotoxicity
- Cases of hepatotoxicity, including fatal hepatic necrosis, have been reported in patients receiving methyldopa. Most cases occurred within the first 2 - 3 months of therapy and resolved with discontinuation.
- The manufacturer recommends liver function tests be performed during the first 6 to 12 weeks of therapy and if signs of hepatitis occur (e.g. fever, jaundice) [2]
- Blood dyscrasias
- White blood cell decreases, including rare cases of granulocytopenia, have been reported in methyldopa users. White counts have returned to normal after discontinuation. Rare cases of reversible thrombocytopenia have also been reported. [2]
- CONTRAINDICATIONS
- Clonidine
- Known hypersensitivity
- Methyldopa
- Active liver disease
- Concurrent therapy with MAO inhibitors
- PRECAUTIONS
- Kidney disease
- Clonidine
- 40 - 60% of clonidine is excreted in the urine as unchanged drug. Kidney disease increases exposure and caution should be used. [1]
- Methyldopa
- Methyldopa is excreted extensively in the urine. Kidney disease increases exposure and caution should be used. [2]
- Liver disease
- Clonidine
- About 50% of clonidine is metabolized by the liver. Liver disease increases exposure and caution should be used. [1]
- Methyldopa
- Methyldopa has been associated with hepatotoxicity and is not recommended in active liver disease. Use caution in chronic disease. [2]
- Heart failure
- Clonidine and methyldopa suppress sympathetic activity, which could theoretically reduce cardiac output
- AHA recommendation
- The AHA 2007 hypertension guidelines state that clonidine should be avoided in patients with heart failure
- The basis for this recommendation is that another alpha-2 agonist (moxonidine) was associated with an increased risk of mortality in heart failure patients [9]
- STOPPING CLONIDINE
- Patients who stop clonidine abruptly may experience withdrawal symptoms, including headache, agitation, tremor, and hypertension. The risk is greater with higher doses and concomitant beta blockers. To help lessen these symptoms, clonidine should be tapered over 2 - 4 days when discontinuing.
- Patients taking clonidine with beta blockers may experience severe rebound hypertension if they abruptly stop clonidine. To prevent this, it is recommended that the beta blocker be stopped several days before clonidine is withdrawn. Clonidine can then be tapered over 2 - 4 days.
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Clonidine and Methyldopa
- Sedating drugs (alcohol, benzodiazepines, etc.) - drugs that cause sedation may worsen the sedative effects of clonidine and methyldopa
- Tizanidine (Zanaflex®) - tizanidine is an alpha-2 agonist used as a muscle relaxer. It should not be combined with clonidine or methyldopa because it may increase the risk of adverse events.
- Medications that slow the heart rate - clonidine and methyldopa can slow the heart rate. When taken with other heart rate-slowing medications, the effect may be potentiated, and bradycardia can occur.
- Common drugs that slow the heart rate include:
- Amiodarone (Cordarone®)
- Beta blockers
- Calcium channel blockers (diltiazem and verapamil)
- Digoxin (Lanoxin®)
- Fingolimod (Gilenya®)
- Ivabradine (Corlanor®)
- Siponimod (Mayzent®)
- Clonidine
- Beta blockers - patients taking clonidine with beta blockers may experience severe rebound hypertension if they abruptly stop clonidine. To prevent this, it is recommended that the beta blocker be stopped several days before clonidine is withdrawn. Clonidine can then be tapered over 2 - 4 days.
- Tricyclic antidepressants (amitriptyline, desipramine, imipramine, etc.) - tricyclic antidepressants may decrease the effects of clonidine [1]
- Methyldopa
- Iron supplements (ferrous sulfate, ferrous gluconate) - iron supplements can reduce the absorption of methyldopa, even with a two-hour space between dosing. The ideal interval between iron and methyldopa administration has not been determined, so patients should take the drugs as far apart as possible. [2,3]
- Lithium - methyldopa may increase lithium exposure. Monitor lithium levels closely when combining. [2]
- MAO inhibitors (Selegiline, Eldepryl®, phenelzine, rasagiline, Azilect® etc) - methyldopa should not be taken with MAO inhibitors.
- Metabolism and clearance
- Clonidine (Catapres®)
- CYP2D6 - substrate [4]
- Methyldopa
- Not well-defined
- LONG-TERM SAFETY
- Alpha-2 agonists have been availabe since the 1960s. Their side effects are well-documented, and they are generally safe when prescribed appropriately.
- DOSING
- BIBLIOGRAPHY
- 1 - Clonidine PI
- 2 - Methyldopa PI
- 3 - PMID 8446138
- 4 - PMID 332218
- 5 - PMID 19821316
- 6 - PMID 20821851
- 7 - PMID 16492490
- 8 - Catapres-TTS® PI
- 9 - PMID 17502569 - Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, Circulation (2007)
- 10 - PMID 20570945
- 11 - PMID 2054263
- 12 - PMID 24175105 - Alpha-methyldopa-induced autoimmune hemolytic anemia in the third trimester of pregnancy, Case Rep Obstet Gynecol (2013)