ALPHA-2 AGONISTS















Overview
  • Clonidine has been around for a long time, and good studies that have evaluated its effectiveness in hypertension are sparse
  • Two older randomized controlled trials comparing clonidine to other meds and placebo are detailed below
Clonidine vs Propranolol vs Placebo for Hypertension, Br J Clin Pharmacol (1977) [PubMed abstract]
  • 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
  • Two-thirds of the patients in the clonidine group complained of drowsiness and dry mouth while taking clonidine

Findings: Clonidine and propranolol were equipotent in reducing blood pressure, but clonidine has more initial side-effects than propranolol
Clonidine vs Others for Hypertension in Male Veterans, NEJM (1993) [PubMed abstract]
  • 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
  • Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
  • All medications were significantly better than placebo for blood pressure reduction
  • Side effects (clonidine vs placebo): fatigue 17% vs 8%; sleepiness 30% vs 6%; dry mouth 37% vs 6% (all statistically significant)

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.













Clonidine (Catapres®)
Drowsiness/fatigue
  • The sympathetic nervous system is the part of the nervous system that increases excitement and awareness (adrenaline)
  • Clonidine decreases sympathetic outflow
  • This can lead to drowsiness and fatigue
  • In studies, up to 40% of patients on clonidine have experienced drowsiness or fatigue
  • Symptoms tend to diminish with continued treatment [1, 3, 4]
Dry mouth
  • Decreased sympathetic outflow can cause dry mouth
  • In studies, up to 40% of patients on clonidine have experienced dry mouth
  • Dry mouth tends to diminish with continued treatment [1, 3]
Dry eyes
  • Clonidine can cause dry eyes
  • This may affect 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
  • In one small study, the average resting heart rate decreased by 7 beats per minute in patients taking clonidine [3]
  • This may be problematic when taken with other medications that slow the heart rate (see drug interactions below) [1]

Clonidine patch (Catapres-TTS®)
Overview
  • These side effects are in addition to those seen with clonidine (see clonidine above)
Skin reactions
  • Skin reactions to the patch are common
  • Fifty percent of patients will experience some sort of reaction including redness or itching
  • In trials, up to 20% of patients have developed contact dermatitis to the patch that required discontinuation [8]
MRI reactions
  • The clonidine patch contains aluminum
  • Patients with aluminum-containing patches have experienced burns when having an MRI
  • The patch should be removed before an MRI is performed [8]
Electrical cardioversion
  • The patch should not be worn during electrical cardioversion because of an increased risk of arcing [8]

Methyldopa (Aldomet®)
Overview
  • In general, most trials involving methyldopa are older and of suboptimal design
  • The frequency of methyldopa side effects is not well-defined
Drowsiness / fatigue
  • The sympathetic nervous system is the part of the nervous system that increases excitement and awareness (adrenaline)
  • Methyldopa decreases sympathetic outflow
  • This can lead to drowsiness and fatigue [2]
Positive direct Coombs test / hemolytic anemia
  • The "direct Coombs test" is a test that detects autoantibodies to red blood cells
  • Autoantibodies can cause red blood cells to be destroyed by the immune system (a process called hemolytic anemia)
  • After 6 - 12 months of therapy, 10 - 20% of patients on methyldopa will develop a positive direct Coombs test
  • A positive direct Coombs test does not mean hemolytic anemia will develop
  • The manufacturer recommends that a blood count be done prior to starting therapy and periodically thereafter
  • The manufacturer also states that "it may be useful" to do a direct Coombs test before therapy and 6 to 12 months after the start of therapy
  • If Coombs-positive hemolytic anemia occurs, stopping methyldopa typically halts the process [2]
Summary
  • Methyldopa can cause autoantibodies to red blood cells which can lead to hemolytic anemia
  • The actual incidence of methyldopa-induced hemolytic anemia is not well-defined
  • In developed nations, methyldopa is primarily used for short periods in pregnancy, so the risk of hemolytic anemia is less of an issue, because it requires time to develop
  • Patients taking methyldopa for extended periods should be aware of the risk and have appropriate lab work done
Liver inflammation (hepatitis)
  • Methyldopa has been associated with liver inflammation
  • Liver inflammation from methyldopa typically occurs within the first 2 to 3 months of therapy
  • The overall incidence of methyldopa-induced liver inflammation is not well-defined
  • The manufacturer recommends liver function tests be performed during the first 6 - 12 weeks of therapy or if unexplained fever develops [2]






Kidney disease
Clonidine
  • The clearance of clonidine is decreased in patients with kidney disease
  • Clonidine should be used with caution in patients with kidney disease
  • Manufacturer makes no specific dosage recommendations [1]
Methyldopa
  • Methyldopa is excreted extensively in the urine
  • Kidney disease decreases the clearance of methyldopa
  • Caution should be used in patients with kidney disease
  • Manufacturer makes no specific dosage recommendations [2]

Liver disease
Clonidine
  • About 50% of clonidine is metabolized by the liver
  • Clonidine clearance would be expected to be decreased in patients with significant liver disease
  • Manufacturer makes no specific dosage recommendations [1]
Methyldopa
  • Methyldopa has been associated with liver inflammation
  • Methyldopa should be used with caution in patients with liver disease
  • Methyldopa should not be used in patients with advanced liver disease [2]

Heart failure
Overview
  • Clonidine and methyldopa can potentially decrease cardiac output and should be used with caution in patients with heart failure
AHA recommendation
  • The AHA guidelines for hypertension state that clonidine should be avoided in patients with heart failure
  • The basis for this recommendation is that another drug (moxonidine) in the same class as clonidine was associated with increased mortality in patients with heart failure [9]
Summary
  • Clonidine and methyldopa may decrease cardiac output
  • In practice, clonidine is often used in patients with heart failure because of its potent blood pressure-lowering properties
  • Based on the available evidence, it is not known what effect clonidine has on heart failure outcomes





Drug interactions

Clonidine and Methyldopa
  • Sedating drugs (alcohol, benzodiazepines, etc.) - Drugs that cause sedation may worsen the sedation of clonidine and methyldopa
  • Tizanidine (Zanaflex®) - tizanidine is an alpha-2 agonist that is used as a muscle relaxer. It should not be combined with clonidine or methyldopa because the risk of adverse events may increase.
  • Medications that slow the heart rate - Clonidine and methyldopa can slow the heart rate. When taken with other medications that slow the heart rate, the effect can be additive.

Clonidine
  • Beta blockers - When clonidine and a beta blocker are taken together, there is a potential for rebound hypertension if clonidine is stopped. To avoid this, it is recommended that the beta blocker be stopped several days before clonidine is withdrawn. Clonidine should be tapered over 2-4 days.
  • Tricyclic antidepressants (amitriptyline, desipramine, imipramine, etc.) - Tricyclic antidepressants may decrease the effects of clonidine [1]

Methyldopa