ALPHA-2 AGONISTS
- AHA - American Heart Association
- BP - Blood pressure
- HCTZ - Hydrochlorothiazide
- HTN - Hypertension
- JNC 8 - Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure
- SBP - Systolic blood pressure
- Alpha-2 agonists
- Combination products
- Sympathetic nervous system
- The sympathetic nervous system is the main "excitatory" nervous system in the body (opposite of parasympathetic system)
- Increased sympathetic activity leads to increased awareness, stress, and adrenaline
- Alpha-2 receptors
- Alpha-2 receptors are found on cells in the sympathetic nervous system
- When alpha-2 receptors are stimulated, sympathetic nervous system activity decreases
- Alpha-2 agonists
- Alpha-2 agonists stimulate alpha-2 receptors in the central nervous system (brain and spinal cord)
- Stimulating alpha-2 receptors decreases sympathetic activity
- Decreased sympathetic activity leads to decreased blood pressure and heart rate [1]
- HYPERTENSION
Clonidine
- We found two old randomized controlled trials that evaluated clonidine in hypertension
- Clonidine vs propranolol vs placebo, Br J Clin Pharmac, (1977)
- A small 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%
- Patients were randomly assigned to crossover between 3 regimens:
- Clonidine titrated to effect. Average dose at end of 12 weeks was 0.540 mg/day.
- Propranolol titrated to effect. Average dose at end of 12 weeks was 576 mg/day.
- Placebo
- There was a 2-week washout period between each regimen
- PRIMARY OUTCOME: average blood pressure at the end of the 12 week treatment period
- The following results were seen:
- Clonidine lowered SBP by an average of 18 mmHg and DBP by an average of 13 mmHg compared to placebo
- Clonidine lowered pulse by an average of 6 bpm compared to placebo
- Propranolol lowered SBP by an average of 17 mmHg and DBP by an average of 13 mmHg compared to placebo
- Propranolol lowered pulse by an average of 14 bpm compared to placebo
- Two-thirds of the patients in the clonidine group complained of drowsiness and dry mouth while taking clonidine [4]
- Veterans Affairs Cooperative Study Group, NEJM (1993) [PubMed abstract]
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
- Main inclusion criteria: DBP 95 - 109 mmHg after blood pressure medication washout period
- Baseline characteristics: average age 59 years; average SBP 152 mmHg, DBP 99 mmHg; black race - 48%
- Patients were randomized to 1 of 7 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 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
- At one year, the following was seen:
- Primary outcome: Diltiazem - 59%, Atenolol - 51%, Clonidine - 50%, HCTZ - 46%, Captopril - 42%, Prazosin - 42%, Placebo - 25%
- Average blood pressure reduction at end of titration phase (clonidine): SBP 16 mmHg, DBP 12 mmHg
- Average blood pressure reduction at end of titration phase (placebo): SBP 3 mmHg, DBP 5 mmHg
- Side effects (clonidine vs placebo): Fatigue 17% vs 8%; Sleepiness 30% vs 6%; Dry mouth 37% vs 6% [3]
- 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 a drug.
Methyldopa
- Cochrane Meta-Analysis
- A Cochrane meta-analysis evaluated trials that used methyldopa to treat hypertension
- Included studies were small and older (1970s-1990s)
- Doses of methyldopa ranged from 500 - 2250mg a day
- An analysis of 6 trials found the following effects:
- Methyldopa lowered the average systolic blood pressure by 13 mmHg
- Methyldopa lowered the average diastolic blood pressure by 8.4 mmHg [5]
- Professional guidelines:
- JNC-8 does not recommend clonidine or methyldopa as first- or second-line agents
- StraightHealthcare analysis:
- Clonidine and methyldopa are effective blood pressure-lowering agents
- Clonidine can have significant side effects, so its use is primarily reserved as a third- or fourth-line agent in patients with difficult to treat hypertension
- Methyldopa is one of the few medications that has been proven safe in pregnancy. Its primary use is in hypertensive pregnant women.
- HYPERTENSIVE URGENCY
- Clonidine has a quick onset of action - blood pressure lowering seen in 30 - 60 minutes after a dose
- Because of this, clonidine is often given in ERs and clinics to lower blood pressure quickly in patients with very high blood pressures ( Systolic BP ≥ 180mmHg, Diastolic BP ≥ 120mmHg)
- An extensive review of hypertensive urgency is available here -
hypertensive urgency
- In short, there is no evidence that rapidly lowering blood pressure in hypertensive urgency provides a benefit [6,7]
- 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®)
- 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®)
- 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]
- StraightHealthcare analysis:
- 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]
- 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]
- 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]
- HEART FAILURE
- Clonidine and methyldopa can potentially decrease cardiac output and should be used with caution in patients with heart failure
- Professional guidelines:
- 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]
- StraightHealthcare analysis:
- 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
- When clonidine is stopped abruptly, withdrawal symptoms including headache, agitation, tremor, and hypertension can occur
- The risk of withdrawal is greater in patients taking higher doses of clonidine and in patients who are also taking
beta blockers
- When stopping clonidine, it should be tapered gradually over 2 - 4 days
- When clonidine is to be stopped in patients taking beta blockers, the manufacturer recommends that the beta blocker be withdrawn first over several days before gradually withdrawing the clonidine [1]
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently.
CLICK HERE for more information on drug interactions.
- HIGH ALERT INTERACTIONS
- NOTE: High alert interactions are interactions that are known to be significant and occur between two medications that are likely to be prescribed together
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.
- Common drugs that slow the heart rate include:
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 the clonidine is withdrawn. Clonidine should be tapered over 2-4 days.
Methyldopa
- METABOLISM AND ELIMINATION
- NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are
taking medications together and are concerned about a possible interaction.
- Clonidine (Catapres®)
- Methyldopa
- OTHER
- Alpha-2 agonists have been prescribed since the 1960s
- They can have significant side effects, but are generally considered safe when prescribed appropriately
- DIFFERENCES BETWEEN DRUGS IN CLASS
- Clonidine is primarily used to treat hypertension that is difficult to control
- Methyldopa is primarily used to treat hypertension in pregnant women
- Generic available:
- Clonidine (Catapres®)
- Clonidine patch (Catapres-TTS®)
- Methyldopa (Aldomet®)
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 1 - Clonidine PI
- 2 - Methyldopa PI
- 3 - 8446138
- 4 - 332218
- 5 - 19821316
- 6 - 20821851
- 7 - 16492490
- 8 - Catapres-TTS® PI
- 9 - 17502569
- 10 - 20570945
- 11 - 2054263
