Drug Class 8: Vasodilators (Hydralazine, Minoxidil, Diazoxide, Sodium nitoprusside)

Types of Vasodilators: Hydralazine, Minoxidil, Diazoxide and Sodium nitroprusside (Detailed in alphabetical order)

8.1 Diazoxide (May cause ‘Diabetes’/Hyperglycemia)

  • Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle.

-Arteriolar vasodilation results in reflex sympathetic stimulation, leading to tachycardia and fluid retention.

  • Clinical indications:

(a) Hypertensive emergency. (b) Intractable hypoglycaemia due to hyperinsulinemia (oral)

  • Precautions:

-(a) Subarachnoid, Subdural, intracerebral, postoperative bleeding and dissecting aortic aneurysm CONTRAINDICATED!

Image

(b) Hypertension with pulmonary edema, aortic coarctation or atrioventricular shunt CONTRAINDICATED!

(c) Heart Failure- May exacerbated by reflex tachycardia and fluid retention induced by diazoxide CAUTION!

(d) Cerebral or coronary artery disease-May be exacerbated by excessive drop in BP CAUTION!

(e) Diabetes-Diazoxide causes hyperglycemia. *Monitor blood glucose closely

-Diazoxide may act directly to increase glucose production and inhibit glucose uptake

(f) Gout-May be exacerbated

(g) Pregnancy-Use with extreme caution, may cause fetal bradycardia, hyperglycemia has been observed in neonates (Cat C-AUS) *DON’T USE IN PREGNANCY!

  • Side effects/Adverse effects

*Common side effects (Oral)

1. Flushing, headache, nausea

2. Tachycardia

3. Hyperglycemia

4. Edema (retention of salt and water retention)

*Infrequent side effects:

1. Hyperuricemia

2. Fever

3. Rash

4. Lymphadenopathy (swollen/enlarged lymph nodes)

5. Loss of taste

6. Hypertrichosis (chronic use)-Abnormal amount of hair growth over body

7. Constipation

8. Dizziness

9. Burning sensation at injection site

*Rare side effects:

-Diabetic Ketoacidosism, Hyperosmolar non-ketotic coma, pancreatitis, neutropenia, eosinophilia, thrombocytopenia

*IV side effects

-Hypotension, bradycardia, angina, arrhythmias, cerebral ischemia, confusion, seizures, loss of consciousness

  • Administration advice/Therapeutic points

*Avoid extravasation during IV administration since cellulitis and pain may results. If extravasation occurs, treatment with cold packs is recommended.

  • Practice points

*Infusion regimens are preferred to minimise risk of precipitous fall in BP

*Diazoxide is often given with a B-blocker and diuretic to obtain maximum anti-hypertensive effect and to prevent tachycardia and fluid retention.

*Diazoxide is given orally to treat intractable hypoglycemia, it is not used orally in chronic treatment of hypertension (poorly tolerated)

  • Drug Interactions

-Diazoxide can increase blood glucose concentration (so any drug that can affect blood glucose concentration can interact)

-Diazoxide causes hypotension. *Administration with other anti-hypertensive drugs (reduce BP) may enhance its hypotensive effect. Take particular care if the hypotensive agents are given IV.

8.2 Hydralazine

Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle. Arteriolar vasodilation results in reflex sympathetic stimulation leading to tachycardia and fluid retention.

Clinial Indication: (a) Hypertensive emergency (Not for chronic treatment) (b) Refractory hypertension (in combination with a B-blocker and diuretic) (c) Heart Failure, with a nitrate (Accepted clinical indication)

Precautions:

1. Idiopathic systemic lupus erythematosus (ISLE) or related diseases-Contraindicated

2. Cerebral Artery disease (*May be worsened by excessive drop in BP)

3. Cardiovascular

-Contraindicated in dissecting aortic aneurysm, Severe tachycardia and Heart Failure with high cardiac output (e.g. due to hyperthyroidism).

-Contraindicated in heart failure due to mechanical obstruction (e.g. aortic stenosis) or corpulmonale (enlargement of the right ventricle of the heart as a response to increased resistance or high blood pressure in the lungs (pulmonary hypertension)

-Angina may be exacerbated by reflex tachycardia.

*Avoid using hydralazine after myocardial infarction until condition has stabilised.

*Coronary artery disease may be worsened by excessive drop in BP.

4. Renal impaired (Reduce dose if necessary)

5. Hepatic impaired (Reduce dose if necessary).

*Note: People with the slow acetylator phenotype have a greater risk of adverse effects (i.e. lupus-like syndrome). Approx 50% of Caucasians and 10-20% of Asians are slow acetylators.

 N-acetyltransferase gene divides people into “slow acetylators” and “fast acetylators”, with very different half-lives and blood concentrations of such important drugs as isoniazid (antituberculosis) and procainamide (antiarrhythmic)

6. Pregnancy-Associated with fetal distress and fetal arrhythmias following IV administration in the last trimester of pregnancy. (CAT C-AUS)

7. Breastfeeding-Safe to use

  • Side effects/Adverse effects

*Common side effects:

1. Flushing, headache, dizziness

2. Tachycardia, Palpitations (Arrhythymias)

3. Edema (Sodium and water retention)

*Infrequent side effects:

Angina, Nasal congestion, lupus-like syndrome (fever, arthralgia, myalgia, malaise)

*Rare

Blood dyscrasia (‘Bad mixture’), rash, paraesthesia

  • Counselling

*This medicine may cause dizziness especially at the start of treatment. If affected, do not drive or operate machinery.

*Important Practice points:

1. Prolonged treatment (>6 months) may induce a lupus-like syndrome. Check antinulcear factor before starting and during prolonged treatment.

2. Beta-blockers and thiazides are often used with hydralazine to prevent tachycardia and fluid retention.

3. Combination of hydralazine and isosorbide dinitrate has been shown to reduce mortality in heart failure. Although it is not as effective as ACE-inhibitor, consider this combination in people unable to tolerate an ACE-inhibitor or ARB.

  • Drug Interactions

-Drug causes hypotension, administration with other anti-hypertensive drugs that also reduce BP may enhance hypotensive effect. Take particular care if the hypotensive agents are given IV.

8.3 Minoxidil

  • Mechanism of action: Predominantly an arteriolar vasodilator with little effect on venous smooth muscle. Arteriolar vasodilation leads to sympathetic stimulation causing tachycardia and fluid retention.
  • Clinical indications: (a) Severe refractory hypertension (use with other anti-hypertensives) (b) Alopecia (loss of hair from body)
  • Precautions

1. Pheochromocytoma (Tumour in the adrenal gland). Overproduction of adrenaline which may increase risk of tachycardia, effective use of B-blockers is crucail before starting treatment with minoxidil.

2. Cardiac

-Contraindicated in pulmonary hypertension secondary to mitral stenosis.

-Increased risk of excessive tachycardia if mitral regurgitation is present.

-Heart failure may worsen due to fluid retention. Angina may worsen due to reflex tachycardia (*Avoid using minoxidil post-MI until condition has stabilised)

3. Pregnancy

-Oral administration may cause hypertrichosis in neonate (CAT C-AUS)

4. Breastfeeding-Use with caution

  • Adverse Effects

Systemic side effects occur mainly with oral minoxidil and can sometimes occur with topical use.

Common:

1. Edema (Sodium and water retention)

2. Cardiospecific-Tachycardia, Pericarditis, Pericardial effusion, ECG changes (ST depression, T wave inversion), Palpitations

3. Headache, Flushing, Dizziness

4. Hypertrichosis (as facial hair 3-6 weeks after starting treatment, may become generalised, resolves 1-6 months after stopping the drug)

Infrequent of rare:

-Breast tenderness, gynaecomastia, menstrual disturbances, changes in skin pigmentation, hypotension, increased angina, intermittent claudication (muscle pain which occurs during exercise), paraesthesia, thrombocytopenia

  • Practice Points

Diuretics and beta-blockers are often used with minoxidil to prevent fluid retention and tachycardia.

8.4 Sodium nitroprusside

Mechanism of action: Non-selective arteriolar and venous dilator

Clinical Indications: (a) Hypertensive emergency (b) Controlled hypotension during surgery to reduce bleeding (c) Acute Heart Failure

Precautions (All of them are contradicated for sodium nitroprusside use)

1. Compensatory hypertension (e.g. atrioventricular shunt or coarctation of the aorta- congenital condition whereby the aorta narrows in the area where the ductus arteriosus insets)

CONTRAINDICATED!!!

2. Vitamin B12 deficiency-CONTRAINDICATED!!! Refer to Vitamin Metabolic Biochemistry Lecture (Increased plasma homocysteine levels and increases damage to vessels. Adding nitroprusside will increase risk of thrombosis.)

3. Cerebral or coronary artery disease-CONTRAINDICATED!!!

4.  Congenital (Leber’s) optic atrophy-CONTRAINDICATED!!!

5. Tobacco amblyopia-CONTRAINDICATED!!!

6. Hypovolemia-CONTRAINDICATED!!!

7. Uncorrected anemia-CONTRAINDICATED!!!

Not contradicated but take extra caution

8. Increased intra-cranial pressure, encephalopathy-Risk of aggration

9. Hypothyroidism-Thiocyanate (degradation product of sodium nitroprusside). Inhibits both uptake and binding of iodine.

10. Hypothermia-Risk of aggravation

11. Pulmonary mpairment-May worsen hypoxemia

12. Renal impaired-Reduced excretion of thiocyanate concentrations during prolonged treatment.

13. Hepatic-Avoid use in severe impairment

14. Elderly-May require lower doses

15. Pregnant-Reserve for use in patients with hypertension not controlled by other agents. Short-term use for control of hypertensive crises may be safe provided that the pH and thiocyanate concentrations in maternal blood are monitored. Cat C-AUS

  • Side effects/Adverse effects

-Excessive hypotension or excessive cyanide accumulation

-Thiocyanate toxicity may also occur, especially with renal impairment

Common:

1. Nausea, Vomiting, Headache

2. Sweating, apprehension (Fear)

3, Restlessness

4. Muscle twitching

5. Retrosternal discomfort

6. Palpitations

7. Dizziness

8. Abdominal pain (with too rapid reduction in BP)

Infrequent:

-Postural hypotension, Hypothyroidism, Paraesthesia, feeling of warmth, rash, flushing, increased intracranial pressure

Rare:

-Thrombocytopenia, Methaemoglobinemia, Phlebitis (inflammation of veins usually in legs)

Toxicity:

-Toxicity may occur, particularly with prolonged infusion or higher than recommended maximum dose. Toxicity is due to accumulation of thiocyanate or cyanide.

*Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light

*In normal renal function, cyanide accumulates with infusion rate of >2 micrograms/kg/min.

-Risk of toxicity is greater in renal impairment because of reduced excretion of thiocyanate.

-Thiocyanate toxicity causes confusion, psychosis, tinnitus, blurred vision, nausea, dyspnea, hypothyroidism and ataxia (lack of voluntary coordination of muscle movements)

Cyanide toxicity causes tachycardia, sweating, hyperventilation, headache, arrhythmias, metabolic acidosis, areflexia, coma, hypotension, pink colour of skin and mucous memranes, shallow breathing, dilated pupils and death.

  • Administration advice

-Dilute with glucose 5%, do not administer by direct injection!

-Infusion solution should be protected from light, e.g. with aluminium foil

-Final infusion concentration should be 50-100micrograms/ml (i.e. 50mg of sodium nitroprusside in 500-1000ml glucose 5%)

  • Practice points

-Monitor intra-arterial BP continuously during infusion and titrate infusion rate carefully to avoid excessive hypotension

-Abrupt withdrawl of sodium nitroprusside may cause rebound hypertension. Withdraw over at lesat 10-30 mins to avoid rebound.

-Usual duration of treatment should not exceed 72 hours because of cumulative thiocyanate toxicity and the possibility of cyanide toxicity; monitor thiocyanate concentrations.

  • Drug Interactions

-Nitrates (including sodium nitroprusside) as well as amyl nitrite causes hypotension. *Additional hypotensive effects may occur if administered with other anti-hypertensive agents.

*Administration with phosphodiesterase-5-inhibitors and nitrates is contraindicated.

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s