Ergot derivatives

Ergotamine and dihydroergotamine

Ergotamine and dihydroergotamine have been used in preventing migraine attacks and dihydroergotamine in the treatment of hypotension (either orthostatic or caused by spinal or epidural anesthesia). When dihydroergotamine was given intravenously after coronary bypass surgery, despite increased filling pressure there was no rise in cardiac output, and despite increased cardiac work the bypass flow fell significantly. The significant decrease in regional myocardial vascular resistance found after the administration of dihydroergotamine may explain the absence of the expected increase in cardiac output and coronary bypass flow.

The combination of heparin with dihydroergotamine has been used in the prevention of thromboembolic complications. It was claimed that these two components act synergistically, allowing a lower dosage of heparin to be used. However, the lower risk of hemorrhagic complications is certainly not counterbalanced by a lowered risk of ergotism [ , ]. Vasospastic reactions after giving heparin with dihydroergotamine seem to occur particularly in traumatized patients or when a limb is injured. Since the risk of vasospasm increases with treatment time, the Swedish Adverse Reactions Committee recommended that the duration of treatment with dihydroergotamine with heparin should not exceed 7 days [ ].

With daily use of dihydroergotamine by injection, there is an ill-defined frequency of nausea, vomiting, abdominal pain, and diarrhea, but also a high incidence of muscle cramps and some cases of lethargy and peripheral edema [ ].

Ergometrine and methylergotamine

Ergometrine (also called ergonovine and d-lysergic acid beta-propanolamide) and methylergotamine stimulate uterine contraction. Ergometrine is used in obstetrics, since its oxytocic effects are relatively more marked than its vascular effects. Nausea and vomiting can occur if it is given orally. Slight bradycardia is common, but tachycardia occurs in some patients, and there can be changes in intracardiac conduction and pacemaker function. Very rarely, hypertensive reactions and cardiac arrest have been described and there are two reports of myocardial infarction in healthy women who were smokers [ ].

The “ergonovine provocation test” has been used in the diagnosis of angina pectoris (by producing vasospasm during angiography) but it can cause myocardial infarction and even death [ ].

Co-dergocrine

Co-dergocrine (brand name Hydergine) is the British Approved Name for a formulation that contains a combination of the methane sulfonates of three dihydrogenated ergot alkaloids: dihydroergocornine mesilate, dihydroergocristine mesilate, and (in the ratio 2:1) α- and β-di-hydroergocryptine mesilates. Dihydrogenation eliminates the vasoconstrictor effects of ergotoxin and enhances its α-adrenoceptor antagonist and 5-HT receptor antagonist properties. Co-dergocrine has other pharmacological effects, including inhibition of brain-specific phosphodiesterases, several of which are still poorly described.

Co-dergocrine has been used for its supposed therapeutic effects in depression, confusion, and lack of self-care in the elderly, and purportedly acts by improving cerebral blood flow. The basis of these indications has been reviewed and has not been validated [ , ].It has also been used topically to treat erectile dysfunction [ ].

Co-dergocrine is claimed to have some effect in brain ageing and has also been promoted as a “metabolic enhancer”, mainly because it protects against metabolic alterations induced by hypothermia and ischemia in animals [ ].

Many double-blind, controlled trials have been conducted with co-dergocrine in senile dementia, and almost all have reported improvements in scores on at least one psychomotor test scale. However, despite this evidence of short-term efficacy, many skeptical clinicians consider it to be no better than placebo, and find support from a double-blind, placebo-controlled trial in which a group treated with the recommended dosage of 1 mg tds for 24 weeks did not perform better after treatment than did the placebo-treated group [ ]. The clinical value of co-dergocrine in patients with claudication and rest pain has been poorly documented.

Vomiting, blurred vision, rashes, nasal stuffiness, bad taste sensations, postural hypotension, and vasospastic reactions are all uncommon [ ]. Diffuse fibrotic processes (for example retroperitoneal fibrosis), repeatedly reported with other ergot derivatives, such as methysergide and dihydroergotamine, have not been observed with co-dergocrine. In elderly people, co-dergocrine only occasionally causes diarrhea, nausea, gastric pain, orthostatic hypotension, and headache. In 40 children, nasal stuffiness and anorexia were most common adverse effects of co-dergocrine [ ].

The ergot alkaloid α-dihydroergocriptine has been used on its own to treat prolactinomas [ ], Parkinson’s disease [ , ], migraine [ ], and restless legs syndrome [ ].

Dihydroergocristine has been used on its own to treat alcohol-induced brain damage [ ] and to stop lactation [ ].

Cardiovascular

Ergot alkaloids can cause severe vasospasm [ ]. The extremities become pale and cold, and arterial spasm in the arms and legs has been demonstrated; even the face can be affected. The condition can develop acutely even after brief use of the drug, and there is real risk of gangrene; if given early, intra-arterial infusion of prostaglandin E ₁ can reverse the spasm. Protracted coronary spasm has also been reported in some cases [ ]. Renal arterial spasm has occurred after a dose of ergotamine of 10 mg in the form of suppositories given over 60 hours [ ], and bilateral papillitis with ischemia of the periaxial fibers has resulted from 2 weeks of maximum-dose treatment. High doses have also led on occasion to mesenteric vascular constriction, ischemic bowel disease, and partial necrosis of the tongue. Arterial stenosis can even result in aneurysm formation [ ]. The absence of symptoms does not mean that there is no adverse effect; in 30 patients who had taken ergotamine 1–5 mg/day for a year all had lowered systolic blood pressures in the foot.

Arterial spasm from ergotamine can be due to overdose, but some patients have an exaggerated response to a therapeutic dose. Interaction with other drugs, leading to potentiation, is another mechanism (see Drug-drug interactions below).

Treatment of migraine can lead to subclinical ergotism for a prolonged period, and thence to occlusive peripheral vascular disease; peripheral systolic pressure (and liver function tests) should be monitored in patients taking regular ergotamine [ ]. Tolerance to these vasoconstrictor effects varies widely among individuals; such symptoms as cyanosis of the limbs, syncope, hypotension, and paresthesia have been seen in sensitive subjects after doses of up to 8 mg taken over as little as 10 days. The Swedish drug authorities have recommended that treatment should not be continued for more than 7 days [ ].

• A 78-year-old woman developed gangrene in three fingertips on the right hand and two on the left after being given dihydroergotamine 10 mg/day as migraine prophylaxis [ ]. She had had Raynaud’s syndrome for at least the previous 5 years and was thought to have a relatively mild form of systemic sclerosis.

• A 44-year-old woman developed claudication and rest pain after gross overuse of ergotamine 100 mg suppositories (up to 6 times a day) for chronic headaches over a period of several years [ ]. Angiography showed occlusion of both femoral arteries. Intra-arterial prostaglandin E (presumably E1) followed by chemical sympathectomy normalized the circulation in both the legs.

• A 63-year-old Canadian woman who had been taking ergotamine (dosage unspecified) for migraine for 20 years developed acute ischemia of the right arm, with no palpable pulses below the axilla [ ]. Angiography showed multiple filling defects in upper limb arteries, partially reversible with intravenous phentolamine. She was given prazosin 2 mg/day and became pain-free after 5 days. Treatment was continued for 3 months and during this time attacks of migraine were treated with sumatriptan without adverse effects. Her pulses were entirely normal after 3 months, as was angiography.

Myocardial infarction has also been reported.

• A 27-year-old woman with familial hypercholesterolemia already treated with lipid-lowering drugs developed acute chest pain after a prophylactic intramuscular injection of 0.5 mg ergometrine, given during the late stages of labor [ ]. Angiography showed three-vessel atherosclerotic disease and occlusion of the left anterior descending coronary artery. Angioplasty with stenting was successful and she made an excellent recovery.

• A 34-year-old woman had a myocardial infarction after being given ergonovine for an atonic uterus after cesarean section [ ]. Within minutes she became unresponsive, with bradycardia and then asystole followed by ventricular fibrillation during cardiopulmonary resuscitation. An electrocardiogram showed an acute anterior infarct and coronary angiography showed diffuse spasm of the circumflex and left anterior descending arteries, with subtotal occlusion of the latter. The spasm was reversed with intracoronary glyceryl trinitrate but she required ventilation for another 2 days and was eventually discharged 11 days after the infarct, with a borderline left ventricular ejection fraction of 45%.

The authors commented that the latter patient was of Asian origin and that such individuals are thought to have increased susceptibility to the vasoconstrictor effects of ergot derivatives.

The role of arterial spasm as a cause of angina after angioplasty has been studied in two men, aged 45 and 58 years, who had emergency angioplasties for acute coronary thrombosis [ ]. Although the primary procedures were successful in both cases, ischemic chest pain returned after 4 and 6 months respectively. Perhaps a little surprisingly, in both cases intravenous ergonovine (0.4 mg) was given during coronary angiography, causing severe arterial spasm, which resolved with intravenous isosorbide dinitrate. There was no evidence of restenosis. The authors noted that recurrence of angina does not necessarily imply restenosis, although it is not clear how many cardiologists will repeat this procedure with their own patients.

• A 48-year-old woman developed a cold pulseless right leg and no measurable blood pressure at the right ankle [ ]. She was a migraine sufferer and had been taking over-the-counter medications, some of which contained ergot derivatives, although the nature and quantity were not specified. Arteriography showed severe stenosis of the superficial femoral artery, with no identifiable tibial vessels. There was an initial improvement with intra-arterial glyceryl trinitrate infusion, and sustained normalization of the circulation in the leg after administration of sodium nitroprusside, nifedipine, prazosin, and heparin. She made a full recovery.

The authors reviewed the pharmacology of the ergot alkaloids and the acute and subclinical ischemic syndromes that they can produce. They pointed out that in some countries, notably in Latin America, ergot-containing formulations are freely available without a prescription.

Acute hypertensive encephalopathy has occurred in a patient given methylergotamine [ ].

Dissection of the internal carotid artery occurred in a 65-year-old man who had been abusing ergotamine compounds for several years on at least 15 days a month [ ]. Rupture of a splenic artery aneurysm in a 46-year-old woman was ascribed to excessive ergotamine ingestion for migraine [ ]. The authors thought that significant vasospasm may have led to damage and weakening of the vessel wall and consequently to the development of a false aneurysm. It should be noted that splanchnic aneurysms are occasionally discovered in otherwise healthy people and carry a 5% risk of spontaneous rupture.

Vasospastic angiitis involving the right ring finger has been attributed to co-dergocrine [ ].

Long-term abuse of ergotamine can occasionally cause fibrosis of the cardiac valves [ , ].

Sinus bradycardia occurred in three of eight patients who were given co-dergocrine [ ].

Respiratory

A newborn infant inadvertently injected with ergometrine and oxytocin developed depression of respiration and convulsions [ ].

Ear, nose, throat

During intranasal administration for migraine, nasal congestion, irritation, and sneezing can occur [ ].

Nervous system

The cerebral vasculature can also be vulnerable to ergot-induced vasoconstriction.

• A 54-year-old woman with a 20-year history of migraine used a nasal ergotamine spray one evening during an episode of migraine [ ]. She used a second dose at 4 p.m. the next day since the migraine had persisted. The following morning she was given subcutaneous sumatriptan 6 mg. Some 30–45 minutes later she developed the symptoms of global amnesia, which resolved by the following morning. Magnetic resonance imaging showed a small infarct in the right thalamus.

It seems likely that the co-administration of two cerebral vasoconstrictors increased the likelihood of such an event.

• A 36-year-old woman developed a “cerebral angiopathy” within 36 hours after starting to take oral metergoline, an ergot derivative prescribed after delivery to suppress lactation [ ]. This angiopathy was apparently due to severe narrowing of small and medium cerebral arteries; its main features were sudden hypertension, seizures, and variable reversible neurological deficits.

Transient cortical blindness, with severe headache and hallucinations, has been associated with the intravenous injection of methylergometrine 0.2 mg in a postpartum patient [ ].

The role of ergotamine and sumatriptan in drug-induced headache has been surveyed in over 2000 patients at a regional headache clinic [ ]. About 600 had taken ergot derivatives previously and a similar number had used sumatriptan, while nearly 250 had experience of both. Drug overuse was defined as the use of at least one dose of either drug on 18 or more days every month for at least 3 months. By these criteria the rates of ergotamine and sumatriptan overuse were estimated at 14% and 3.5% respectively. Drug-induced headache was much more common among ergotamine overusers than sumatriptan overusers (68% versus 32%).

Sensory systems

Bilateral ischemic optic neuropathy can develop secondary to acute ergotism after administration of ergotamine tartrate [ ].