Question:
Write about the development of Clonidine for prophylaxis against migraine.
Answer to Question: C04252 Pharmacy
Introduction
Migraine is a term that is used to describe mild-to-severe headaches.
A migraine is caused by neurological changes that cause headaches.
Studies show that migraine headaches often have a positive relationship with light, sound and smell.
Intensity of migraine is often increased when there is too much light, troublesome sounds, or foul or unpleasant smells.
Possible symptoms include nausea and vomiting.
Some sufferers report feeling pain on one side while others feel pain on both.
Migraine-associated pain is often described as a throbbing pain or pounding.
Because there are two types of headaches, one is migraine and the other is tension.
Boehringer Ingelheim Pharma was determined to find a peripherally effective adrenergic component for nasal congestion. This compound was to be used in nasal drops. Helmut Stahle was the chemist assigned this task.
It was believed decongestive agents were derived from an imidazoline structure.
Clonidine was found by him after introducing chlorine atoms into the 2- and 6 positions of his phenyl-ring.
Clonidine had more antihypertensive properties than decongestant (5).
Clonidine is indicated for lowering blood pressure. It can also be used in the prevention of vascular migraine headaches and treatment of severe dysmenorrhea.
Clonidine causes sympathetic outflow to decrease by stimulating centrally active alpha2A receptors in the brainstem.
Clonidine (an imidazole derivative) is metabolized via cytochrome P450.
Clonidine, when combined with other drugs, is therapeutically effective in lowering bloodpressure.
Clonidine may also be used in neuropathy, addiction to alcohol and smoking, restless leg disorder, diabetes diarrhoea and menopause symptoms.
Clonidine, which was first approved by the US in 1974, is still widely used for many indications.
Clonidine’s main use is for hypertension. But, in some places, it may also be used for cancer pain management and attention deficit syndrome.
Clonidine can be used in the NHS primarily for hypertension, menopause flushing and other purposes.
Tourette syndrome and sedation are some of the unlicensed uses of clonidine.
Clonidine is also available in injection (150mcg), tablet (25mcg), or 100mcg forms.
Adults take 50-100mcg each day. After that, the dose can be increased slowly 2nd or 3rd time until it is under control.
Most side effects include fatigue and sedation. (1)
Clonidine tablets have a 5-hour duration of activity and a 12-hour half-life. It can be extended up to 41 hour in the case of severe impaired renal function.
Clonidine should be taken after meals and before bed to reduce its sedating effect.
Clonidine is primarily used to activate presynaptic receptors in locus coreruleus. It also reduces norepinephrine levels.
This antihypertensive effect is linked to the reduction in plasma norepinephrine levels.
Clonidine extended delivery tablet is an adjunctive therapy used in children with attention deficit hyperactivity disorders in the USA.
Sudden withdrawal can cause hypertension rebound due to rebound in sympathetic outputflow.
Clonidine therapy must be stopped gradually to avoid rebound side effects.
(2) Sudden withdrawal from high doses Clonidine can lead to agitation.
Galactose intolerance should be avoided as Catapres (Clonidine), tablets contain lactose monohydrate.
Clonidine and its derivatives are abundantly excreted from the urine. Patients with renal insufficiency should adjust their dosage accordingly.
Clonidine can be excreted in urine 70% of the time as an unchanged parent drug and 20% as a faeces from administered drug.
Contact lens wearers may experience reduced lacrimation from clonidine.
Clonidine is available Catapres as a tablet and an injection, under Boehringer Ingelheim’s brand name. There are many generics on the market. (3)
Clonidine’s first use was in 1966.
The drug was first used to treat hypersensitivity.
Clonidine was originally widely used in treating nicotine, alcohol withdrawal syndromes and opium addiction. Tourette’s syndrome and attention-deficit/hyperactivity disorder (ADHD).
Clonidine was eventually approved by the U.S Food & Drug Administration to be used for high blood pressure.
Clonidine was also found specifically to work on nerve cells in brain, which helped to lower blood pressure (3).
The clinical study that confirmed the use of clonidine to treat migraine was completed.
Clonidine was administered in a 25 microgram dose thrice daily. This resulted in a decrease of 3.94 to 2.26 migraine attacks per month.
However, when the dosage was increased to 50 micrograms, migraine attacks decreased from 4 to 1.88.
44% of patients with 25 micrograms had reduced attacks. The 46% showed no change, and the 10% who did experienced an increase in attacks.
58% of patients who took the 50-microgram dosage reported fewer attacks. The 40% had no improvement.
The incidence of attacks was higher in the remaining 11%.
For both types of dosages, the duration of attacks was taken into account.
The duration of pain decreased in the 25 microgram dosage for 38% of patients. It remained the same in the 60%, and was slightly elevated in 2%.
The 50 microgram dose of clonidine showed the same results. It reduced the duration of pain in 52% of patients while it remained the exact same in 46%. In 2%, however, the effects were elevated.
Although the side effects of increasing the dosage of clonidine were not unexpected, such as nausea and sedation, it led to sedation in 22%.
This trial can be considered to be important in the prevention of migraines with the use of effective doses of clonidine (7).
Clonidine is a potential treatment for migraine. The causes of migraine depend on serotonin levels, which regulate pain in your nervous system.
Migraines can also result from changes in brainstem and the interactions between trigeminal neuron.
If the brain level of serotonin drops, it triggers the trigeminal to produce neuropeptides. These neuropeptides move to the outer brain portion (meninges), and can cause migraine pain (4).
A positive correlation exists between migraine and hypertension. It means that migraine pain is also increased when there is an increase in hypertension.
Clonidine is an imidazole-derived imidazole that has been widely used to treat hypertension.
Studies have shown that low doses of clonidine can effectively lower hypertension, and consequently reduce migraines. Figure 1 shows how Clonidine activates the alpha-adrenoreceptors in brain, which reduces the sympathetic outflow of the CNS (central nervous system) and peripheral resistance, heart rate and renal vascular pressure and blood pressure (5).Figure 1: Clonidine acting pathway [Source: (6)]
According to the above disclosure, migraines are a serious issue that can lead to impairment of daily functioning and poor concentration.
Clonidine, out of the many available medications, is considered to be the best.
Clonidine, when taken in small quantities, can help to relieve migraine pain. Clonidine works by directly attacking the brain cells and central nervous system.
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StaEhle H. a historical perspective: the development of Clonidine.
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Sprenger T. and Goadsby, PJ. Current practice and future directions of the acute and preventive management of migraine.
The Lancet Neurology.
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