Migraine – Diagnosis and Treatment Question And Answers

Treatment of migraine—short note. List the drugs used for the prophylaxis of migraine.

• Migraine is a common disorder characterized by severe throbbing and unilateral headache often associated with nausea, vomiting, giddiness, and fatigue lasting for several hours.
• In classical migraine, a brief ‘aura’ of visual disturbances occurs prior to the headache.
• Trigger factors stress, anxiety, excitement, food (like chocolate and cheese), and hormonal changes.
• These factors stimulate the release of vasoactive substances from nerve endings.
• However, the exact pathophysiology is not understood.

Read And Learn More: Pharmacology Question And Answers

Drugs Used In Acute Attacks:

Mild:

• Analgesics like aspirin, paracetamol, and other NSAIDs are effective for mild pain.
• They should be taken at the initiation of the attack.

Moderate to severe:

• Ibuprofen, diclofenac, naproxen, or mefenamic acid may be given in combination with caffeine.
• Because caffeine also has an analgesic effect and promotes the absorption of NSAIDs.

Severe migraine:

• May not respond to NSAIDs and may require:
• Ergotamine oral, SL or rectal
• Sumatriptan → very effective but short-acting → dose needs to be repeated if pain recurs.
• Antiemetics like metoclopramide may be needed—it promotes gastric emptying and also speeds up the absorption of aspirin.

Prophylaxis:

When the attacks are frequent (2–3 per month) and severe, prophylaxis is needed to prevent them. Drugs used for the prophylaxis are:

1. β-adrenergic blockers: Propranolol reduces the frequency and severity of attacks. The initial dose is 40 mg twice daily and is gradually increased to a maximum of 160 mg twice daily. The mechanism of action is not exactly known but is the most commonly used drug for the prophylaxis of migraine. To be avoided in asthmatics.
2. Calcium channel blockers: Flunarizine has weak Ca⁺⁺ channel-blocking properties and is thought to be selective for the CNS. Adverse effects include hypotension, flushing, dry mouth, constipation, and sedation. Verapamil can be used.
3. Tricyclic antidepressants: Amitriptyline may be tried but it is associated with many adverse effects. It may be considered in patients who also have depression.
4. Antiepileptics: Sodium valproate and gabapentin have prophylactic value in migraine. Topiramate, a newer antiepileptic drug, reduces the frequency of attacks. Started with 25 mg OD, the dose is gradually increased up to 50 mg once or twice a day.
5. Methysergide, pizotifen, and cyproheptadine: Block 5-HT receptors but due to adverse effects they are not preferred.

Prostaglandins/Eicosanoids:

Eicosanoids are 20-carbon (Nicosia—20 in Greek) unsaturated fatty acids derived from arachidonic acid in the cell membrane. The important eicosanoids are prostaglandins (PG), prostacyclin (PGI₂), thromboxanes (TXA), and leukotrienes (LT).

The prostanoids act on many tissues to bring about the following effects:

1. CVS:

• PGI₂ and PGE₂ cause vasodilation while TXA₂ causes vasoconstriction. PGE₂ and PGF_2α are weak cardiac stimulants.
• The vasodilator prostaglandins PGE₂ and PGI₂ are responsible for maintaining the patency of the ductus arteriosus during fetal life.

2. GIT:

• Most PGs and TXs stimulate GI smooth muscle resulting in colic and watery diarrhea.
• PGE₂ inhibits gastric acid secretion and increases mucus production → protective effect on gastric mucosa.

3. Airways:

• PGE₂ and PGI₂ → relax bronchial smooth muscle
• TXA_2α and PGF_2α → contract bronchial smooth muscle.

4. Platelets:

• TXA₂ induces platelet → aggregation, while PGI₂ inhibits platelet aggregation. In low concentrations, PGE₂ enhances platelet aggregation but in higher concentrations, it inhibits platelet aggregation.
• TXA₂ biosynthesis in the platelets is irreversibly inhibited by long-term administration of low-dose aspirin.

5. Reproductive system:

Female reproductive system:

• Uterus:
  • PGE₂ and PGF_2α contract uterus which is more sensitive to PGs during pregnancy.
  • They also soften the cervix and may be involved in the initiation and progression of labor.
  • PGs are produced by fetal tissues during labor.
    • They also play a role in dysmenorrhea and menorrhagia.

Male reproductive system:

• PGs present in the semen facilitate the movement of sperm and fertilization by coordinating the movement of the uterus.
• PGs also have a role in penile erection as they relax the smooth muscle of the corpora cavernosa.

6. Kidneys:

• PGs are synthesized both in the medulla and the cortex, ↑ ↑ renal blood flow, and regulate renal function, particularly during renal impairment.
• PGE₂ and PGI₂ cause renal vasodilation, have a diuretic effect, and also oppose the action of ADH.
• PGs regulate the excretion of sodium and water → important role in maintaining BP.
• PGE₂ also stimulates renin release.
• NSAIDs inhibit PG synthesis and their long-term use can result in renal dysfunction.

7. Central and peripheral nervous system:

• PGs increase body temperature; PGD2 also induces sleep.
• Nerves: PGs sensitize sensory nerve endings to pain and on intradermal injection cause pain. They also modulate pain centrally.

8. Inflammation and immunity:

• PGs increase the blood flow in the inflamed areas and facilitate leukocyte infiltration and the development of edema.
• They also suppress lymphocyte function, proliferation, and cytokine release to inhibit the immunologic response.

9. Bone: PGs stimulate bone resorption and formation through osteoclastic and osteoblastic
activities.

10. Endocrine system:  PGs stimulate the release of insulin and growth hormone, have thyrotropin-like effects on the thyroid, and also stimulate the production of steroids by the adrenals.

11. Eye: PGE and PGF_2α reduce the intraocular pressure probably by facilitating the drainage of aqueous humor through the uveoscleral pathway.

12. Cancer:

• PGE₂ is considered pro-oncogenic and is found to promote the growth and metastasis of cancers.
• The use of NSAIDs has been shown to restrict tumor formation.

Prostanoids Adverse effects:

Adverse effects depend on the type of PG, dose, and route. Diarrhea, nausea, vomiting, fever, hypotension and pain due to uterine contractions are common.

Prostanoids Uses:

Question 6. List the PG analogs used clinically and write the uses for each.
Answer:

1. Gynecological and obstetrical:

• Abortion: PGE₂ (dinoprostone), and PGF_2α are used for I-and II trimester abortion and ripening of the cervix during abortion. They are used with mifepristone to ensure complete expulsion of the products of conception in early pregnancy.
• Induction of labor: As an alternative to oxytocin, PGE_2α (intravaginal) is used as it does not cause fluid retention.
• Cervical priming: Intravaginal PGE₂ is used as a gel to soften the cervix.
• Postpartum hemorrhage: PGF_2α (IM) is used as an alternative to ergometrine.

2. Glaucoma:

• PGF_2α analog latanoprost (eye drops) is the first-line drug to lower intraocular pressure in glaucoma.
• Bimatoprost, travoprost and unoprostone are also used.

3. Cardiovascular:

• Patent ductus arteriosus:
  • The vasodilator prostaglandins PGE₂ and PGI₂ produced in the ductus arteriosus during fetal life maintain its patency during this period and at birth the ductus arteriosus closes.
  • In neonates with some congenital heart diseases, patency of the ductus arteriosus needs to be maintained even after birth and is maintained with PGs until surgical correction is done.
  • Alprostadil is given as an IV infusion.
• To prevent platelet aggregation during hemodialysis and cardiopulmonary bypass.

4. Peptic ulcer: PGE₁ (analog misoprostol) and PGE₂ (analog enprostil) are used for the prevention of peptic ulcer in patients on high-dose NSAIDs.

5. Peripheral vascular diseases:  PGI₂ or PGE₁ IV infusion causes vasodilation and provides relief from pain in intermittent claudication and in Raynaud’s disease.

6. Pulmonary hypertension:

• Epoprostenol (PGI₂) infusion has been used to lower pulmonary hypertension.
• Longer-acting analogs iloprost and treprostinil are available.

7. Erectile dysfunction:

Alprostadil injected into the cavernous or as a urethral suppository is used as an alternative to sildenafil in erectile dysfunction.

Uses of prostaglandin analogs:

Leukotrienes:

• Leukotrienes are products of arachidonic acid metabolism synthesized by the lipoxygenase pathway and are found in the lungs, platelets, mast cells and white blood cells. (‘Leuko’— because they are found in white cells; ‘trienes’—they contain three double bonds).
• LTA 4 is the precursor from which LTB₄, LTC₄, LTD₄, LTE₄, and LTF₄ are derived.
• LTC₄, LTD_4, and LTE₄ are together known as slow-reacting substances (SRS-A) of anaphylaxis.
• The LTs produce their effects through specific receptors.

Leukotrienes Actions:

• Leukotrienes cause vasoconstriction, alter vascular permeability leading to edema, increase airway mucus secretion, and causes bronchospasms.
• Given subcutaneously they cause wheal and flare.
• Leukotrienes have a role in inflammation including rheumatoid arthritis, psoriasis, and ulcerative colitis.
• They also contribute to bronchial hyperresponsiveness in bronchial asthma.
• LT receptor antagonists like montelukast and zafirlukast and LT synthesis inhibitors like zileuton is useful in the treatment of bronchial asthma and allergic rhinitis.