Lecture 16 & 17 : Migraine Case Study (Chem) & Migraine Pharmaceutical Care

Question 1

What is a migraine?

Answer 1

• Disorder characterised by episodic attacks of head pain and associated symptoms: photophobia, allodynia, N&V
• Inherited tendency
• Neurobiologically based

Question 2

What are the different phases of a migraine attack?

Answer 2

• Pre-headache: Prodrome and Aura. Warning symptoms upto 48hrs before. Aura
• Headache: Mild/ Moderate. Unilateral pulsing pain
• Resolution/ Postdrome: Symptoms occuring days after headache resolution

Question 3

What different medicines can be given for migraine?

Answer 3

• Painkillers: Most effective at first signs of headache
• Triptans: Cause BV around brain to contract which reverses dilation
• Anti emetics

Question 4

What is serotonin?

Answer 4

• Monoamine neurotransmitter (5-HT - 5 hydroxytryptamine)
• Has amine and hydroxy group
• Implicated in lots of diseases: pain, Parkinsons disease, depression, migraine

Question 5

How is serotonin synthesised? + how many serotonin receptors are classified and which is the most important for migraine?

Answer 5

• Tryptophan has an -OH stuck on it (hydroxylation) then decarboxylated to serotonin
• 7 types. In receptor 1. 5HT1

Question 6

What type of receptors are 5 HT receptors and which do triptans bind to?

Answer 6

• 7 transmembrane G-protein coupled receptors
• Pre and post synaptic
• 5HT1d in CNS primarily but also 5HT1F and 1B

Question 7

Define agonist, antagonist and partial agonist?

Answer 7

• Agonist: Chemical that binds to a receptor and causes a specific response
• Antagonist: Binds to receptor and blocks the response
• Partial agonist: elicits a partial response, even at maximum occupancy

Question 8

What is the structure of triptans like and which parts are changed to be like triptans?

Answer 8

• General structure reflects serotonin (mimicking the agonist)
• Modification of 5-hydroxyl and the amine
• These have modifications on physical properties, CNS penetration and Log P

Question 9

What is Sumatriptan and how does it bind to 5HT1D receptor?

Answer 9

• Type of triptan. Analogue of serotonin and more metabolically stable
• 3 H bonds and a salt bridge (strong electrostatic attraction)
• The salt bridge has a tertiary amine -> high pKa -> strong base -> protonated at all physiological pH

Question 10

Name examples of triptans?

Answer 10

• Sumatriptan
• Zolmitriptan
• Naratriptan
• Rizatriptan

Question 11

How are sumatriptan and zolmitriptan metabolised by?

Answer 11

• Are substrates for hepatic monoamine oxidase type A enzyme
• Oxidation

Question 12

How is Eleptriptan and Frovatriptan metabolised and how does it change the properties?

Answer 12

• They have longer half life and metabolised by CYP450 enzymes
• Undergo positive dealkylation/ oxidative dealkylation
• Increase water solubility, more polar -> better for next phase

Question 13

How much is Sumatriptan metabolite excreted?

Answer 13

• 60% metabolite excreted in urine

Question 14

What is an indole ring and give an example?

Answer 14

• a bicyclic, fused ring structure made up of a benzene ring and a five-membered pyrrole ring that contains nitrogen.
• neurotransmitter serotonin

Question 15

What is CGRP?

Answer 15

• 37 amino acid neuropeptide derived from gene encoding calcitonin.
• Functions as a messenger in nerve cells and as a vasodilator
• Exists in 2 forms, a (predominates in CNS & PNS) and B

Question 16

Where does CGRP bind?

Answer 16

• Binds to CGRP receptors found throughout body
• They are heterotrimers. Composec of calcitonin like receptor (CLR), Gs protein structure & RAMP1
• Receptor component protein important for signalling

Question 17

How is CGRP released?

Answer 17

• Gs protein action The increased levels of secondary messengers inside the neuron lead to the activation of protein kinase pathways
• These kinases then promote the release of CGRP from the nerve endings

Question 18

What effects do CGRP cause?

Answer 18

• CGRP is released during the activation of the trigeminal nerve, role in pain transmission.
• The peptide induces dilation of cranial blood vessels and promotes inflammation, contributing to pain and prolonged migraine attacks.

Question 19

What are the 2 different treatments for CGRP transmission?

Answer 19

• CGRP Receptor Antagonists (Gepants - Ubrogepant) These block CGRP from binding to its receptors, preventing the cascade that leads to migraine pain and related symptoms.
  * CGRP Monoclonal Antibodies (Fremanezumab, Erenumab) long-acting, high selectivity treatments that bind to either the CGRP ligand itself or the CGRP receptor, effectively preventing the peptide from exerting its pain-inducing effects.

Question 20

How are small molecules (CGRP anatagonists) metabolised and how are monoclonal antibodies degraded?

Answer 20

• Metabolised by CYP450
• Largely changed, protein bound
• Not by liver. Are degraded by proteolytic cleavage (making into smaller peptides) and no reactions to inducers or inhibitors of CYP450

Question 21

Do CGRP targeted agents need to cross the BBB?

Answer 21

• The trigeminal ganglion is the key site of action in CGRP - expressed outside BBB - dont need to penetrate to act
• Monoclonal Antibodies cant cross (too big)

Question 22

How does Sumatriptan work?

Answer 22

Serotonin (5-HT1) Receptor Agonist:

• Specifically binds to 5-HT1B and 5-HT1D receptors in the trigeminal ganglion.
• Activation of 5-HT1B receptors causes the constriction (narrowing) of cranial blood vessels.
• This action helps counteract the abnormal vasodilation (widening of blood vessels) believed to contribute to migraine pain.
• Activation of receptors inhibits the release CGRP and substance P.
• Sumatriptan reduces inflammation and pain transmission associated with migraines.

Question 23

What is a new class of drugs that target 5HT1F receptors and name an example?

Answer 23

• Ditans
• Agonist activity is restricted to the 5-HT1F and no vasoconstrictive effect - can treat those w/ cardio disease
• Lasmiditan

Question 24

What is the major metabolic pathway of Lasmiditan?

Answer 24

• Reduction to ketone.
• Drug is metabolised hepatically and extra hepatically by non-CYP450 enzymes
• Inducers/ inhibitors unlikely to influence pharmacokinetics

Question 25

What are the different types of headache?

Answer 25

* Migraine w/ aura * Tension type * Cluster headache * Medication overuse headache

Question 26

When is further investigation needed in the clinical assessment of headache?

Answer 26

- Worsening w/ fever - Sudden onset w/ maximum intensity within 5 mins - Change in personality - Impaired level of consiousness - Recent head trauma

Question 27

Where is the location, pain quality, pain intensity and duration of a tension-type headache?

Answer 27

* Bilateral * Pressing tightening * Mild to moderate * 30 min -> continuous

Question 28

What is the pain location, pain quality, pain intensity and symptoms of a migraine?

Answer 28

* Unilateral/ Bilateral * Pulsating * Moderate-severe * Unusual sensitivity to light/ sound

Question 29

What is the pain location, pain quality, pain intensity and symptoms of a cluster headache and duration?

Answer 29

* Unilateral (around eye, along side of face) * Variable (sharp, burning, throbbing) * Severe or severe * On same side as pain: red watery eyes, facial sweating, constricted pupil * 15-180 mins

Question 30

What are some migraine triggers?

Answer 30

- Lack of sleep - Fatigue - Stress - Hormones - Food, vision, sound - Vasodilators -

Question 31

When should you use a headache diary and what should you write into it?

Answer 31

* Primary headache diagnosis * Frequency, duration, severity * Symptoms * All meds * Triggers

Question 32

What are some medication advice to give for overuse medicines headaches?

Answer 32

* Stop taking acute meds for at least 1 month * Stop triptans, ergotamines and simple analgesics abruptly * Will have worsening and withdrawal 1-2 weeks (N &V, hypotension, anxiety, sleep disturbances) * Restrict analgesics to no more than 2 days in a week

Question 33

What are questions to ask when a patient presents with a headache?

Answer 33

- Location (back/ front) - Type of pain: sharp/ dull/ throbbing - How long (quick onset)/ sensitivity - Fever/ temps of hands and feet - Trauma to head - Meds (tried/taken) - Severity - Symptoms: rash, stiff neck, muscle pain

Question 34

What drugs can be used for initial treatment and which for long term use?

Answer 34

* Oral triptans * Propanalol, Topiramate, Amitriptyline, Candesartan, Sodium Valporate

Question 35

What are some non-drug options that can be used in prevention of migraine?

Answer 35

* Behavioural intervention * Acupuncture * Riboflavin (Vit B2)

Question 36

What are some counselling points for topiramate?

Answer 36

* For people w/ child bearimg potential * Risk of fetal malformations, risk of reduced effectiveness in hormonal contraceptives

Question 37

What are some specialist drugs used for migraines?

Answer 37

* Botulinum toxin A (BOTOX): prophylaxis on chronic migraine where 3/ more oral treatments have been tried * CGRP Mono antibodies (bind and block reducing blood vessel size) and receptor antagonists (inhibits function of CGRP)

Question 38

What do NICE guildlines recommend for acute treatment of tension type headache?

Answer 38

* Aspirin, Paracetamol or an NSAID considering patient preference, co morbidities * Warning: Aspirin not suitable under 16 to Reyes syndrome * Dont offer opioids

Question 39

What are 2 anti emetics used in migraine?

Answer 39

* Metoclopramide: Not children under 1, not in neurological disease * Prochlorperazine: Not in CNS depression, liver/renal dysfunction, neurological disorders (Parkinsons), caution in elderly & Hypothyroidism

Question 40

What are the rules regarding contraceptive pills and migraines?

Answer 40

* Migraine w/ aura: Should not take contraceptive pill due to stroke risk * Without aura can take unless have hypertension or family history of stroke