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Stage 3 - Case 1 (Pain) > Lecture 16 & 17 : Migraine Case Study (Chem) & Migraine Pharmaceutical Care > Flashcards

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

1
Q

What is a migraine?

A
  • Disorder characterised by episodic attacks of head pain and associated symptoms: photophobia, allodynia, N&V
  • Inherited tendency
  • Neurobiologically based
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2
Q

What are the different phases of a migraine attack?

A
  • 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
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3
Q

What different medicines can be given for migraine?

A
  • Painkillers: Most effective at first signs of headache
  • Triptans: Cause BV around brain to contract which reverses dilation
  • Anti emetics
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4
Q

What is serotonin?

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

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

A
  • Tryptophan has an -OH stuck on it (hydroxylation) then decarboxylated to serotonin
  • 7 types. In receptor 1. 5HT1
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6
Q

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

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

Define agonist, antagonist and partial agonist?

A
  • 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
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8
Q

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

A
  • 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
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9
Q

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

A
  • 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
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10
Q

Name examples of triptans?

A
  • Sumatriptan
  • Zolmitriptan
  • Naratriptan
  • Rizatriptan
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11
Q

How are sumatriptan and zolmitriptan metabolised by?

A
  • Are substrates for hepatic monoamine oxidase type A enzyme
  • Oxidation
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12
Q

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

A
  • They have longer half life and metabolised by CYP450 enzymes
  • Undergo positive dealkylation/ oxidative dealkylation
  • Increase water solubility, more polar -> better for next phase
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13
Q

How much is Sumatriptan metabolite excreted?

A
  • 60% metabolite excreted in urine
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14
Q

What is an indole ring and give an example?

A
  • a bicyclic, fused ring structure made up of a benzene ring and a five-membered pyrrole ring that contains nitrogen.
  • neurotransmitter serotonin
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15
Q

What is CGRP?

A
  • 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
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16
Q

Where does CGRP bind?

A
  • 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
17
Q

How is CGRP released?

A
  • 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
18
Q

What effects do CGRP cause?

A
  • 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.
19
Q

What are the 2 different treatments for CGRP transmission?

A
  • 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.
20
Q

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

A
  • 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
21
Q

Do CGRP targeted agents need to cross the BBB?

A
  • 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)
22
Q

How does Sumatriptan work?

A

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.
23
Q

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

A
  • Ditans
  • Agonist activity is restricted to the 5-HT1F and no vasoconstrictive effect - can treat those w/ cardio disease
  • Lasmiditan
24
Q

What is the major metabolic pathway of Lasmiditan?

A
  • Reduction to ketone.
  • Drug is metabolised hepatically and extra hepatically by non-CYP450 enzymes
  • Inducers/ inhibitors unlikely to influence pharmacokinetics
25
Q

What are the different types of headache?

A
  • Migraine w/ aura
  • Tension type
  • Cluster headache
  • Medication overuse headache
26
Q

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

A
  • Worsening w/ fever
  • Sudden onset w/ maximum intensity within 5 mins
  • Change in personality
  • Impaired level of consiousness
  • Recent head trauma
27
Q

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

A
  • Bilateral
  • Pressing tightening
  • Mild to moderate
  • 30 min -> continuous
28
Q

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

A
  • Unilateral/ Bilateral
  • Pulsating
  • Moderate-severe
  • Unusual sensitivity to light/ sound
29
Q

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

A
  • 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
30
Q

What are some migraine triggers?

A
  • Lack of sleep
  • Fatigue
  • Stress
  • Hormones
  • Food, vision, sound
  • ## Vasodilators
31
Q

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

A
  • Primary headache diagnosis
  • Frequency, duration, severity
  • Symptoms
  • All meds
  • Triggers
32
Q

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

A
  • 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
33
Q

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

A
  • 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
34
Q

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

A
  • Oral triptans
  • Propanalol, Topiramate, Amitriptyline, Candesartan, Sodium Valporate
35
Q

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

A
  • Behavioural intervention
  • Acupuncture
  • Riboflavin (Vit B2)
36
Q

What are some counselling points for topiramate?

A
  • For people w/ child bearimg potential
  • Risk of fetal malformations, risk of reduced effectiveness in hormonal contraceptives
37
Q

What are some specialist drugs used for migraines?

A
  • 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)

Stage 3 - Case 1 (Pain) (12 decks)

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