Lecture 16 & 17 : Migraine Case Study (Chem) & Migraine Pharmaceutical Care Flashcards
What is a migraine?
- Disorder characterised by episodic attacks of head pain and associated symptoms: photophobia, allodynia, N&V
- Inherited tendency
- Neurobiologically based
What are the different phases of a migraine attack?
- 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
What different medicines can be given for migraine?
- Painkillers: Most effective at first signs of headache
- Triptans: Cause BV around brain to contract which reverses dilation
- Anti emetics
What is serotonin?
- Monoamine neurotransmitter (5-HT - 5 hydroxytryptamine)
- Has amine and hydroxy group
- Implicated in lots of diseases: pain, Parkinsons disease, depression, migraine
How is serotonin synthesised? + how many serotonin receptors are classified and which is the most important for migraine?
- Tryptophan has an -OH stuck on it (hydroxylation) then decarboxylated to serotonin
- 7 types. In receptor 1. 5HT1
What type of receptors are 5 HT receptors and which do triptans bind to?
- 7 transmembrane G-protein coupled receptors
- Pre and post synaptic
- 5HT1d in CNS primarily but also 5HT1F and 1B
Define agonist, antagonist and partial agonist?
- 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
What is the structure of triptans like and which parts are changed to be like triptans?
- 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
What is Sumatriptan and how does it bind to 5HT1D receptor?
- 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
Name examples of triptans?
- Sumatriptan
- Zolmitriptan
- Naratriptan
- Rizatriptan
How are sumatriptan and zolmitriptan metabolised by?
- Are substrates for hepatic monoamine oxidase type A enzyme
- Oxidation
How is Eleptriptan and Frovatriptan metabolised and how does it change the properties?
- They have longer half life and metabolised by CYP450 enzymes
- Undergo positive dealkylation/ oxidative dealkylation
- Increase water solubility, more polar -> better for next phase
How much is Sumatriptan metabolite excreted?
- 60% metabolite excreted in urine
What is an indole ring and give an example?
- a bicyclic, fused ring structure made up of a benzene ring and a five-membered pyrrole ring that contains nitrogen.
- neurotransmitter serotonin
What is CGRP?
- 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
Where does CGRP bind?
- 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