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Sikazawe CNS 1A
Headache (HA) Anti-migraine Medicinal Chemistry
| Term | Definition |
|---|---|
| 4 drug classes that Sikazawe wanted us to focus on only includes? | Ergolines (Ergotamine, Dihydrogotamine); Triptans (Sumatra, Zomi, Nara, Rita, Almo, Ele, Frovatriptan); Ditans (Lasmiditan) Gepants (Uprogepant, Rimegepant, Alogepant, Zavegepant |
| Ergotamines are derived from _______ and very lipophilic (cLogP >3); Non-selective affinities for 5-HT ___,___,____; Poor oral BA due to 1st pass effect hence ____, ____, _____ dosing | Ergoline; 1B, 1D, 1F; SL, Rectal, Inhalation |
| 1/2 life of Ergotamine is 2-2.5 hours, BUT EFFECTS last longer due to ____ _______ dissociation | Slow receptor |
| Ergoline undergoes biosynthesis to get to Ergotamine which is broken down via ____ where we get-OH and N-demethylation where we see removal of Methyl metabolites | 3A4 |
| Dihydroergotomaine (D.H.E.45) is a lipophilic cLogP-> 4.8; and is a ________ derivative. It is non-selective 5-HT 1A,B, D agonist; It has poor oral BA (1st pass effect, hence it changes its formulation to _____, __. __. __ | Ergotamine; Nasal, IV, SC, IM |
| Dihydroergotamine (D.H.E.45, Migranal) is longer acting with a 1/2 life of 9h. What contributes to the longer 1/2 life? | metabolism. |
| Metabolism of Dihydroergotamine starts with and ends with? | Ergotamine—> undergoes db reduction by adding H+ and convert to sb becoming more flexible and prone to be more active allowing accessing receptors more quickly. DHE—> undergoes 3A4 leading to 8’B-hydroxydihydroergotamine (1/2 life 10-13h, CLogP-> 4.8 |
| 8’ B-hydroxydihydroergotamine compared to DHE is more? | potent than DHE and has a higher plasma conc.—> longer half-life than parent drug |
| Ergloine characteristics. They are non-selective, 5-HT, a-adrenergic receptors, etc. They embed __ and ___ FGs; Highly lipophilic; Poor oral BA, due to 1st pass metabolism; longer DoA—> slow receptor dissociation or active metabolites. Slow receptor dissociation correlates to _______ whereas the active metbolite correlates to ________ | DA and 5-HT; Ergotamine; DHE |
| Structures included in Ergolines can be________ and ________ | phenethylamines and Indolethylamines |
| Triptans are derived from ________ which undergoes _______ _______ leading to formation of 5-HTP which undergoes further processing via LAAD (L-aromatic AA decarboxylase) giving us 5-HT. 5-HT then undergoes metabolism to 5-OH IAA via what 2 enzymes? | Tryptophan; Tryptophan hydroxylase; 1. MAO. 2. ALDH |
| Sumatriptan (Immitrex, Imigrain is a _________. This is the first selective 5-HT1 agonist for migraines; has poor oral BA (14%) with a 1/2 life of 2h. | Sulfonamide |
| Sumatriptan is metabolized via MAO/ALDH to ______ (Major metabolite) | Indole acetic Acid (IAA) |
| 5-HT serotonin derivatives MOA are identical (5-HT1B/1D) bc they are involved in ______ and that ________ inflammation | vasoconstriction; neurogenic |
| To counter the 14% oral BA of sumatriptain, it was placed with ______ solution needles SQ injection increasing to 97% BA | succinate |
| Zolmitriptan (Zomig) is a cyclic ______. Oral BA improved to 40% vs Sumatriptan’s 14%; it is Lipophilic with a 1/2 life of 3h; N-does ethyl active metabolite is ______ more potent | carbamate; 2-6x |
| Zolmitriptan (Zomig) is also metabolites by not just CYP 1A2 (de methylation) to N-does ethyl-zolmititriptan (active) but also by MAO-A and ALDH to become ______ | IAA (Indole acetic acid metabolite |
| Naratriptan (Amerge) is a _________ triptan. Its oral BA improved at 70% and with a 1/2 life of 6h. | Sulfonamide *Sikazawe mentioned this is a “gentle triptan due to being longer acting and more manageable.” **Contains a constrained analog unlike the first 2 Triptans (Steric hinderance and not metabolized by MAOs) |
| 50-70% of Naratriptan (Amerge) is excreted in urine unchanged. Metabolism is done via _____ leading to greater than 70% excretion unchanged. CYP enzymes involved and ________ ⬆️ elimination (30%) | 1A2; smoking *meaning may need more dose |
| Rizatriptan (Maxalt) is a __________ triptan. Has 45% oral BA via 1st pass effect. It has a slower absorption rate and a 1/2 life of 2.5h. Its n-desmethyl metabolite is _____ | 1,2,4-triazole; active |
| Rizatriptan (Maxalt) is metabolized by _____/______(A)/______ to IAA (51%) | 3A4/MAO(A)/ALDH |
| Frovatriptan (Frova) is an _______ triptan. Its ____-isomer is active; oral BA is 60% with an 1/2 life of about 26h. This triptan is NOT metabolized by ________-A | Amide, R-(+); MAO-A |
| Frovatriptan is primarily metabolized by _________ and its metabolite __________ is active | CYP1A2 (remember smoking); N-Desmethylfrovatriptan |
| Perhaps _______can be used with MAO since it doesn’t require for metabolism; and this triptan has the highest affinity for 5-HT 1B (most potent) | Frovatriptan (Frova) |
| There are 3 Triptans not metabolized by MAO because of _________ _______. What are the 3 Triptans? | Steric hinderance (rings close to amine group) Frovatriptan (Frova), Eletriptan HBR (Relpax) |
| Eletriptan HBr (Relpax) is a _______ triptan and is an agonist at 1B/1D/1F. Its lipophilic and has 50% oral BA with a 1/2 life of 4h; Greater than 90% is metabolized by _______ to an ACTIVE N-desmethyl (1/2 life 10h) | Sulfone; CYP3A4 *steric hinderance |
| SAR of Triptans includes: (Slide 15) | *Indoleethylamine or Tryptamine *has secondary or tertiary N *R1 and R2 -> alkyl or cyclic *x-> polar groups |
| Triptans need a minimum of _____ attachments. | 1. Aspartic acid bonding 2. H-bonding (Threonine) 3. Binding of pi structure (phenylalanine) |
| Characteristics of Triptans includes ______ ________. Remember that 5-HT1B/1D agonists are vasoconstrictors and inhibitors of neurogenic inflammation; Triptans are metabolized by CYPs _____,______), ______/ALDH. | Indole Alkylamines; 1A2/3A4)/ MAOs |
| Sumatriptan/Rizatriptan/Zolmitriptan/Almotriptan—> have potential DDIs with MAOIs; SAN do not have active metabolites meaning—> _____ | fewer SE since no desmethyl metabolites |
| Lasmiditan (Reyvow) is a _______-_______. It’s a SELECTIVE 5-HT 1F receptor agonist (non-vasoconstricting). Its metabolism is primarily via non-CYP/non-AKR enzymes but IS a potential _____ INHIBITOR. 1/2 life 6h. | Pyridinoyl-piperidine; 2D6 *only DITAN available |
| Lasmiditan, according to Sikazawe, its 400x more selective for 1F than other receptors. this reduces the release of _____ peptide that has vasodilating properties | CGRP |
| 2nd gen Gepants—> Ubrogepant (Ubrelvy)—> is a _______ calcitonin gene-related peptide receptor (CGRP-R) antagonism | Carboxamide *remember that CGRP is a potent vasodilator peptide (37-amino acids) |
| BCRP and P-gap transporter inducers/inhibitors may ALTER systemic levels of _______. Metabolism is via 3A4 and UGTs; elimination 1/2 life is 5-7h. | Ubrogepant |
| Rimegepant (Nurtec) is a _______ CGRP-R antagonist 2nd gen Gepant. Oral BA is 60%; metabolism is via 3A4. BCRP and P-gp transporter substrate, inducers/inhibitors may ALTER ________ levels. 1/2 life. Is 11h eliminated mostly unchanged | Carbamate; Rimegepant |
| Atogepant (Qulipta is a __________ CGRP-R antagonist; its major metabolism is via 3A4 and UGTs; BCRP and P-gp, OATP substrate, inducers/inhibitors may ALTER ______ levels. Elimination 1/2 life is 11h | Carboxamide; Atogepant; *remember that UGTs are apart of the gluconuride phase II metabolism |
| What are the protein MABS? *all are CGRP receptor antagonists with long DoA of 25 days and high MW greater than 150kDa which are cleaved proteolytically and degraded prior to elimination to short AA peptides | Erenumab (Aimovig Fremanezumab (Ajoby) Eptinezumab-jjmr (Vyepti) |
| These protein MABS are still accessible to the brain since parts of the BBB are not well covered. ; These MABS either bind to the ____ or bind to the _____ itself | receptor; ligand |
| Other proteins apart from the MABS, is Botox (onabotulinumtoxin A) or BT-A—> what is the source? | Hall strain Clostridium botulinum type A; |
| Botox is a neurotoxicity polypeptide 150 kDa for chronic _____given IM | migraine |
| Botox has 2 chains (the shorter chain is the active site, whereas the long chain is for _______ or _______ onto the receptor | binding; landing |
| MOA of Botox is to? | inhibit ACh release and is a neuromuscular blocker. Its short chain cleaves SNAP-25 (key protein for ACh docking and release *not just CNS but can be seen in the periphery as well *its mainly a paralytic agent but can be used for migraine prophylaxis |
| T/F: Anti-migraine Triptans and Ergolines both embed the Indoleethylamine functionally. | True. *be sure to be able to point out the structures Triptans contain (indoleethylamine) whereas Ergolines contain a indoleethylamine as well as phenylethylamine |
Created by:
Xander635
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