Help
Options
Didn't know it?
click below
click below
Knew it?
click below
click below
Don't Know
Remaining cards (0)
Know
retry
shuffle
restart
0:00
Embed Code - If you would like this activity on your web page, copy the script below and paste it into your web page.
Normal Size Small Size show me how
Normal Size Small Size show me how
Sikazawe CNS 1 B
Epilepsy AED Medicinal Chemistry
| Question | Answer |
|---|---|
| GABA Biosynthesis and deactivation—> we start with L-glutamic acid (excitatory NT) that is metabolized by _____ and Vit B6 to give us GABA (inhibitory NT)—> acted on by GABA-T to give us Succinic Acid Semialdehyde (SSA) | GAD (Glutamic acid decarboxylase |
| Located on GABA (inhibitory NT) contains a _____ ______ at the amine group. Which changes hte name to? | Gamma carbon; Camma amine butyric acid |
| GABA needs 4 carbons; GABA T is produced in the synapse and can deactivated the GAMMA carbon by _____ _____ | oxidative elimination of the amine to produce an aldehyde and give SSA |
| remember that GAT-1 facilitates the reuptake of that NT known as _____ ______ | reuptake metabolism |
| General MOA of Na+ Ca2+ (VGSCs and VGCCs)—> | modulation of Voltage gated channels |
| increasing of GABA activity leads to—> | increasing GABA biosynthesis*, inhibiting GABA reuptake* or metabolism **; Allosteric* modulation of GABA receptor |
| Attenuation of Excitatory Glutamate activity via ion channels affects which channels? | ❑ NMDA* (N-methyl-D-aspartate) ❑ AMPA* (L-a-amino-3-hydroxy-5-methyl-4-isoxazole propionate) ❑ KA* (Kianate) |
| Phenobarbital is a ________ barbituate; lipophilic weak acid (pKa 7.4, is 50% ionized @ physiological pH >80% bioavailable, t1/2 2-6 days (why? slow redistribution) Alkalizing urine ↑ excretion of drug & metabolites Induces ____ and ______ | Prototype; 3a4, UGT; Slow redistribution—> accumulates in lipophilic tissue and diffuse out slowly Anjali zing using?—> can aid during overdose situation. |
| Phenobarbital (contains H+ make it acidic due to electron withdrawal) is broken down by CYPs And can undergo? | aromatic hydroxuylaition and UGT’s (O-gluc) |
| Primidone (Mysoline) is a ______ of phenobarbital; CYP and UGT INDUCER; Metabolized to _________ and PEMA (maj. metabolite); PEMA renal clearance is LOW in ELDERLY. | Prodrug; Phenobarbital |
| Primidone (1/2 life 10-12h) undergoes oxidative metabolism to phenobarbital (minor metabolite) to _______ (PEMA) (less potent but TOXIC METABOLITE) | phenylethylmalonamide (1/2 life 24-48h) |
| Phenytoin (Dilantin) Is a Hydantoin. PO phenytoin is > 70% BA. Injectable phenytoin leads to —> | Erratic ADME - poor H2O solubility Crystallizes when given IM Solns. absorb CO2 & crystalize; *if phenytoin is cloudy—> means it starts absorbing CO2 from air.) |
| Fosphenytoin (Cerebyx) a hydantoin drug is a ______ prodrug of _______. -Is bioactivated by phosphatases (to release phosphates) To overcome erratic absorption of phenytoin. | phosphate; phenytoin *this is a solution to erratic absorption of phenytoin. |
| Phenytoin induces UGTs and what CYPs? | 1A2, 2C9, 2C19, 3A4; Arenes & Quinones = hypersensitivities (e.g., Gingival hypertrophy & Skin rashes) |
| Phenytoin effect on 2C9 and 2C19 catalyze Ar-OH excreted as ____ | |
| Metabolism of Phenytoin (PHT)—> CYP leads to PHT-aren’t-oxide containing a reactive ______. Further metabolized to give a hydroxylated hydantoin ____ ______; which undergoes further oxidation to a quinone metabolite ____ ___ _____ | epoxide; OH-hydnatoin; PHT-o-quinone (reactive metabolite |
| Ethosuximide (Zarontin) is the ________ toxic succinimide. Metabolized by ______ to -PH metabolites and then UGTs; It can undergo Hypersensitivity rxns such as _________,___-___ _____, etc | least; Agranulocytosis, PD-like symptoms, etc) *1/2 life—> 40-60h *agranulocytosis—> decrease in WBC count (now need to monitor) *Succinimides are known to cause morphological changes to liver and kidneys* |
| Carbamazepine or CBZ (Tegretol) is an ________. Slows oral absorption and is an AUTOINDUCER (3A4 and UGT; variable 1/2 life 8-29h) and clearance; therapeutic levels may take a month to achieve the right conc. In blood. | iminostilbene; *takes time to achieve right therapy levels due to autoinducing action |
| CBZ-IQ (contains an immunoquinone). CBZ converts via 3A4 to CBZ-E (contains an _______ (active). And via Epoxide hydrolyzed converts to a ____-____ | epoxide; trans-diol |
| Oxcarbazepine (OXC) (Trileptal) is a _____ analog of CBZ; does not epoxidase - less toxic; 1/2 life--> 2h; Metaboliusm via ____ (stereoselectively) to racemic (80% -S/ 20%R ) MHD ___________ | ketone; Mono-OH-carbazepine also caled Licarbazepine |
| The theory from converting Carbamazepine to Oxcarbazepine was to make it less _______. To accomplish this, they removed the double bond and added a ______ | Toxic; carbonyl |
| Oxcarbazepine is metabolized via AKR(Aldo-keto reductase and redices the carbonyl to give a _____ *remember that Oxcarbazepine is part of what class of drugs? | hydroxy group placed on MHD which is then broken down by O-Gluc Imimnostilbene |
| Eslicarbazepine Acetate (Aptiom) is an _____ prodrug of S-(+)- MHD or S-(+)- Licarbazepine and induces ______ and inhibits _____ | ester; 3A4; 2C19 |
| The theory behind Eslicarbazepine Acetate or Aptiom was to "tease out" the active isomer and made a prodrug that must undergo ______ to give rise to S-(+)-MHD (active) which can then undergo UGT (O-gluc) | Esterase hydrolysis (in order to bioactivate that active isomer) |
| Felbamate or FBM (Felbatol) is a _________. This drug has a Black Box warning for causing? | Carbamate; Aplastic anemia & and is HEPATOTOXIC |
| Felbamate undergoes ADH hydrolysis to give CBMA which is the acronym for what major metabolite? | 3-carbamyoyl-2-phenyl-porpionic acid. |
| 3-carbamyoyl-2-phenyl-porpionic acid (Major metabolite of Felbamate) can undergo further metabolism to _________ which is electrophilic and is the culprit to the black box warning for causing aplastic anemia | 2-phenylpropenal (Atropaldehyde) |
| CBMA can undergo (biscarbonate oxidation?)_______ to form an INACTIVE major metabolite | ALDH |
| Cenobamate (XCOPRI) is a _________ and rapidly absorbed by PO (80% oral BA); 1/2 life is 30-76h. It undergoes extensive metabolism via _______, hydrolys, & hydroxylation (2E1/2A6/2B6) | carbamate; UGT2B7 *reliance on phase II metabolism; |
| Cenobamate is a ____ ________ _______ of GABA and binds to site and promotes better interaction and enhances GABA giving a Log P that is lipophilic but rapidly absorbs | (+) allosteric modulator *Sikazawe pointed out that this has the sugar structure (perhaps for better interaction) CLARIFY before exam** |
| Gabapentin (Neurontin) structure is known as a? | Cyclohexyl GABA (remember that GABA contains 4 carbons) (amine-3C-Coboxylic Acid group) |
| Pregabalin (Lyrica) is a __-____ _____ that is 3-10x more potent vs Gabapentin | 3-Isobutyl (S-isomer - Active) |
| The Gaba-like drugs (Gabapentin and Pregabalin) resemble GABA but have ____ _____ GABA activity. 1/2 life is 5-7h Uptake is via ______ L-amino Acid transporter (LAT) -90% excreted unchanged-- Few metabolic DDI | NO DIRECT; Saturable *Sikazawe pointed out: "increase the dose but decreases oral BA ("the higher you go on the dose, the less you start seeing and with low BA, less is getting through. |
| Vigabatrin (Sabril) is a 4-______ analog of GABA; it an ________ inhibotr of GABA-T; rapidly abosrbed (BA ->60%); 1/2 life 6-8h, excreted in urine; the __-(+)-isomer is active; However this drug is NOT an ___-1 substrate | *vinyl; Irreversible; S; LAT GABA is not able to be metabolized to SSA with blocking GABA-T |
| Lamotrigine (Lamictal) is a _,_,_-triazine and its metabolism has a mjor metabolite _______ and forms allergic rxns known as ______ | 1,2,4; N2-glucuronides; GSH-conjugate |
| Lamotrigin (Lamictal) is co-administered with ______ ____ to inhibit UGTs; however Lamotrigine may cause____/____ insufficeiceny to increase | Valproic Acid; Rena;/Hepatic |
| Lamotrigine underoges metaboliusm to GSH-conjugate (minor metabolite forms an epoxide intermediate that can undergo GST (Glutathione-S-transferase) that has been implicated in causing the _____ _____ | allergic rxn |
| Miscellaneous drugs categorized by Sikazawe are which ones? | Lamotrigine (Lamictal); Topiramate or TPM (Topamax); Zonisamide (Zonegran); s-(-)- Letetiracetam (Keppra); Vaproic Acid or VPA (Depakote); Tiagabine (Gabitril) |
| Topiramate or TPM (Topamax) is a _______ __________ derived from D-FRUCTOSE | Sulfamate monosaccharide |
| Topirmaate has greater than 80% oral BA and enters the brain via _-____ ______. Its an inducer of ____ and a _____ INHIBITOR. This drug inhibits _____ ______which is a metabolic acidosis concern | *D-Glucose transporter; 3A4; 2C19; Carbonic Anhydrase *Sikazawe: "Topiramate has the advantage of resembing a glucose structure (entering the brain) |
| Metabolism of Topiramate is via _________ | Sulfatase (breaks off the Sulfamate on its structure) |
| Zonisamide (Zonegran) is a ___________ witha 1/2 life of 50-70h; but __-__ in the presence of DME induction. This drug INHIBITS _____ ______--> metabolic acidosis | Sulfonamide; 27-46h; Carbonic Anhydrase |
| Zonisamide (Zonegran) involves CYP enzymes 3A4/2D6 to form _____ and undegoes further metabolism to form ____ | SMAP (2-(Sulphamoylacetyl)-phenol); SMAP Gluconronide (major metabolite) All metabolites per slide: N-acetyl zonisamide, SMAP & O-Glucs |
| S-(-)-Levetiracetam (Keppra) is a _______ The S-(-)- isomer is 1000x more potent; The ADVANTAGE is that its not metabolized by ____,____, or __. 60% is excreted unchanged and undergoes what type of metabolism?? Elimination 1/2 life is 7-8h | Pyrrolidinone; CYPS, UGTs, or EH (meaning less PK to worry for. Amide Hydrolysis to -COOH |
| Valproic Acid or VPA (Depakote) has a pKa of 4.7; ionized _______ ___ is the active species. 90% protein bound and MOA is ____-_____ with a 1/2 life of 9-18h; VPA is broken down by UGT to form VPA Glucuronide (major urnary metbaolite that is inactive) | Valproate ion; Multi-Modal |
| DDIs/Toxicity of Valproic Acid--> Complex metabolism via CYPs UGTs, etc; Inhibits _____ ____, ___. What are the limitations of Valproic acid? | 2C9, UGTs, EH (epoxide hydrolases); Dose dependent, Hepatotoxicity & Teratogenicity |
| Toxicity of Valproic Acid stems from the ______ from ene and expoxide metabolites | Alkene (double bond) |
| What are the reactive metabolite species that Sikazawe pointed out of Valproic Acid? | E-2-4-diene-VPA (toxic) and 4-5-Epoxy-VPA (Toxic) |
| Tiagabine (Gabitril is a ____ ____ inhibitor (GAT-1 inhibition); | GABA uptake |
| Tiagabine is a derivative of ______ ___ which is the main compound to help its mechanism to affect the GABA uptake in GLIAL cells. Has an oral BA of 90-95%) and is inactivated by ____ and ____. Its 1/2 life is 7-9h | Nipecotic Acid; 3A4 and UGTs |
| Lacosamide (Vimpat) is a derivative of _______. Its R-isomer is more active. 1/2 life is approx 13h and requires ________ 2C19. It has no effect on CYPs and undergoes 95% renal excretion. | SERINE; polymorphic |
| Peramanel (FYCOMPA) is a ______ and a ______ _________ is rapidly abosrbed orally (100% BA). Half life is ______ and may be longer with _____ _____. Undegoes extensive metabolism via CYP3A4 then Glucoronudation | PYRIDONE; *AMPA ANTAGONIST; 105h; Liver Impairment (**AMPA antagonist not on slide but from Sikazawe) |
| Perampanel undegoes 3A4 to form an ______-OH that is further broken down by UGT -> O-Gluc. | Aromatic OH (to give that hydroxylated intermediate which is the UGT can glucoronudate. |
| Remember to look at Slide 4 of the Slide Deck which shows the __ drug core structures that Sikazawe wants us to know | 6 |
Created by:
Xander635
Popular Pharmacology sets