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Sikazawe CNS 1C
CNS Analgesics Opioid Med Chem
| Question | Answer |
|---|---|
| Opiates are: | natural or synthetic structural analogs of morphine |
| Opioids are: | natural (peptides included) or synthetic agents with morphine - like effects |
| Narcotics are: | Agents possessing both analgesic & sedative properties |
| Pain is: | acute, chronic, Nociceptive, Neuropathic |
| Opioid antagonists: | Bind opioid receptors & block opioid agonist effects |
| Mixed agonists/antagonists are: | Mixed activity @ opioid receptors-are analgesics |
| Enkepalins are: | proteins with opioid activity |
| Endorphins are: | mammalian tissue opioid peptides |
| Analgesia is: | Loss of pain w/o loss of consciousness |
| Opioids are for ____ _____, have differnt Chemical classes; Lipophilicity can be (rigid vs flexible); all require Cationic N (pKas 8-10) for binding. Metabolism is via? | severe acute/chronic pain; O and N dealkylation, Sulfations & Gluconidations *Concerns: Addition, Sedation, OD, RD, GI disturbances, etc |
| Opioid Chemical Classes: Rigid contain ________ whereas Flexible opitiods contain (3) | Phenanthrene; -phenylpiperidines; Anilidopiperidines; Phenylalkylamines |
| Morphine--> is a naturally occurring molecule. __-(-)-Morphine is the ______ mu opioid agoinst; oral BA is 40% via 1st pass effect; 3-6x more potent if given IM. OD concerns with metabolites, enterohepatic cycling. | Levo; eutomer |
| Morphine can go through 3A4 and be converted to _______ (weakly active) or through UGT (glucoronudation/sulfation) to become ____ | Normorphine (N-dealkylation); 3-O-Gluc (50% inactive and may accumulate in renal faiure))/6-O-Gluc (10-15% active and more potent) |
| Metabolite 6-O-Gluc is 2-3 x more potent than morphine and provides 85% anlagesia but we worry since it may undergo: | enterohepatic cycling |
| IM formulation of morphine is ______. | preferred (3-6x more potent) |
| Due to OD concerns with morphine, ____ initial PO & _____ maintenance doses are advised | high; low |
| Codeine is a _____ derivative of morphine; weak u-agonist (potent anti-tussive; slowly metabolized to morphine via 2D6. | 3-OCH3 |
| If a pt is a poor metabolizer of 2D6 and is taking Codeine. Will they have analgesia? | No, Poor metabolizers will be stuck with more codeine in their system and expereince less or no analgesia. *rapid metabolizers will experience more analgesia effect. |
| -(-)- Hydromorphone (Dilaudid) is a ________ derivative of morphine. Its a potent mu agonist and is 8x more potent than morphine. | 7,8 dihydro/6-keto |
| The change of the double bond b/w 7-8 seen in morphine was changed to a single bond in hydromorphone introducing ______ and changing the alcohol to a ketone | *flexibility *improved potency and PK side effect profile |
| CLARIFY (opioid or opiate)Hydrocodone is a ____ to _______ derivative of Hydromorphone which increased brain entry. Hydrocodone is 1/2 morphine's potency but is a potent anti-tussive agent. In combination with APAP, its called ______ or _______ (for pain); + Aspirin | 3-OH to 3-OCH3; Vicodin/Lortab *added methyl group decreased Mu activity and enhances anti-tussive *addition of APAP made a "cut-back" on opiate content by adding NSAID |
| Oxycodone is a 14beta-OH form of _______, equipotent to Morphine. Oral BA (65-87%). Adding APAP, drug is named ______; adding ASA. drug is named _______. | hydrocodone; Percocet; Percodan *Addition at the 14C of an -OH group enhanced the H-bonding |
| Extended release of Oxycodone is _______ and Oxycodone has several active metabolites such as: 2D6 O-demethylation affords Oxymorphone (lost methyl group) | Oxycontin |
| Meperidine HCL (Demerol) is a _________. it is 10x less potent than morphine and enters the brain _____ (cLogP=3). has a short DOA (1/2 life <4h, undergoes CYP and ester hydrolysis metabolism which may require more frequent dosing and monitoring for toxicity. | Phenylpiperidines; rapidly |
| Meperidine metabolism through 3A4/Brain 2D6 to give ________ or undergoes Ester Hydrolysis to give an ______ product | Normeperidine (which undergoes renal elimination); inactive |
| The issue with meperidine is the metabolite Nromeperidine (weak activity) that is linked with: | CNS excitation and grand mal seizures. 3A4 induction can promote seizures as it increases formation of normeperidine that has a 1/2 life of 35h. *issue mainly lies in pts that have renal impairment |
| Fentanyl citrate (Sublimiaze) is an __________. the Mu agonist is 80x more potent than morphine) and has rapdi onset with a logP of 4. Short DoA and metabolized via 3A4 (n-dealkylation and distributes into the tissues | Anilidopiperidines |
| Formulations of Fentanyl includes: | Patches provide approx. 72 h blood drug levels Lollipops (buffered at pH 9-10 to improve buccal bioavailability by changing the pH of the mouth to promote absorption) *Fentanyl analog (Sufentanil (500X > Morphine) |
| Methadone HCl (Dolophine) is a __________. It is Equipotent to morphine @ mu; R-(-)-isomer is active; Advantages: High PO bioavailability; t1/2 = 15 – 60h. | Phenylalkylamines |
| DoA for Methadone is influenced by metabolism and ionization: | Metabolism involves 3A4 &2B6 Ionization: Methadone ionizes in acidic pH & is un-ionized in basic pH ; Renal elimination and re-absorption can be altered by pH; Swish/Spit solution is basic therefore drug absorption is pH driven |
| The theory behind the swish/spit solution of methadone was by using a longer lived opiate agent but less dosage to minimize _____ and take advantage of ionization to promote absorption from mouth and controlled pH. | withdrawal |
| Methadone metabolism--> 3A4/2B6 (major pathway)--> Normethadone (n-dealkylation)(active) --> and can undergo ________ and _______ to give you EDDP* (urine metabolite used to quantify compliance) | cyclization; Dehydration *compliance check with EDDP metabolite is called a diphenylphyrollidine. |
| Tramadol HCl (Ultram) is a ____________. It has a dual action for analgesia which is: | Phenylalkylamines; -SERT/NET inhibition - (+)-isomer (SERT)/(-)-isomer (NET) -Mu active metabolite Notes: Mu Active O-desmethyl metabolite; Avoid: 2D6/3A4 inhibition; co-use with 5HT agonists or MAOIs (it already gives serotonin) *Sikazawe--> SNRI (allow build up of 5-HT/NE; affords active metabolite; |
| Tramadol (NET inhibitor) ---> undergoes 2D6 to form __ ____ ____, which can undergo further metabolism via UGT/ST--> O-gluc/sulfate | Mu receptor agonist (6x more potent than Tramadol |
| Tapentadol HCl (Nucynta) is a _________. Mu-opioid agonist & NET inhib. (MAOI use cautioned); Above synergism = analgesia; Log P = 2.9; 32% bioavailable - extensive 1st - pass effect; T1/2 = 4h - due to metabolism. | Phenylalkylamines |
| Taoentadol undergoes metabolism via ___to give you O-Gluc metabolite. | UGT *exposed -OH group provided the metabolic pathway |
| Oliceridine(Olinvyk) is a ________. It is anovel biased mu-opioid agonist (selectively activates MOR GPCR) without β-arrestin signaling. oral BA (6%) = An IV opioid (T1/2 = 1-3h). What is the downside to Oliceridine? | Phenylalkylamines; Equivalent doses of Oliceridine & Morphine have similar abuse potential |
| Metabolism of Oliceridine becomes inactivated via 3A4/2D6 and leads to? | No active metabolites |
| Naloxone is an _____ ______ that provides no analgesia. Its a modification of _________ N-allyl; 3OH. Is racemic, levo-naloxone is the more active eutome; Its the drug of choice for opioid overdose with a high affinity (ki =1nM) competitive antagonist | OPIOID Antagonists; Oxycodone *high affinity--> able to dislodge opioids that are bound due to better affinty |
| What are the limitations of Naloxone? | Metabolusm (poor BA) since its undergoes rapid inactivation via N-dealkylation & 3-O-Gluc.) *T1/2 = 1-2 h (IM) & 2-3h (IN, slower absorption); Infusions in severe opioid toxication |
| major metabolite of Naloxone is ____ | N3G |
| Naltrexone (Vivitrol) is a OPIOID Antagonists that provides no analgesia. Its a slow-release ______ IM injection. It is a derivative of Oxycodone and its more lipophilc and potent than Naloxone. | microsphere |
| Naltrexone (Vivitrol) hadthe removal of CH3 and added a different bulky group on the amine known as? | N-cyclopropylmethyl (N-CPM); 3-OH. |
| Naltrexone undergoes AKR1C4 metabolusm to give you ____. Perhaps its polymorphic and reducing the ketone to an alcohol yet some may not benefit from this metabolism whether they are poor or rapid metabolizers. | 6betaN Notes: T1/2 = 4h; PO bioavailability (5-40%) – 1st pass effect 2X >more potent than Naloxone Preferred by former heroin addicts (No euphoria/Suppresses alcohol cravings) Maj. & active metabolite is 6-ß-Naltrexol (t1/2 = 12h) – higher plasma conc. than NTX (naltrexone) |
| A drug that is a Peripherally Acting mu-Opioid Receptor Antagonists (PAMORAs) is known as? Do not cross BBB & block mu-receptors only in the periphery, why? | Methylnaltrexone (Relistor) & Alvimopan (Entereg); Methylnaltrexone contains a quaternary amine and Alvimopan contains a Zwitter ion (2 charges) or amphoteric therefore cant cross the BBB *Enhance GI motility after surgery and reverse opioid induced constipation |
| Methylnaltrexone (Relistor) & Alvimopan (Entereg) uses are to? | relieve peripheral SE of opioids (e.g., constipation, urinary retention) without affecting analgesia |
| Naloxogel is another Peripherally Acting mu-Opioid Receptor Antagonists (PAMORAs). Brand name is? | Movantik |
| Naloxogel (Movvantik) is an antagonist used to treat opioid induced constipation and in its structure has a ______ _______. It blocks mu-opioid receptors only in the periphery why? | PEGylated naloxol; because it keeps getting kicked out (P-gp efflux) due to PEG group not passing into the CNS Notes: 7 EG (ethylene glycol) units |
| Opioid SAR and CBDA--> what is the most common core? | Phenylpiperidine Notes: Tertiary N for ionic interactions R1 = CH3 are µ agonists R1 ≥ 3C chains are µ partial agonists/antagonists R2= H or OH or C=O Levo-(-)- isomers are eutomers @ µ receptors CBDA: Ionic, Hydrophobic, H-bonding |
| Rigid Phenanthrene opioids are: | Morphines Orvinols Morphinans Benzazocines |
| Flexible opioid classes are? | Phenylpiperidines Anilidopiperidines Phenylalkylamines |
Created by:
Xander635
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