-
Methylxanthines
- Caffeine
- -AKA: trimethylxanthine, morning thunder
- -Can be superimposed on Theophylline (Theo-Dur)
- -not effective in treating ADHD
- -Prototype for 1A2 (inducible)
- - FDA: “Narrow Therapeutic Index (NTI) drug (TI<2) and implications for generic
- substitutions*! (or highly variable PK (within-subject AUC or Cmax>30%)
- -FDA does not use this for bioequivalence; some STATES consider variable PK for classification of NTI and might have stricter classifications than the FDA, pharmacies must comply with the strictest law for
- that state
-
CYP1A2
- -inducible
- -probe/marker for caffeine or theophylline
- -M/R measures caffein to paraxanthine ratio
- -minor metabolites include theophylline and uric acid
- -substrate for R-warfarin
- -combination of multiple drugs metabolized by 1A2 increases the plasma concentration of both drugs (decreased metabolic clearance)
- -induced by cigarettes, charcoal foods, heterocyclic amines, cabbage, phenobarb, phenytoin, rifampin
- -monomorphic
- -ontogeny: expressed in adults not in fetus
-
CYP1A1
- -extrahepatic
- -biotoxification of polycyclic armontic hydrocarbons
- -2010 Gulf of Mexico shrimp "smell test"
- -monomorphic
- -preclinical data cannot always predict human effect (rat is 80% similar to humans)
-
Polycyclic aromatic hydrocarbon (PAH)
- -forms a covalent bond with DNA through epoxide intermediate
- -Gulf of Mexico shrimp 2010: "smell test" GC-MS for crude oil PAH levels
-
Caffeine PD
- 1. adenosine antagonist
- 2. inhibits phosphodiesterase (prevents cAMP--- AMP)
- 3. blocks GABA activation of glutamtergic Cl- channel preventing hyperpolarization and promoting excitatory glutamatergic neurotransmission
-
Antiobesity agents (stimulants)
-phenylethylamine pharmacophore
- Examples:
- amphetamine
- phentermine
- bupropion-naltexone
- sibutramine
-
Antiobestity (non-stimulant)
Orlistat
- -suicide inhibitor
- -beta lactone transesterfied
- -acetylated lipase binds to the critical active site so TGs cannot be absorbed
-
Benzodiazepines
-seven membered ring with 2 N and a benzene ring
- Indications:
- anxiolytics
- hypntics
- adjuncts to treat convulsant disorders
- skeletal muscle relaxants
-
Chlordiazepoxide
- -first benzodiazepine
- -low potency
- -accumulation (long half life) PD does not equal PK
-
Diazepam
- -benzodiazepine
- -anxiolytic
- -metabolized to oxazepam contains a glucoronide
- -UGT2B15 - important in the clearance if xenobiotics and drug metabolism
-
clorazepate
- -not technically a prodrug because it is not metabolized by an enzyme but by acid catalyzed decarboxylation
- -metabolized to nordazepam (metabolite of chlordiazepoxide and diazepam) (European form of diazepam)
-
Oxazepam
- -benzodiazepine
- -marker for UGT2B15
-
Lorazepam
- -benzodiazepine
- -chlorine attached to oxazepam
- -chlorine that increases potency
- -PGx: inducbile and polymorphic
-
Alprazolam
- -benzodiazepine
- -prototype triazolo derivative
- -potent (has a chlorine)
-
Triazolam
-benzodiazepine
-
Flurazepam
- -benzodiazepine
- -aliphatic amine (protonated, basic)
- -ammonium is what passes through the body
- -renal clearance
- -half life of a hypnotic
-
Midazolam
- -benzodiazepine
- -adjunct for anesthesia
- -CYP3A4 substrate/probe
-
CYP3A4
- -CYP3A4 is in the gut unlike the other CYPs
- -inducible
- -not polymorphic
- -enteric and hepatic first pass
- -as you move down the small intestines 3x less (proximal to distal gradient)
- -sex dimorphism: women express more than men
- -food inhibitors: grapefruite juice (inhibits OAT) which binds tightly to 3A4
- -CYP3A7 largely silenced as infants transition to CYP3A4 - CYP3A4 increases with age
-
Nifedipine
-additional 3A4 marker
-
Cortisol
- -noninvasive 3A4 expression marker
- -based on metaboism of an endobiotic and not a radioisotope
- -erythromycin C14 breath test
-
Beta-Carboline
- -pro convulsant
- -not a drug but an BNZ anxiogenic endobiotic
- -Tryptophan + EtOH can be superimposed
-
Flumazenil
- -BNZ antagonist
- -reverses BZN anesthesia, BZN OD
- -proconvulsant anxiogenic compound
-
Zolpidem and Zaleplon
- -GABA agonists
- -hypnotics
- -potent GABA-A-alpha omega 1 agonist
-
Eszopiclone
- -GABA agonist
- -S enantiomer --- developed through racemic switch
- -metabolized by 3A4 and 2E1
-
GABA and BZN omega receptors
- -BNZ indirectly acts on GABA-A ionotropic receptors
- -GABA is synthesized by decarboxylation of glutamate
-
GABA-A ionotropic receptor complex
- -BZN facilitate GABA binding and function moving chlorine into the cytosol
- -opposite effect of caffeine
- *GABA is inhibitory
- -BZN binds allosterically
-
-
Buspirone
- -depressant
- -serotonergic partial agonist
- -anxiolytic
- -not GABA-ergic
-
Ramelteon
- -hypnotic
- -oxygen isostere of melatonin
- -melatonin agoinst (mimics melatonin)
- -circadian rhythm
-
Fospropofol
- -prodrug of propofol
- -used for the induction of anesthesia
-
Propofol
- -"milk of anesthesia"
- -induces anesthesia but DO NOT USE off label as hypnotic
-
Ethanol
- -absorbed duodenum
- -metabolized by ADH
- -DDI with aspirin increases bioavailability of EtOH
- -ethanol + ADH = Acetaldehyde (flush) + ALDH = Acetate (vinegar)
-
Methanol
- -"wood" alcohol
- -POISON
- -methanol + ADH = formaldehyde + ALHD = Formic acid
- -Tx: give EtOH because it is a better ADH substrate
-
CYP2E1
- -inducible
- -interindividual differences in expression
- -substrates are small molecules, volatile anesthetics
- -limited evidence of polymorphism
-
Chlorzoxazone
- -probe/marker substrate for CYP2E1
- -muscle relaxant
- *Metabolic ratio is usually D/M but in this case it is M/D
-
Acetominophen
- -Phase II metabolism - conjugation and glutathion S- transferases
- -ring oxidation by 2E1 increases with alcohol induction (toxic)
- -Tx: N-acetylcysteine
-
Glutathione S-Transferase (GST)
- -bonds glutathione
- -yields mercapturic acid
-
Common pharmacophore of anticonvulsants
N-C(=O)(X)
X = N, O, C
-
Barbituates
- -used as a second line BZN
- -acidity allows water-soluble salts which cause a low TI
-
Phenobarbitol
- -prototypic GENERAL enzyme inducer
- -barbituate
-
Pentobarbital
- -used for lethal injection
- -exit Marilyn Monroe
-
Metholbarbital and Primidone
- -barbituates
- -prodrugs
- -Metholbarbital is N-methylated to phenobarbitol
- -Primidone is C-oxidized to phenobarbitol
- -metabolized by 2Cs
-
CYP2C9
- -inducible
- -polymorphic
- -EM is wild type *1
- -PM requires lower dose
-
S-Warfarin
- -metabolized by 2C9
- -eutomer and substrate
- -FDA recommends 2C9 genotyping (not ID on Amplichip)
-
CYP2C19
- -inducible
- -polymorphism (EM, IM, PM)
-
Mephenytoin
- -anticonvulsant
- -synthesized from hydantoin
- -CYP2C19 is a marker for prototyping
- -no longer available
-
Phenytoin and Fosphenytoin sodium
- -anticonvulsant
- -synthesized from hydantoin
- -metabolized by 2C9 and 2C19
- -over proportionality (nonlinear PK)
- -Fosphenytoin is the prodrug; reacts with water to form phenytoin
-
Carbamazepine and Oxacarbazepine
- -anticonvulsant
- -biotoxification to epoxide
- -oxacarbazepine overcomes biotoxification because of the ketone instead of the epoxide
-
Valproic Acid
- -anticonvulsant
- -UGT based DDI
- -increase GABA; decrease in succinic acid
- -increases anabolism (synthesis); decrease catabolism (break down)
- -activating glutamate decarboxylase and inhibiting GABA transaminase
-
Lamotrigine
- anticonvulsant
- inhibits sodium channel
- as seen in local anesthetics, decreasing action potential
-
Gabapentin
- anticonvulsant
- calcium channel blocker
-
Tiagabine
- anticonvulsant
- GABA uptake inhibitor
-
Topiramate
- anticonvulsant
- sodium channel blocker
- potentiates GABA
- glutamate antagonist
-
Levetiracetem
- anticonvulsant
- MOA unknown
-
Clonsazepam
- anticonvulsant
- benzodiazepine MOA
- metabolized by 3A4 - nitro group to amine
-
Strychnine
- -convulsant/analeptic
- -glycine antagonist
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