Download Med Chem II Tutoring

MED CHEM II TUTORING
Brandy Hollums
[email protected]
ANTIEPILEPTIC AGENTS
• Classical AEDs
• 1. Recognize drugs by name, structure, and chemical class
• 2. SAR of classical AEDs
• 3. Acidity and water solubility
• 4. Prodrugs (Primidone and Fosphenytoin)
• 5. Hydantoin and its bioisotere
• 6. Uses and side effects (metabolites and idiosyncratic toxicity; teratogenicity e.g. cleft
palate)
CLASSICAL AEDS
O
R
R'
O
N H
R"
NH
N
H
O
R" =
Barbiturates
CH2
Succinimides
Hydantoins
NH2
Phenacemide
-Minimum structure requirement is Imide
-If R and R’ are lower alkyls (CH3 and CH2CH3) will treat absence seizures (petit mal)
-If aryl group (aromatic) will treat generalized tonic clonic and partial seizures
**This means we can look at the structure to know what kind of seizure they treat
without knowing anything else about the drug!**
WHAT KIND OF SEIZURE WOULD THE
FOLLOWING DRUG NOT TREAT?
• A. absence seizures
• B. status epilepticus
• C. grand mal seizures
• D. partial seizures
O
H
N
HN
O
O
CH2CH3
WHICH OF THE FOLLOWING ARE
PRODRUGS?
O
H
N
HN
O
O
CH2CH3
H
N
O
HN
O
MEPHOBARBITAL UNDERGOES NDEMETHYLATION AND IS CONVERTED TO
_________.
• A. Primidone
• B. Diazepam
• C. Phenobarbital
• D. Phenytoin
O
HN
CH3
N
O
Et
O
Ph
O
H
N
N-Demethylation
HN
O
O
Et
Ph
+
CH2O
THE MAJOR METABOLITE OF PRIMIDONE
IS:
• A. Phenobarbital
• B. PEMA
• C. Deoxybarbituate
• D. Mephobarbital
H
2 N
O
H
N
O
O
2
HN
+
HN
O
CH2CH3
H 2N
O
CH2CH3
O
H 2N
O
CH2CH3
PRIMIDONE
Bioactivation (Metabolism) of Primidone (Enrichment)
H
N
O
CYP2C9/19
HN
H
O
H
N
H
O
O
Spontaneous
HN
O
HN
CH2CH3
O
O
H2N
CH2CH3
O
O
H
N
O
D A
eh l
yd co
ro ho
ge l
na
se
Primidone
Hydrolysis
HO
O
CH2CH3
Phenobarbital
(Minor metabolite)
H 2N
O
O
Hydrolysis
H2N
HO
HN
CH2CH3
O
CH2CH3
Inactive
O
CH2CH3
PEMA
Major Metabolite
(less active)
THE FOLLOWING STRUCTURE WOULD
BE USED FOR ALL SEIZURES EXCEPT:
• A. absence seizures
• B. tonic clonic seizures
• C. partial seizures
• D. grand mal seizures
H
N
O
HN
O
WHICH OF THE FOLLOWING IS NOT
TRUE OF HYDANTOINS?
• A. Retain antiepileptic activity but not as sedative as barbiturates
• B. Hydantoins are more acidic that barbiturates
• C. Structurally similar to barbiturates
• D. Have shorter stability than barbiturates once mixed with water.
WHICH OF THE FOLLOWING ARE SIDE
EFFECTS OF PHENYTOIN THAT MAKE IT
UNDESIRABLE FOR PRESCHOOL CHILDREN?
• A. Sedative effects
• B. gingival hyperplasia
• C. neurotoxicity
• D. hirsutism
THE FORMATION OF _______ MAY LEAD TO
THE IDIOSYNCRATIC AND TERATOGENIC
EFFECTS OF AEDS/
• A. Catechols
• B. Glutathione
• C. Haptens
• D. Diols
Metabolism of Phenytoin (Enrichment)
O
OH
O
O-Glucuronide
HN
HN
O
N
H
O
O
N
H
O
ortho-Quinone
(reactive)
5-(4-Hydroxyphenyl)-5phenylhydantoin
OH
OH
OH
OCH3
O
HN
O
O
CYP2C9
CYP2C19
HN
N
H
Phenytoin
O
O
Catechol
N
H
N
H
O
3-O-Methylcatechol
O
Arene oxide
(reactive)
Ep
ne
io se
h
t a
ta er
lu nsf
G ra
t
N-Glucuronide
SG
eH
O-Glucuronide
yd
ro
las
e
OH
OH
HN
HN
N
H
ox
id
OH
OH
O
N
H
HN
O
O
HN
O
O
N
H
HN
O
5-(3-Hydroxyphenyl)-5phenylhydantoin
O-Glucuronide
O
N
H
O
Diol metabolite
O-Glucuronide
WHAT ARE SIDE EFFECTS OF ALL AEDS
THAT CONTAIN AROMATIC RINGS?
• A. SJS
• B. TEN
• C. Neurotoxicity
• D. Nephrotoxicity
WHICH OF THE FOLLOWING CLASS OF
AEDS IS THE BIOISOTERIC REPLACE OF
HYDANTOINS?
• A. Barbiturates
• B. Succinimides
• C. Phenacemides
• D. Benzodiazepines
WHAT IS THE DOC FOR ABSENCE
SEIZURES?
• A. methsuximide
• B. phenytoin
• C. ethosuximide
• D. carbamazepine
1,4-BENZODIAZEPINES
• 1. Recognize the drugs by name and structure
• 2. MOA
• *only 3 BZDs used to treat epilepsy-clonazepam, clorazepate, diazepam.
MISCELLANEOUS AEDS
• 1. Recognize the drugs by name and structure.
• 2. Note those that cause the following side effects: idiosyncratic toxicity;
teratogenicity; hepatotoxicity; kidney stones; visual disturbances.
• 3. Note their effect on CYPs (i.e., induction of CYPs; inhibition of CYPs; or no
effect on CYPs)
• 4. Functional groups (amide, amine, carboxylic acid; sulfamate; ether, ester,
lactam lactone, alcohol; sulfonamide; ketone; carbamate).
• 5. MOA of the AEDs.
• 6. Effect of pKa and pH on the absorption and excretion of drugs.
WHICH HAS THE HIGHEST RISK OF
CLEFT PALATE?
• A. Lamotrigine
• B. Valproic Acid
• C. Carbamazepine
• D. Gabapentin
WHICH AED HAS THE STRUCTURE OF
GABA?
• A. acetazolamide
• B. carbamazepine
• C. valproic acid
• D. gabapentin
NH2 COOH
WHICH AED HAS CYP INTERACTIONS?
• A. Levetiracetam
• B. Zonisamide
• C. Gabapentin
• D. Tigabine
WHICH AED ACTS ON VOLTAGE GATED
CALCIUM CHANNELS?
• A. Carbamazepine
• B. Ethosuximide
• C. tigabine
• D. lamotrigine
WHICH AED HAS IRREVERSIBLE VISUAL
DISTURBANCES?
• A. gabapentin
• B. felbamate
• C. topiramate
• D. vigabatrin