Medchem Final Flashcards
1
Q
What are the Three Severe toxicities of trimethylated oxazolidinedione
A
- Photophobia
- teratogenicity
- aplastic anemia
2
Q
Basification of the urine with sodium bicarbonate is useful in cases of barbiturate poising.
Explain fully in terms of pKa & pH why this is so?
A
Barbiturates are weak acids with pKa of 8(7.4-8.5)
Under normal circumstances most of the parent drug(that gets filtered) is REABOSRBED from the kidney tubule where urine pH is 6, because its UNCHARGED.
At higher urine pH, due to basification, more drug is CHARGED so less is reabsorbed
3
Q
What are five important features of a successful drug treating insomnia
A
- Reduced sleep LATENCY
- Increased sleep MAINTENANCE
- Increased sleep QUALITY
- Decreased next-day impairment
- Less tendency for habituation/dependence
4
Q
What is the biological target for each drug?
Zaleplon
Ramelteon
Suvorexant
A
- alpha-1 subunit of GABAA receptor
- MT1/MT2 receptors
- Orexin 1/2 receptor
5
Q
What is unusual about the tablet formulation of Zaleplon?
A
- Blue color (indigo carmine)
- Opacifer (titanium dioxide)
Present in tablet to provide alert if drink is “spiked”
6
Q
Lamotrigine is a useful antiepileptic by virtue of its folate antagonism (T/F)
A
False
7
Q
5,5’- Disubstituted barbiturates do not exhibit keto-enol tautomerism (T/F)
A
True
8
Q
Pregabilin is poorly bioavailable because it saturates the intestinal uptake transporter (T/F)
A
False
9
Q
2-SORA drugs are being developed for treating addiction (T/F)
A
False
10
Q
In order to possess appreciable sedative-hypnotic activity a barbituric acid derivative must have a logP of 2-3 (T/F)
A
False
11
Q
Narcolepsy in dogs led to the discovery of MT1 receptors that can be targeted to treat insomnia (T/F)
A
False
12
Q
Valproate’s induction of glutamic acid decarboxylase contributes to its antiepileptic effects (T/F)
A
True
13
Q
Primidone must undergo a decarboxylation event ot generate the active metabolite, PEMA (T/F)
A
True
14
Q
The ultra-short duration of action of tiopenal is due to rapid hydrolysis in the brain (T/F)
A
False
15
Q
The pH of fosphenytoin for injection is 12 (T/F)
A
False
16
Q
What is a serious toxicity of Vinylgaba that delayed its approval by the FDA?
A
- psychoses
- depression
- visual field distrubances
17
Q
A patient is taking lamotrigine and will be started on valproic acid. The dose of lamotrigine should be?
(Increased/Decreased/unchanged)
A
Decreased
18
Q
What is the mechanism of Valproate?
A
Valproate is an INHIBITOR of the UGT- enzymes that are directly N-glucoronidate lamotrigine to metabolically inactive drug.
19
Q
What is Sleep Latency?
A
The TIme period until one falls asleep
20
Q
Zaleplon is marketed as the best drug for sleep latency. How does the pharmacokinetics make this argument?
A
Zaleplon’s short tmax (rapid onset) is the key pharmacokinetic parameter
21
Q
What is the configuration of Ramelteon at is chiral center
A
S
22
Q
N-1: methyl group
A
contributes to both increased logP and increased pKa
higher pKa means that more of the drug is UNIONIZED at physiological pH facilitating it crossing BBB
23
Q
C-5:
A
increased carbon load UNSATATURATION elevate logP above the values for sedative hypnotics (1.5-2).
Increased lipophilicity and higher pKa
24
Q
How are ESL & OXC an advance over the prototypic drug Carbamazepine?
A
OXL & SLC avoid formation of Epoxide intermediate–> improve side effect profile and tolerability
OXC & SLC weaker P450 inducers than CBZ–>fewer drug interactions
25
Ezcopiclone is a good choice of hypnotic to increase sleep maintenance (T/F)
True
26
Barbiturates cause acute intermittent porphyria (T/F)
False
27
Flumazenil antagonizes the sedative effects of the z-drugs (T/F)
True
28
Tiagabine is a GABA-mimetic (T/F)
T/F
29
The major GABA receptor in the brain is composed of alpha1, beta2, gama2 subunits (T/F)
True
30
Diazepam forms the active metabolite, oxazepam and temazepam (T/F)
True
31
CBZ's unusual carbamyl substituent is believed to be responsible for the drugs side-effects (T/F)
False
32
Almost none of the dose of phenobarbital is excreted unchanged in the urine (T/F)
False
33
1,5,5'-Trisubsitituted barbiturates do not form lactim tautomers (T/F)
False
34
The 3C's describe the symptoms of barbiturate overdoes (T/F)
False
35
The mechanism of vinylgaba's suicide inhibition of GABA-T involves radical intermediates (T/F)
False
36
Suveroxant is a 1-SORA drug (T/F)
T/F
37
pKa
- pKa of the sedative hypnotic barbiturates is 7.4-8.5
| - In the acidic urine (pH 6) environment of the kidney tubule >90% is unionized and so it is extensively REABSORBED
38
log P
- logP of the sedative-hypnotic barbiturates is 1.5-2
- As lipophilicity increases, so generally does the plasma protein binding
- High protein binding means poor kidney filtration
39
Flurazepam & Triazolam are promoted as sleep-inducing agents, what is the pharmacokinetic parameter that argues for their use in insomnia?
short tmax (rapid onset)
40
Between Flurazepam & Triazolam which one causes significant sleep hangover?
Why?
1. Flurazepam
2. can cause significant sleep hangover due to accumulation of its LONG LIVED active metabolite
2. Triazolam's active metabolite has a short t1/2 due to rapid glucoronidation
41
Induction of P450's UGTs and Gama-ALA sunthetase all contribute to barbiturate drug interactions (T/F)
True
42
In order to possess appreciable sedative-hypnotic activity a barbituric acid derivative must have a logP of 2-3 (T/F)
False
43
Eszopiclone is a good choice of hypnotic agent to treat problems with sleep maintenance (T/F)
True
44
Esicarbezapine is a pro-drug for oxcarbazepine (T/F)
False
45
Tolerance to the benzodiazepines is due to auto-induction of their metabolism (T/F)
False
46
Midazolam dihydrochloride solution for injection has a pH of 3.5 (T/F)
True
47
Rebound insomnia occurs most frequently upon withdrawl of the longer-acting benzodiazepine (T/F)
False
48
Ramelteon and Buspirone are mildly effective hypnotic drugs (T/F)
False
49
A patient is currently taking phenytoin, and will be started on valproate. The dose of phenytoin should be?
(increase/decreased/unchanged)
Decreased
50
What is the mechanism for drug-interaction between phenytoin and valproate?
Valproate inhibits P450s (such as CYP2C9) that metabolize phenytoin, leading to increase exposure to phenytoin
51
What is the target receptor?
1. Methohexital
2. Ketamine
3. Propofol
1. GABAA
2. NMDA
3. GABAA
52
What is the mechanism by which the pharmacological effect is terminated?
1. methohexital
2. ketamine
3. propofol
1. Redistribution
2. Redistribution
3. Redistribution & metabolism
53
How is each drug formulated?
1. methohexital
2. ketamine
3. propofol
1. basic
2. acid
3. fat emulsion
54
What are 2 disadvantages of R-ketamine that have prompted consideration of the introduction of the S-enantiomer as a replacement racemate?
1. R-enantiomer is a partial agonist at NMDA receptor, reducing, the antagonistic effect of the S-enantiomer
2. R-ketamine is thought to be responsible for post-anesthetic emergence phenomena
55
Hypersensitivy reactions are fairly common with anticonvulsant therapy, including lamotrigine. What side effect occurs in up to 20% of Lamotrigine patients?
Skin Rash
56
1,5,5'-trisubsitiuted barbiturates from lactim tautomers (T/F)
True
57
Zolpidem acts selectively in the alpha-1 containing subunit of the GABA receptor (T/F)
True
58
Pregabilin is a GABA-mimetic drug (T/F)
False
59
Zaleplon is a good choice of hypnotic to treat problems with sleep maintenance (T/F)
False
60
Many of the barbiturates rival the TCA in terms of their low therapeutic indices (T/F)
True
61
Rebound insomnia occurs most frequently upon withdrawal of longer-acting benzodiazepines (T/F)
False
62
None of the dose of phenobarbital is excreted unchanged in the urine (T/F)
False
63
Ramelteon's hypnotic effects are a consequence of preferential action at MT1 receptors (T/F)
True
64
Phosphate ester oral pro-drugs related to chloral hydrate were developed to avoid drug's bitter taste (T/F)
True
65
Auto-induction of barbiturate metabolism reduces tolerance to these drugs (T/F)
False
66
Explain how Vinylgaba effects the glutamate-->GABA-->GABA metabolite pathway in order to exert its anticonvulsant effects
Vinylgaba is a mechanism based inhibitor that forms a stable enzyme adduct with GABA-T
67
Why was fospropofol developed?
- Propofol is insoluble in water and was formulated in a fat emulsion
- this causes allergy risks and supports bacterial growth
- pain on injection
68
Identify the receptor target?
1. Remifenatil
2. ketamine
3. thiopental
1. mu-opioid
2. NMDA
3. GABAA
69
Mechanism by which action is terminated?
1. remifenatil
2. ketamine
3. thiopenatl
1. redistribution
2. redistribution
3. redistribution
70
The major GABA receptor in the brain is composed of alpha2, beta2, gama2 subunits (T/F)
False
71
Zaleplon is a good choice of hypnotic to increase sleep maintence (T/F)
False
72
Flumazenil antagonizes the sedative side effect of the z-drugs (T/F)
True
73
CBZ's unusual carbamyl substituent is believed to be responsible for the drug's side-effects (T/F)
False
74
1,5,5'-trisubstituted barbiturates from lactim tautomer's (T/F)
True
75
Pregabalin is a GABA-mimetic drug (T/F)
False
76
Almost none of the dose of phenobarbital is excreted uncharged in the urine (T/F)
False
77
Melatonin has important pharmacological actions at both MT1 & MT2 receptors (T/F)
True
78
Why would there be pain at the injection site of water-soluble sodium salt?
Sodium phenytoin-water soluble salt for injection
| has a pH of 12 which causes venous irritation and a burning sensation at the site of injection
79
Ramelteon is the analog for which sleep-inducing hormone?
What is receptor it interacts with?
What is the configuration?
Melatonin
MT1/MT2
S-configuration
80
Phosphate ester oral prodrugs of chloral hydrate were developed to avoid the drug's bitter taste (T/F)
True
81
Zolpidem acts selectively on the alpha2-containing subunits of the GABA receptor (T/F)
False
82
Clonazepam is a long-acting, 1,4-benzodiazepine (T/F)
True
83
Drug interactions occur infrequently with the benzodiazepines (T/F)
True
84
5,5'-disubstituted barbiturates that are also methylated at N-1 and N-3 form lactim tatuomers (T/F)
False
85
CBZ and phenytoin share some 3-dimensional structural similarities and are useful for treating a similar spectrum of epilepsies (T/F)
True
86
Very little parent barbiturate is excreted in the urine because barbiturates are weak bases and urine is slightly acid (T/F)
False
87
A patient is currently taking lamotrigine and will be started on phenytoin. The dose of lamotrigine should be?
(increased/decreased/unchanged)
Increased
88
What is the mechanism of the DDI between lamotrigine and phenytoin?
- Phenytoin induces UGT enzymes, which are responsible for the N-glucoronidation of lamotrigine the pathway by which it is almost exclusively metabolized
- induction of UGTS will lead to decreased lamotrigine levels, which means an increase dose would be needed
89
A patient is currently taking CBZ, and will be started on felbamate. The dose of CBZ should be?
(increased/decreased/unchanged)
Unchanged
90
What is the mechanism of the DDI between CBZ and Felbamate?
- Felbamate induces CYP3A4 which metabolizes CBZ to its active epoxide metabolite
- CBZ levels will decrease, but CBZ epoxide will increase and since it also exhibits anticonvulsant activity no dose adjustment is needed.
91
What property of the diazepine ring helps formulate the drug for IV injection?
Ring opening (reversible) below pH 4
92
What property of the imidazole ring helps formulate the drug for IV injection?
Basicity
93
Propofol can be a dangerous drug if its use is not monitored closely. What is the most important adverse side-effect that needs to be monitored?
Respiratory depression
94
WHat 2-deoxy analog of phenobarbital is used as an anticonvulsant? What therapeutic advantage dose is have over phenobarbital?
1. Primidone
| 2. treats grand mal & partial sezuires
95
Oxazepam would be a rational choice of sedative/hypnotic benzodiazepine in patients with liver disease (T/F)
True
96
How does VinylGaba interact with the GABA receptor?
is a mechanism based inhibitor of GABA-transaminase which metabolizes GABA and thus GABA levels would increase explaining the anticonvulsant activity
97
How does Flumazenil interact with the GABA receptor?
antidote to BZP overdose by competing for BZP binding site on GABA receptor between alpha & gama subunit
98
How does Tiagabine interact with the GABA receptor?
acts as anticonvulsant by inhibiting GABA reuptake by GAT-1 transporter
99
Identify molecular targets which anticonvulsant drugs interact with to cause pharmacological effect?
1. GABA reuptake receptor
2. GABA receptor
3. Ion channels (Calcium/Sodium)
100
What is the bioisostere of oxazolidinedione that replaced it as the most effective treatment of petit mal seizures?
Methylene
succinimide
ethosuximide
101
Chloral hydrate and ethanol both compete for the same metabolic enzyme (T/F)
False
102
Clonazepam is a long-acting 1,5-benzodiazepine (T/F)
False
103
The new sedative-hypnotic "Z-drugs" have much lower addictive potential than the benzodiazepines (T/F)
False
104
Oxcarbazepine has a strong DDI with Valproic acid (T/F)
False
105
what receptor does Eszopiclone act on?
alpha1-subunit of GABA receptor
106
Lamotrigine is an anticonvulsant that displays bi-directional metabolic DDI with valproic acid and phenobarbital. Explain
1. Lamotrigine is eliminated by UGTs (N-glucoronidation)
2. VPA inhibits UGTs and when administered with lamotrigine t1/2 increases from 24hrs-->48 hrs
3. Phenobarbital induces UGTS & t1/2 decreases from 24 hrs-->12hrs
107
Identify the receptor subtypes, enzymes or transporters with which the following drugs interact to produce their therapeutic effect:
1. Ramelteon (hypnotic)
2. Eszopiclone (hypnotic)
3. Tiagabine (anticonvulsant)
4. Ketamine (anesthetic)
5. Remifentanil ( anesthetic)
1. Melatonin/MT1
2. alpha1-subunit GABA receptor
3. GABA Transporter (reuptake inhibitor)
4. NMDA receptor
5. mu-opioid receptor
108
Why would you treat a barbiturate overdose with sodium bicarbonate?
NaHCO3 alkalinizes the (normally) acidic urine, so more of the barbiturate in the kidney tubule is ionized and less Is reabsorbed. Promotes renal excretion
109
What would be a likely side-effect of flurazepam?
| Why?
- sedation "hangover"
- N-dealylation of flurazepam gives a long-lived active metabolite N-DESALKYLFLURZEPAM, which like nordiazepam contributes to excessive sedation ("hangover") effects of drug
110
What positive property of flurazepem allows for its use as sedative hypnotic?
-high lipophilicity of flurazepam results in RAPID ABSORPTION and a QUICK ONSET of effect
111
List 3 limitations of the older antiepileptic drugs
- neurotoxicity(excessive sedation)
- teratogenicity
- limited efficacy (limited to certain seizures types: complex partial, myotonic, & antonic seizures)
- pharmacokinetics ( DDI, over-release on metabolism)
112
Based on your knowledge of barbiturate SAR, what would you expect thiamylal's pKa to be?
4.5/7.5/8.5
7.5
