Exam 1 Anticonvulsants, Sedative-hypnotics Flashcards
Anticonvulsants that induce CYP450
Phenytoin, Carbamazepine, Phenobarbital induce CYP450
Anticonvulsants that inhibit Na Channels
Phenytoin (Dilantin) Carbamazepine (Tegretol) Lamotrigine, Valproate, Topiramate
Drugs that can cause SJS
Phenytoin Carbamazepine Phenobarbital Lamotrigine Valproate
Drugs that inhibit T type Ca channels
Ethosuximide
Valproate
What drugs work by enhancing GABA inhibitory activity
Valproate
BZs: Diazepam (Valium), Lorazepam (Ativan)
Barbiturates: Phenobarbital, Gabapentin
What drugs work by decreasing excitatory glutamate activity
*those that inhibit Na and T type Ca channels, help block NMDA glutamate receptor
Na channel inhibition: carbamazepine, phenytoin, lamotrigine, topiramate, valproate
Ca channel inhibition: ethosuximide, valproate
DOC partial seizures
Carbamazepine (Tegretol)
What types of seizures are there?
Partial:
- simple
- complex
- partial with secondary generalized
Generalized
- tonic/clonic
- myoclonic
- absence
- atonic
what happens with activation of NMDA glutamate receptors
activation of glutamate receptors results in seizures
What does blockade of GABA receptors cause and what drug can do this
Flumazinel blocks GABA receptors
*blocking GABA R causes SEIZURES
GABA anticonvulsant MOA involves what
enhancing GABA inhibitory activity
- inhibit GABA metab
- stimulate GABA receptors
- meds that work through GABA MOA: Phenobarbital, gabapentin, valproic acid, BZ (Diazepam/Valium, Lorazepam/Ativan)
Describe and classify and absence seizure
absence is a generalized seizure (petit mal)
- sudden onset; brief 10-30 sec
- loss of awareness, NOT LOC
- may be some mild clonic mvmt
what causes generalized seizures
reciprocal firing of thalamus and cortex
describe tonic clonic (grand mal) seizures. What class do they belong to
Tonic clonic = generalized seizure
- initial tonic rigidity (15-30s)
- subsequent tremor
- eventually clonic jerking 1-2 min
- LOC
- pt stuporous and confused
describe partial seizures
begin in focused area in cortex then spread
describe and classify simple seizures
SImple seizures are Partial
focal, brief 20-90 sec
*grimacing, focal clonic jerking of an extremity
*no LOC
Describe and classify complex seizures
Complex seizures are partial
- longer than simple (<2 min)
- altered or LOC, Hallucinations
- temporal lobe; auto mvmt
Describe and classify Partial with secondary generalized tonic-clonic
LOC
Muscle contractions alt with relaxation
GABA NT and enhancement of GABA inhibitory activity is protective against
both generalized and partial seizures
What channels are over-active in absence seizures
T type Ca channels
Anticonvulsant Drugs that are known to cause SJS include
Phenytoin, Carbamazepine, Phenobarbital, Lamotrigine, Valproic acid
Phenytoin Uses
partial, generalized tonic clonic seizures
Phenytoin (dilantin) PK
not water soluble so not injectable (fosphenytoin is injectable form)
- first order elimination at low dose
- zero order at therapeutic and higher doses
- small change in dose/elimination can cause big changes in plasma levels
what drug interactions does phenytoin (dilantin) have
interacts with drugs that alter CYP450 is phenobarbital and carbamazepine (both induce)
*Phenytoin is metab by and induces CYP450
use and SE of phenytoin (Dilantin) include
*used for partial and tonic-clonic seizures
*Nystagmus, diplopia, ataxia, sedation,
GINGIVAL HYPERPLASIA
*long term:
coarsening of facial features, mild peripheral neuropathy, abnormal vit D metab, SJS, PregCatD
Use Carbamazepine (Tegretol)
DOC partial seizures
- gen tonic clonic
- bipolar
- TRIGEMINAL NEURALGIA
MOA and PK of Carbamazepine (Tegretol)
MOA: blocks Na channels, inhibits NE release and reuptake
PK: induces and is metab by CYP450
*lots of drug interactions
Drug interaction of Carbamazepine (Tegretol)
bc it is metab by and induces CYP450…
- increases metab of: pheny, ethosuximide, valproic acid, haloperidol, oral contraceptives
- metab ^ by: Phenobarb, phenytoin, valproic acid
- metab inhibited by: cimetidin, fluoxetine
Side Effects of Carbamazepine (Tegretol)
Diplopia, ataxia, GI upset, drowsiness
- aplastic anemia and agranulocytosis
- SJS
- preg cat D
MOA of Phenobarbital (Luminal)
Prolongs opening of Cl channel at GABA R
alters Na and Ca conductance at high conc.
Primary use of Phenobarbital (luminal)
partial seizures, Gen tonic clonic (like Phenytoin)
How is Phenobarbital (Luminal) metabolized?
good oral absorption
Crosses BBB
Liver metab
Induces CYP450 with chronic use - increases metab of phenytoin and carbamazepine
Is there a withdrawal/dependence component to Phenobarbital (Luminal)
Yes
withdrawal: can be severe - restless, anxiety, weakness, orthostatic hypoTN, hyperactive reflexes and seizures
*severe physio and psych dependence
What are potential SE of Phenobarbital (luminal)
CNS depression (can last 10-22 hr) Paradoxical excitement Vertigo, N/V, allergic rxn May depress vasomotor and resp centers *severe physio and psych dependence
what are contraindications to barbiturate
- Enhances porphyrin synthesis (CI in porphyria)
- pulmonary insufficiency: may cause resp depress
- SUPRA-ADDITIVE effects: when combined with other CNS depressants (alcohol) the effects are more than what is expected
- withdrawal can be severe: restlessness, anxiety, weakness, orthostatic hypoTN, hyperactive reflexes and seizures
what are the OD and toxicity components of Barbiturates
Low MOS, no ceiling effect (bc Barb work independently of GABA)
effects supra-additive esp with EtOH
OD sx: coma, resp depression, hypoTN
How do you treat Barbiturate OD and toxicity
Tx is supportive
May be cleared with diuresis and alkalinization of the urine
Do not treat with stimulants bc stimulants increase mortality rate
What are the effects of BZ?
- most commonly used group of anxiolytics and sedative hypnotics
- cause CNS depression: decrease in anxiety often with drowsiness
- hypnosis with high doses
Why are BZ the most commonly used group of anxiolytics and sedative hypnotics
By of the PK and duration of action in BZ
*conversion to metabolites increase half life, increasing duration of action
How are BZ metabolized/absorbed/administered
Oral absorption
may be given IV in emerg or for pre-anesthesia
Elderly do not metab BZ as quickly
CYP3A4 metab in liver, converted to active metab
describe the metabolism of diazepam, including half life information (*diazepam is BZ)
Diazepam (43hr) –> desmethyldiazepam (24hr) –> oxazepam (8hr)
Total half life ~ 75 hr; Diazepam is LONG acting
Action and half life of Flurazepam (a BZ)
Flurazepam 74 hr half life, long acting
*cyp3A4 metab
What are the intermediate BZ and their half life
Alprazolam (Xanax): <6hr, converted to short acting metabolites
Oxazepam/Lorazepam (6-24 hr) converted to inactive metabolites
What BZ is short acting and what is it used for
Midazolam (Versed) <2 hr, used as pre anesthestic
What MOA do BZ use
bind to specific sites on GABAa receptor
- effect DEPENDENT on GABA (unlike barbs)
- increases affinity of receptor to GABA prolonging its action
- ceiling effect
What anxiety disorders are benzodiazepines not used in
OCD: SSRI
Phobia/Panic: SSRI
PTSD: antidepressants
anxiety in children & adolescents: antidepressants
What is used to treat insomnia? SE?
Flurazepam (Dalmane) and temazepam (restoril) used as hypnotics (fly to sleep.. flurazepam, temazepam, insomnia)
*minor depression of REM sleep, may cause hangover effect *flurazepam is long acting
What is used to treat insomnia that is due to difficulty falling but not staying asleep?
Shorter acting drugs
?Midazolem (Versed) is short, Alprazolam and Lorazepam are intermediate?
What is used to treat status epilepticus
Diazepam and Lorazepam
*Lora has Daily seizures (lorazepam, Diazepam, epilepsy)
Diazepam and Lorazepam are used to treat what seizure condition
status epilepticus
?? is used in prep for anesthesia for short surgical procedures? How is it administered? SE?
Midazolam (Versed) - a short acting BZ
given IV
*anterograde amnesia
What BZ is sometimes used for acute muscle spasm and pain due to injury
Diazepam (Valium)
*im dying from the muscle spasms
Because long term use of alcohol or barbiturates can produce physical dependence and result in severe withdrawal, what is used to taper withdrawal?
Longer acting BZ are used to provide a more tapered withdrawal
Chlordiazepoxide, Diazepam, Lorazepam
What are SE of BZ
CNS depression
Less common blurred vision, hallucination
Paradoxical excitement (due to dis-inhibition of suppressed behavior) - more common in elderly
Supra-additive (BZ+Barb+EtOH)
Sleep-related behaviors (sleep driving, eating, walking)
*effect most common in first few weeks, decrease as tolerance develops
Is tolerance common in BZ use? what about physical dependence?
Tolerance common, but generally don’t increase dose
- physical dependence may occur, abuse potential (though schedule IV)
- taper slowly following chronic use
BZ withdrawal effects include
- rebound anxiety and insomnia
- makes sense bc BZ are used to treat anxiety and insomnia
- Muscle weakness, tremor, hyperalgesia, N/V, wt loss, convulsions
- taper BZ slowly following chronic use
What is the OD risk with BZ?
relatively safe, but OD generally results in long deep sleep (1-2d), schedule IV drug
*fatalities may occur in people with respiratory difficulties, in children, and when combined with alcohol
Fatalities due to BZ use may occur in
people with respiratory difficulties, children, and when combined with alcohol
What is Flumazenil (Mazicon)
BZ antagonist, used to reverse the effects of BZ by competing for GABA receptor
ex: used to reverse Midazolam (Versed) which sometimes causes respiratory depression
Besides reversing the effect of BZ, Flumazenil (Mazicon)…?
reverses the effects of other drugs ie “z drugs” (zolpidem, Zaleplon, Eszopiclone
How long is Flumazenil’s (the BZ antagonist) duration of action? What is the main adverse effect? and who should not be given Flumazenil
Duration: 30 min
Major adverse effect: triggers withdrawal and seizures in pt who are physically dependent on BZ
*Do not use in pt with hx of seizures
Besides barbs and BZ, what other group of sedative hypnotics are there
the z drugs:
Zolpidem (Ambien), Zaleplon (sonata), & Eszopiclone (Lunesta)
How do the z drugs (zolpidem, zaleplon, eszopiclone) work? and what properties do they have
Bind to BZ1 subtype of GABA receptor to increase GABA mediated inhibition –> sedation zZZzzZz
*Z drugs has very strong and rapid SEDATIVE effects, but no anxiolytic/anticonvulsant/muscle relaxant properties
PK of the z drugs?
Good oral absorption
Peak levels 30-60 min, short DOA thus morning drowsiness is unlikely (but eszopiclone is longer)
Metab in Liver (CYP3A4); thus half life may be prolonged in severe hepatic disease
What are the side effects of the z drugs?
Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)
- generally very high MOS
- Gi: diarrhea, nausea
- CNS: drowsy, dizzy
- Sleep related behaviors (like BZ)
- Amnesia occurs with higher than recommended doses; confusion/memory loss/psychosis in elderly
- may increase depressant effects of other sedative drugs SUPRAadditive
- low tolerance/dependence
- rebound insomnia after rapid dc
- withdrawaL CNS stim, anxiety, seizures with abrupt cessation after long term use of eszopiclone
Withdrawal occurs with what z drug and what are the sx
withdrawal with eszopiclone (bc longer half life)
sx: CNS stim, anxiety, seizures with abrupt cessation after long term use
What is Ramelteon (Rozerem) and how does it work
Ramelteon (Rozerem) = Melatonin analogue; resets sleep-wake cycle; promotes sleepiness with no GABA effect
Does Ramelteon (Rozerem) rely on GABA to promote sleepiness
*resets sleep/wake cycle
No, Ramelteon (Rozerem) is a melatonin analogue
Pk of Ramelteon (Rozerem)?
Oral absorption, CYP450 metab (3A4, 2C9) in liver; extensive first pass metabolism
*additive sedation with alcohol and other sedative hypnotics
What are side effects of Ramelteon (Rozerem), the melatonin analogue
very few
drowsiness, dizziness, nausea
What is Diphenhydramine (Benadryl)
Not classical sedative, but older antihistamine with sedative properties
*active ingredient in majority of OTC preparations for insomnia
What is Diphenydramine (Benadryl) and other older antihistamines with sedative properties useful for
occasional insomnia
*especially useful for insomniac who has been addicted to BZ or alcohol
How does Chloral Hydrate (Noctec) work
converted to trichloroethanol which causes sedation; acts similarly to Barbiturates on GABAa receptor
Is Chloral Hydrate (Noctec) safe? can if cause any harmful SE?
Chloral Hydrate has low MOS
- high doses induce RESP and VASOMOTOR dep
- causes gastric irritation, N/V, allergic rxn, and potentially cardiac arrhythmia
*long term use may cause liver damage and fatal intoxication
Long term use of Chloral Hydrate (Noctec) may cause
liver damage and fatal intoxication
What is chloral hydrate (noctec) used for
note: cheap
* used in children for sedation during pediatric dental procedures
* used in nursing homes and chronic care instit.
- use as sedative hypnotic NOT RECOMMENDED
What is Buspirone (BuSpar) and how does it work
Buspirone relieves anxiety w/o causing sedation
- partial agonist at POSTsynaptic 5-HT1A (serotonin) receptor to inhibit cell signaling
- Full agonist for PREsynaptic 5-HT1A receptors to decrease release of 5-HT
- takes 2 wk for effect, no muscle relaxant or anticonvulsant properties
What is Buspirone (BuSpar) used for
relieves anxiety without producing sedation (2 wk for effect) specifically:
- gen anxiety and anxiety w/ depression
- ADHD and autistic pt with anxiety
- PMS
- no muscle relaxant or anticonvulsant properties
- does not potentiate CNS depression with EtOH or BZ
Does Buspirone (BuSpar), and anxiolytic, have an addiction potential? What is it not good for treating?
Buspirone (BuSpar) has very low addiction potential thus is an excellent choice of anxiety in recovering alcoholics/addicts
*not good for severe anxiety and/or panic disorder
What drugs are good for Insomnia/sedation and anxiety in recovering alcoholics or addicts
for Insomnia and sedation: Diphenydramine (benadryl)
For anxiety: Buspirone (BuSpar)
What is the PK of Buspirone (BuSpar) and anxiolytic
good oral absorption
high 1st pass (like Ramelteon, melatonin analogue)
CYP 3A4 liver metab
What is the safety of Buspirone (BuSpar)? What SE might it have?
fairly safe even in high doses
*may cause light-headedness, restlessness, HA, drowsiness, N/V
DOC for enuresis (bed wetting)
tricyclic antidepressants
