Pharm II- Exam III

Which drugs are spasmolytics?

Diazepam (both)
Baclofen
Dantrolene
Tizanidine (both)
Botulinum Toxin

Which drugs are antispasmotics?

carisoprodol
chlorzoxazone
cyclobenzaprine
diazepam (both)
metaxalone
methocarbamol
orphenadrine
tizanidine (both)

What are antispasmodics indicated for?

-Spasms from peripheral musculoskeletal
-muscle spasms (cramping)

What are spasmolytics indicated for?

-muscle spasticity from upper motor neuron lesions

What is the MOA of baclofen?

-Derivative of GABA--\> *GABA-B receptor agonist*
-Reduces release of excitatory neurotransmitter from *presynaptic terminals* of primary afferents--\> this inhibits activation of alpha motor neurons (3 actions)
1: closure of presynaptic calcium channels,
2: increased postsynaptic K+ conductance, and
3: inhibition of dendritic calcium influx channels.

What is baclofen indicated for?

-Most beneficial for spasticity related to MS and spinal cord injury
-primary dystonias, Tourette's syndrome

What is the MOA of dantrolene sodium?

-*Inhibits calcium release from sarcoplasmic reticulum*, interfering with muscle contraction

What is dantrolene indicated for?

-Has a *limited role in treating spasticity* due to its adverse effects as its more typical role is in the treatment of neuroleptic malignant syndrome or malignant hyperthermia
-Special application: *treatment of malignant hyperthermia*

What is the MOA for diazepam?

-Enhances activity (*indirect acting*) of *GABA-A* by potentiating the inhibitory effects of GABA on alpha motor neurons--\> reduces spasticity partly in the spinal cord and produces sedation at the doses required to reduce muscle tone

What is diazepam indicated for in respect to motor and vestibular disorders?

-reduces spasticity partly in the spinal cord and shows benefits in patients with *cord transection*.
-*muscle spasm of almost any origin*
-As antispasmodic: Used in treating *spasms associated with musculoskeletal injuries* (primary dystonia, tourette's)
-used in *spasms induced by tetanus toxin*
-Vestibular disorders for symptomatic relief of vertigo: *Meniere's disease and Ramsay Hunt syndrome*

What is the MOA for tizanidine?

-Centrally acting *alpha2 agonist*--\> *Inhibits release of excitatory neurotransmitters* pre-synaptically that leads to a reduction in postsynaptic activation of the upper motor neuron

What is tizanidine indicated for?

-Both spasmolytic and antispasmotic
-used to treat spasms due to peripheral MSK conditions and spasticity due to upper motor neuron lesions

What is the MOA of botulinum toxin type A?

neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of ACh from vesicles

What are the indications of botulinum toxin type A in respect to motor and vestibular disorders?

-treatment of cervical dystonia in adults to decrease the severity of abnormal head position and neck pain; upper limb spasticity
-didn't specify A or B: torticollis, blepharospasms, laryngeal dystonias, strabismus, Cerebral palsy, CVA, cosmetics

What is the MOA of carisoprodol?

-Metabolized via CYP2C19 to meprobamate, a barbiturate--\> Barbituate activity (activity at GABA-A)
-Centrally acting and changes interneuronal activity in the descending reticular formation and spinal cord

What is carisoprodol indicated for?

-muscle spasms (cramping) due to peripheral MSK conditions

What is the MOA of cyclobenzaprine?

-It is thought to exert its effects through decreasing the excitability of alpha and gamma motor neurons while also leading to CNS depression through the brain stem
-Structurally related to the tricyclic antidepressants and produces antimuscarinic side effects.

What is cyclobenzaprine indicated for?

-muscle spasms (cramping) due to peripheral MSK conditions
-Ineffective in treating muscle spasm due to cerebral palsy or spinal cord injury

What is the MOA of chlorzoxazone?

-Blocks multisynaptic reflex arcs in the spinal cord and subcortical area of the brain.

What is chlorzoxazone indicated for?

-muscle spasms (cramping) due to peripheral MSK conditions

What is the MOA of metaxalone?

unclear as it has no activity on skeletal muscle or nerve fibers. Thus, it is suspected that its effects are primarily due to CNS depression.

What is metaxalone indicated for?

-muscle spasms (cramping) due to peripheral MSK conditions--\> effects due to CNS depression

What is the MOA of methocarbamol?

suspected to be associated with its sedative properties

What is methocarbamol indicated for?

-muscle spasms (cramping) due to peripheral MSK conditions--\> effects due to sedation

Which antispasticity agent causes the most severe general muscle weakness?

Dantrolene sodium

When baclofen is abruptly stopped, what can happen?

risk of hallucinations or seizures from withdrawal

When tizanidine is abruptly stopped, what can happen?

rebound hypertension, tachycardia, and increased spasms

When carisoprodol is abruptly stopped, what can happen?

-Metabolite meprobamate (barbiturate) withdrawal can occur- no symptoms listed

When benzodiazepines are abruptly stopped, what can happen?

What are the ADR's of diazepam?

-sedation
-drowsiness
-impaired psychomotor performance

What are the ADR's of baclofen?

-high doses: excessive somnolence, respiratory depression, and coma ND/OR
-sedation, dizzy, confusion
-Increased seizure activity has been reported in patients with epilepsy
-Tolerance may develop with long-term use
-withdrawal syndrome

What are the ADR's of tizanidine?

-Dose-related hypotensive effect
-dizziness
-Sedation
-dry mouth
-elevation in hepatic enzymes

What are the ADR's of dantrolene?

-generalized muscle weakness
-Black box warning for hepatotoxicity

What are the ADR's of botulinum toxin?

-Dysphasia (most common)
-Respiratory tract infections
-muscle weakness
-urinary incontinence
-falls
-fever
-pain
-Anaphylaxis
-BBW: *Distant spread of toxin effects; swallowing and breathing difficulties*; especially in children treated for spasticity

What are the ADR's of cyclobenzaprine?

-Strong antimuscarinic actions
-may cause significant sedation
-confusion
-transient visual hallucinations

What are the ADR's of carisprodol?

-respiratory depression can occur especially when combined with opioids, benzodiazepines, or barbiturates

What are the ADR's of chlorzoxazone?

-Sedation- common
-Rare: hepatotoxicity or GI bleeding
-Red/orange urine discoloration may occur
-respiratory depression may occur when combined with opioids, benzodiazepines, or barbiturates.

What are the ADR's of metaxalone?

-leukopenia
-hemolytic anemia
-hepatic transaminase elevation.
-Respiratory depression can occur when it is used with opioids, benzodiazepines, or barbiturates

What are the ADR's of methocarbamol?

-Respiratory depression can occur when used concomitantly with other medications
-Urine discoloration (brown, green, black) is also possible.

What are the ADR's of orphenadrine?

-anticholinergic
-GI irritation
-rare incidence of aplastic anemia
-CNS depressant effects are magnified when used with other CNS depressants

Which antispasticity agents cause dependence with severe withdrawal?

-Benzodiazepines
-Carisoprodol
-Baclofen (idk about dependence but definitely withdrawal)

Why is carisoprodol a controlled substance in Schedule IV?

• Because it is metabolized via CYP2C19 to meprobamate, a barbiturate
• Barbiturate activity --\> potential for dependence and abuse

Which drugs are approved for the chorea symptoms of HD?

*Tetrabenazine* and Deutetrabenazine

What is the MOA of tetrabenazine?

-MOA is thought to be depletion of stored neurotransmitters (DA, 5HT, NE, histamine) from presynaptic terminals of striatal neurons
-also, some weak antagonistic activity at D2 receptors

What is the MOA of deutetrabenazine?

-Vesicular monoamine transporter type 2 (VMAT2) inhibitor
-VMAT transports neurotransmitter substances (NE, DA) form the cellular cytosol into the synaptic vesicle

What is the MOA of botulinum toxin?

•Causes neuromuscular blockade through inhibition of calcium-induced ACh release at the NMJ

What is the indication of botulinum toxin in respect to dystonias?

-Local injection into two or more involved neck muscles; symptoms resolve for several weeks to months

What is the MOA of valbenazine?

VMAT2 inhibitor in presynaptic nerve terminal that results in decreased DA release

Which drugs can be used in Tourette's syndrome?

-alpha 2 agonist: clonidine, guanfacine
-typical antipsychotic: haloperidol, fluphenazine, pimozide
-atypical antipsychotic: Risperidone, olanzapine, aripiprazole
-Botulinum toxin type A
-GABA agents are last line

What is the MOA of clonidine and guanfacine in the use of Tourette's?

decreased central sympathetic activity is thought to inhibit the overactive dopaminergic pathway that causes the syndrome

What class is fluphenazine in?

typical antipsychotic

What class is pimozide in?

typical antipsychotic

What is the MOA of typical antipsychotics in use of Tourette's syndrome?

dopamine-2 receptor blockers

What is the MOA of atypical antipsychotics in use of Tourette's syndrome?

5HT2 and D2 antagonist to regulate DA function

What is the major problem with pimozide?

QT prolongation and torsades de pointes

What are the drugs of choice for restless leg syndrome?

*Dopamine agonists* (pramipexole, ropinorole, rotigotine TD-patch)

What is the augmentation effect that occurs with dopaminergic agents in therapy of RLS?

-Worsening of symptoms that occurs during treatment with any dopaminergic agent (*resistance*)
-Appearance of more severe RLS symptoms earlier in the day- typically occurs in the afternoon or early evening prior to the scheduled daily dose
-DA agonist dose should be reduced or split if augmentation occurs
-occurs with levodopa/carbidopa

How is acute labyrinthitis treated?

-*Meclizine* for dizziness
-*Antimicrobial* if purulent
-PO or IV *fluids* for dehydration (from vomitting)
-*Prochlorperazine* IM or rectal: antiemetic

How is Meniere's disease treated?

Symptomatic:
-*anticholinergics*: minimize vagal
-*antihistamines*: meclizine or prochlorperazine for N/V
-*diazepam* or *lorazepam* for stress
-*diuretics*: triamterene/HCTZ- for pain and pressure

Others:
-Chemical labyrinthectomy (otic gentamycin)--\> ototoxicity- kill that ear so the other can take over
-Corticosterioids (dexamethasone) injection
-surgical labyrinthectomy
-vestibular neurectomy

How is Ramsay-Hunt syndrome treated?

-corticosteroids
-acyclovir or valacyclovir
-diazepam for vertigo
-analgesics for pain

How is otic gentamycin beneficial in Meniere's disease?

Chemical labyrinthectomy
- Ototoxic aminoglycoside that is delivered to the middle ear
- Ototoxicity reduces the balancing function of the injected ear and allows the other ear to control balance

How are corticosteroids beneficial in Meniere's disease?

-dexamethasone injection: Slightly less effective than gentamicin but less likely to cause further hearing loss
-reduce inflammation

What is the MOA for scopolamine?

- Muscarinic cholinergic antagonist
- allows more rapid adaptation by enhancing neural storage of new information

What route of administration is approved for scopolamine?

Transdermal patch applied behind the ear and is effective for up to three days

What is scopolamine approved for?

-prevents motion sickness

What are ADR's of scopolamine?

dry mouth, drowsiness, blurred vision

What is the MOA for meclizine?

-antihistamine
-Histaminic neurons are located in the centers for vomiting, salivation, and other symptoms associated with motion sickness
-Antihistamines that cross the blood-brain barrier can prevent and block the symptoms of motion sickness

What is meclizine approved for?

motion sickness

What is dimenhydrinate approved for?

motion sickness

What is the MOA of dimenhydrinate?

-antihistamine
-Histaminic neurons are located in the centers for vomiting, salivation, and other symptoms associated with motion sickness
-Antihistamines that cross the blood-brain barrier can prevent and block the symptoms of motion sickness

Which drug for motion sickness causes the most drowsiness?

Dimenhydrinate

Which drugs can precipitate seizures?

-amphetamines
-antipsychotics
-baclofen (withdrawal)
-bupropion
-methyphenidate
-quinolones (ciprofloxacin, levofloxacin, moxifloxacin)
-tramadol

What are the DOC for generalized seizures?

-carbamazepine
-phenytoin
-valproic acid
-lamotrigine
-levetiracetam

What are the DOC for focal seizures?

-Carbamazepine
-Phenytoin
-Lamotrigine
-Levetiracetam
-Zonisamide
-Eslicarbazepine
-Lacosamide
-Perampanel
-Pregabalin
-Topiramate ER

What are the DOC for absence seizures?

-Ethosuximide
-Valproic acid
-Lamotrigine

What are the DOC for myclonic seizures?

-Clonazepam
-Valproic acid

What are the DOC for Lennox-Gastaut seizures?

-Clobazam
-Cannabidiol
-Rufinamide

What are the treatments for seizure clusters?

-Oral: clonazepam (waffer and tab), diazepam, lorazepam
-Rectal: diazepam
-Nasal: midazolam, diazepam

What are the major indications for phenytoin?

-DOC for generalized tonic-clonic seizures, focal seizures, mixed seizures, and seizure prophylaxis in neurologic procedures
-2nd line drug in the management of status epilepticus (after termination with IV lorazepam)

Compare the infusion rate for phenytoin vs. fosphenytoin. Why?

-Restricted to a maximum rate: start 15-20 mg/kg with a maximal rate of *50 mg/min* only in normal saline--\> Monitor for *hypotension, arrhythmias, cardiac, or respiratory depression*
-Fospehnytoin: Faster infusion rate- Max infusion rate of *150 mg PE/min* due to *hypotension*

What are the symptoms of chronic phenytoin/fosphenytoin toxicity?

*-gingival hyperplasia*
*-hypertrichosis*
*-osteomalacia*
-nystagmus, *ataxia*, decreased mentation

What therapeutic measures can help with the gingival hyperplasia from phenytoin/fosphenytoin?

D/C medication should reverse effect

Which anti-epileptic drugs are teratogenic?

-Phenytoin/fospheytoin
-Valproic acid, sodium valproate, divalproex sodium
-topiramate

What are the indications for carbamazepine in respect to anticonvulsant and neuropathy?

· DOC for management of *generalized tonic-clonic, simple or complex partial, mixed partial or generalized seizure disorder*
· *Trigeminal neuralgia*
· Unlabeled: bipolar disorder, resistant schizophrenia, management of alcohol withdrawal and 2nd-line agent for restless legs syndrome

What are the ADR's of carbamazepine?

-*GI distress*--\> Take with food: divide doses and take with large amount of water or food to minimize GI upset
-CNS: *nystagmus, ataxia*
-dermatologic reactions: *rash, potential for severe lesions*
-metabolic: *SIADH with resulting hyponatremia*

Who should be screened before receiving phenytoin and carbamazepine?

-BBW: genetic screening recommended for patients of Asian descent for HLA-B*1502 gene (SJS or TEN)

What are the indications for valproic acid?

- monotherapy and adjunctive therapy in simple and complex absence seizures, and adjunctively in multiple seizure types that include absence seizures
- monotherapy and adjunctive therapy in the treatment of patients with focal seizures that occur either in isolation or in association with other seizure types

What are the boxed warnings for valproate?

*hepatotoxicity, pancreatitis*, teratogenicity

What is the indication for ethosuximide?

DOC for absence seizures

What is the basic MOA of carbamazepine?

blockade of sodium influx

What is the basic MOA of phenytoin?

-inhibition of sodium channel activation --\> decreases synaptic release of glutamate
-enhances release of GABA

What is the basic MOA of valproic acid?

enhancing actions of GABA at central neurons

What is the basic MOA of ethosuximide?

blocking neuronal calcium channels

What is the BBW for carbamazepine?

*genetic screening* recommended for patients of Asian descent for HLA-B*1502 gene (SJS or TEN)

What is the BBW for perampanel?

monitoring of psychiatric, behavioral, mood, or *personality changes* (may be life-threatening)

What is the basic MOA of clonazepam?

GABA-A receptor agonist--\> opens Cl- channels to hyperpolarize cell (prevent depolarization)

What is the treatment for status epilepticus?

• DOC for terminating are *IV lorazepam (Ativan) or diazepam (Valium)*
• Concurrent administration of a longer-acting anticonvulsant: IV loading dose of *phenytoin sodium (in NS) or fosphenytoin sodium* (in D5W, faster infusion rate)
• Refractory: IV phenobarbitol --\> midazolam

What is the basic MOA of gabapentin?

• *Inhibition of N-type calcium channels* causing decreased release of glutamate
• *binds to presynaptic α2δ subunit of calcium channels*, possibly resulting in decreased release of the excitatory neurotransmitters glutamate, noradrenaline, substance P, and calcitonin gene-related peptide

What is the basic MOA of levetiracetam?

-Inhibition of voltage dependent N-type calcium channels
-facilitation of GABA-ergic inhibitory transmission
-reduction of delayed rectifier potassium current

Which anti-epileptics can cause hyponatremia?

Carbamazepine, Oxcarbazepine, *Eslicarbazine*