Medications for Nervous System Flashcards
Divisions of the Nervous System
- Central nervous system
- Peripheral nervous system
a. somatic motor system
b. autonomic nervous sytem
- parasympathetic nervous system
- sympathetic nervous system
Consequence of Alpha1-adrenergic blockade
Orthostatic hypotension, reflex tachycardia
Consequence of muscarinic cholinergic blockade
Dry mouth, blurred vision, urinary retention, constipation, tachycardia
Consequence of H1 (histamine) blockade
sedation, weight gain
Consequence of 5-HT2 (serotonin) blockade
weight gain
Consequence of D2 (dopamine) blockade
extrapyramidal symptoms, prolactin release
Psychosis
= dysregulation of dopamine
= imbalance of DA and serotonin
Antipsychotics
First generation antipsychotics (FGA)
- typical/conventional agent
- D2 antagonist, reduce dopamine transmission
Second generation antipsychotics (SGA)
- atypical agent
- reduce serotonin transmission
- low affinity for D2 receptors, may block other dopamine receptor subtypes
Onset of antipsychotic action
Week 1: medicated cooperation stage
Week 2 - 6: improved socialization stage
Week 2-months: elimination of thought disorder stage
Baseline achieved: maintenance stage
Positive symptoms and choice of agent
= associated with too much dopamine in mesolimbic area
(mesolimbic controls reward and desire)
FGA (D2 blockers) or SGA can be used
Negative symptoms and choice of agent
= associated with not enough dopamine in mesocortical area
(mesocortical control emotion and motivation)
SGA preferred to restore balance of serotonin and dopamine
*serotonin has an inhibitory effect on dopamine
Conventional Agents (FGA)
blockade of D2 receptors in mesolimbic area
- relieves positive symptoms
have low, medium and high potency
side effects come from blockade of the following receptors:
ACh, H1, NE, serotonin, dopamine in other pathways
A drug that has low potency..
requires more dose to achieve same effect
Example of a low potency FGA
Chlorpromazine (Largactil)
- low D2 affinity, non-selective
side effects: sedation, orthostatic hypotension, anticholinergic effects, weight gain
Example of a high potency FGA
Haloperidol (Haldol)
- high D2 affinity, selective
side effects: EPS, prolactin release (sex hormone causing lactation and breast growth)
Extrapyramidal Symptoms (EPS)
= spectrum of movement disorder
due to blockade of D2 receptors in nigrostriatal region creating DA/ACh imbalance
(excess ACh because D2 receptors are blocked, more ACh floating around?)
occurs early in therapy - acute dystonia: severe muscle spasm - parkinsonism: tremor, rigidity - akathisia: restlessness, pacing occurs late in therapy - tardive dyskinesia: involuntary twisting
Management for EPS
anticholinergic drugs are used to restore balance between DA and ACh
i.e. benztropine, diphenhydramine
Neuroleptic Malignant Syndrome (NMS)
= idiosyncratic reaction, rare, unpredictable but can be fatal
more likely with high potency agents
symptoms: sudden high fever, muscle rigidity, sweating, increased HR, labile BP, altered LOC, confusion, seizures, coma, arrhythmia, death
management: d/c antipsychotic, supportive measures, drug therapy
FGA Drug Interactions
Anticholinergic agents
- histamines, OTC sleep aids
CNS depressants
- alcohol, antihistamines, benzodiazepines, barbiturates)
Dopamine agonists (Levodopa) - activates dopamine receptors and exacerbates psychosis
Atypical Agents (SGA)
less affinity for D2 receptors so less EPS
strong blockade of 5-HT2 (serotonin) receptors
- helps to restore balance between DA and 5-HT
side effect: weight gain
also block H1, alpha-adrenergic, muscarinic-cholinergic receptors
Example of SGA
Olanzapine (Zyprexa)
Risperidone (Risperdal)
Clozapine (Clozaril)
Advantage and Disadvantage of SGA
Advantages:
- good for positive and negative symptoms
- good for preventing relapse
- less EPS, better adherence
Disadvantages:
- side effects: weight gain, diabetes, ++ cholesterol
- some agents prolong QT interval, risk of arrhythmia
- more expensive
Depot Formulations
= long-acting injectables (IM or SC)
convert to depot once stabilized on oral regimen
Advantages:
- slow, steady absorption
- dosing interval is 2-4 weeks, enhanced adherence
- lower rate of relapse than oral therapy
Disadvantages:
- may get more EPS with SGA depot formulations
Clozapine (Clozaril)
- most effective agent, not used as first line but when other drugs have failed
- can cause agranulocytosis (lowered WBC)»_space; weekly or biweekly monitoring of WBC and neutrophil required
hold or d/c if WBC drops
Neuropathophysiology of Depression
Monoamine hypothesis: deficit of NE, 5-HT or DA neurotransmission
Antidepressants work to increase NT levels in synaptic cleft
- prevent reuptake into presynaptic membrane
- inhibit metabolism of NT
Pharmacotherapy of Depression
Acute phase
- 8-12 weeks
- goal is remission of symptoms: 1-3 weeks for somatic symptoms, 1-2 months for depressive symptoms
Maintenance phase
- minimum 6 months, may require 2+ years
- goal is prevention of relapse
SIDE EFFECTS OCCUR EARLY
Symptoms of Depression
a. principal symptoms
- depressed mood, loss of interest or pleasure
b. somatic symptoms
- changes in sleep pattern, changes in appetite, weight and fatigue
c. other depressive symptoms
- lethargy, feelings of guilt or worthlessness, poor concentration, suicidal thoughts
5 Anti-Depressant Drug Classes
- Selective Serotonin Reuptake Inhibitors (SSRIs)
- Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
- Tricyclic antidepressants (TCAs)
- Atypical antidepressants
- Monoamine Oxidase Inhibitors (MAOIs)
- seldom used today
Selective Serotonin Reuptake Inhibitors (SSRI)
= block 5-HT reuptake pump, increase 5-HT in synapse
little effect on other NTs
= long half-life, dose once daily
= safe and well tolerated, common first-line agent
Prototype: FLUOXETINE (Prozac)
SSRIs Side Effects
= do not block H1, NE, 5-HT or ACh receptors
a. sexual dysfunction
b. nausea, HA, weight gain
c. CNS stimulation: nervousness, insomnia, anxiety
Serotonin Syndrome (drug interaction)
= condition caused by excessive serotonin transmission when combining more than one drug that increases serotonin
= onset within hours to days of starting second drug
= resolves with d/c but can be fatal
symptoms: confusion, agitation, hallucination, increased muscle tone, tremor, rigidity, sweating, fever
**avoid combining SSRI with SNRI, TCA, MAOI, certain opioid analgesics, migraine drugs (triptans)
Dosing and Administration of SSRIs
a. once daily, usually AM due to stimulant effect
b. start low, go slow
c. take with food to decrease GI side effects
d. washout period if switching agents to prevent serotonin syndrome
e. taper off to d/c, prevent withdrawal (headache, agitation)
Tricyclic Antidepressants (TCAs)
= block neuronal reuptake of NE and 5-HT
= long half life, dose once daily
= especially effective in severe cases
= second-line therapy because not always safe or well-tolerated
Prototype: AMITRIPTYLINE (Elavil)
TCAs Side Effects
- sedation (H1 blockade)
- orthostatic hypotension (alpha1 blockade)
- anticholinergic effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia (muscarinic cholinergic blockade
- weight gain (5-HT2 blockade)
a. cardiac toxicity
b. diaphoresis
c. seizure, lower threshold
d. hypomania
TCAs Drug Interactions
a. anticholinergic agents, antihistamines
b. CNS depressants
- alcohol, opioids, barbiturates
c. MAOIs
causes sever HTN
Dosing and Administration of TCAs
a. once daily, q HS, night time to promote sleep and reduce daytime side effects
b. start low, go slow
c. caution in elderly or patients with seizure or cardiac conditions
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
= block reuptake of NE and 5-HT into nerve terminal
= similar efficacy to SSRIs and TCAs
Prototype: VENLAFAXINE (Effexor XR)
SNRIs Side Effects
= do not block H1, NE, 5-HT or ACh receptors
a. nausea
b. weight loss/anorexia
c. HA
d. insomnia
e. sexual dysfunction
f. increased blood pressure
Dosing and Administration of SNRIs
a. once daily, AM
b. start low, go slow
c. take with food to reduce GI side effects
Atypical Antidepressants
= unique agent that blocks DA and NE reuptake
= similar efficacy to SSRIs and TCAs
= not suitable with preexisting seizure disorders
= short half life, dose 2-3 times daily
Prototype: BUPROPION (Wellbutrin)
Atypical Antidepressants Side Effects
= do not block H1, NE, 5-HT or ACh receptors
a. agitation
b. HA
c. nausea, weight loss
d. dry mouth
e. insomnia
f. constipation
g. psychosis (rare)
Bupropion (Wellbutrin)
= avoid in patients with seizure disorder, psychosis, anorexia or bulimia
= do not combine with SSRIs»_space; risk of seizure
= dose 2-3 times daily, space 8-12 hours apart or use long-acting once daily formulation
- is also used for smoking cessation
Important Considerations in Pharmacotherapy in Depression
- antidepressants cannot be used prn
- therapeutic effect requires at least 1 month, consistently
Patient Education:
a. time required to see effect
b. side effect profile
c. need to continue even after symptoms improve
d. avoid abrupt discontinuation
e. dose spacing for bupropion
f. cannot be used prn
Anti-Epileptic Drugs (AEDs)
= control seizure disorder, prevent recurrence while minimizing side effects
= suppress discharge of neurons wtihin a seizure focus (reduce firing) and propagation of seizure activity
= drugs interrupts electrochemical or biochemical communication
a. suppression of sodium or calcium influx
b. potentiation of GABA
c. blockade of receptors for glutamate
drug selection depends on seizure type
eventually withdraw medication with continuing control
Older (conventional) AEDs
a. phenytoin
b. carbamazepine
c. valproic acid
d. phenobarbital
e. benzodiazepine
Newer AEDs
a. gabapentin
b. lamotrigine
c. topiramate
d. levetiracetam
e. pregabalin
Phenytoin (Dilantin)
= inhibits Na+ influx, inhibit action potential
useful for most major forms of epilepsy
- small dose change creates large change in blood levels
- high risk of toxicity
- NARROW THERAPEUTIC INDEX
Therapeutic Drug Monitoring (TDM)
- helps with dose titration to keep blood levels in appropriate therapeutic range
- monitor patient adherence
- determine cause of poor seizure control
- identify cause of drug toxicity
- manage drug interactions
Phenytoin Side Effects
a. CNS effect: sedation, ataxia, ocular effects (double vision), cognitive impairment
b. gingival hyperplasia: overgrowth of gum tissue
c. rash
d. GI upset
e. hirsutism: coarsening of facial features
f. arrhythmia and hypotension if IV infused too rapidly
Phenytoin Drug Interactions
phenytoin induces CYP450 enzymes to REDUCE levels and efficacy of many other drugs:
- warfarin
- oral contraceptives
- corticosteroids
- TCAs
- cyclosporine
other AEDs can increase phenytoin levels
additive effects with other CNS depressants
Carbamazepine (Tegretol, CBZ)
= inhibit NA+ influx, inhibit action potential
- absorption delayed…metabolized in liver, half-life decreases with prolonged therapy (induces its own metabolism)
- NARROW THERAPEUTIC INDEX
Carbamazepine Side Effects
a. neurologic effects visual disturbances, ataxia, vertigo, HA b. hematologic effects (lower platelet count) leukopenia, anemia, thrombocytopenia c. GI upset, dry mouth d. hepatotoxicity e. water retention f. rash
Carbamazepine Drug Interactions
induces CYP450 enzymes to REDUCE levels and efficacy of many other drugs:
- warfarin
- oral contraceptives
- digoxin
- TCAs
- valproic acid
- cyclosporine
- CBZ itself!
Valproic Acid
= inhibits Na+ and Ca2+ influx, augments GABA activity
= reduce action potential, increase GABA action
different forms:
Valproic acid, valproate (Depakene)
Divalproex sodium (Epival)
Valproic Acid Side Effects
a. GI upset
b. hepatotoxicity (not suitable for liver disease)
c. tremor, hair loss, weight gain, rash
d. highly teratogenic
- avoid in pregnancy
- use effect contraception and take folic acid to prevent neural tube defects in case pregnancy occurs
Principles for dosing and administration of Conventional AEDS (phenytoin, CBZ, valproic acid)
a. start low, go slow
b. dosing is individualized (use TDM as guide)
c. administer with food
d. never stop abruptly
Drugs that Potentiate GABA
++ GABA»_space; suppress seizure activity
a. Benzodiazepines and barbiturates
- directly bind to GABA receptors and enhance activity, mimic action of GABA at high doses
b. Gabapentin
- promote release of GABA
GABA-receptor Chloride Channel Complex
act on chloride channels to increase frequency or prolong duration of channel open
chloride moves into cell to prevent action potential
Barbiturates
phenobarbital
enhances GABA action, bind to and activate GABA receptor
- uses: status epilepticus and maintenance therapy
= long acting, once daily, effective, cheap
- NARROW THERAPEUTIC USE
- VERY STRONG RESPIRATORY DEPRESSANT
Barbiturates Side Effects
drowsiness, lethargy, depression, impaired cognition
dependence
induces CYP450
Gabapentin (Neurontin)
= promote release of GABA
most commonly used newer agent, adjunctive therapy of partial seizures
not metabolized, excreted unchanged in urine
short half life, 2-3 times daily
Gabapentin Side Effects and Interactions
drowsiness, dizziness, ataxia, fatigue, nystagmus
- effects mild-moderate and decreases over time
- rapid dose titration can reduce these effects
few drug interactions
- antacid decreases gabapentin bioavailability
- additive sedation with CNS depressants
Status Epilepticus (SE)
seizure for > 20 mins becomes medical emergency!
- can lead to irreversible brain damage
Maintain VENTILATION, correct HYPOGLYCEMIA, terminate SEIZURE
- establish IV line
- administer glucose, AEDs
- draw electrolyte and glucose levels - respiratory support may be required
a. LORAZEPAM or DIAZEPAM
b. PHENYTOIN
c. PHENOBARBITAL
Other Uses of AEDs
- bipolar disorder
- neuropathic pain
- migraine prophylaxis
- sedation, sleep induction
- arrhythmia
- leg cramps
Medications that Increase Risk of Seizure
- bupropion
- TCAs
- clozapine
- some antibiotics (i.e. penicillins, cephalosporins)
- cyclosporine (immunosuppresant)
- alcohol
- street drugs: cocaine, heroin, ecstasy, amphetamine
- herbals: ginseng, green tea, st john’s wort
Sedative-Hypnotic Drugs
depress CNS function
low dose: relieves anxiety (anxiolytic)
high dose: promotes sleep (hypnotic)
main classes:
a. benzodiazepines
b. barbiturates
c. non-benzodiazepine agonist
Barbiturates
secobarital
barbiturates have multiple uses due to general CNS depressive effects: daytime anxiety, insomnia, epilepsy, general anesthesia
= short acting, for anxiety
= long acting (phenobarbital) for seizures
- NARROW THERAPEUTIC INDEX
- poor safety profile: respiratory depression, tolerance, dependence, abuse, drug interactions
Benzodiazepines (BZD)
= binds to GABA-R, enhances GABA actions
= onset depends on lipid solubility (how quickly it crosses BBB into CNS)
= duration depends on lipid solubility and hepatic metabolism
drug for choice for anxiety and insomnia
safer than barbiturates: less abuse, dependence, tolerance, safer
Prototype: LORAZEPAM (Ativan)
Selection of BZD
driven by onset, duration and accumulation with repeated dosing
Insomnia - want rapid onset (highly lipid soluble)
Anxiety - want intermediate duration (active metabolites)
*generally discourage use in elderly, but if using, choose agent that does not accumulate and use short-term
Relative Onset and Duration of BZD
Diazepam - very rapid onset, 100hr
Clonazepam - rapid onset, 34hr
Lorazepam - intermediate onset, 15hr
Triazolam - rapid onset, 2 hr
BZD Side Effects and Interactions
daytime sedation, confusion, anterograde amnesia
weak respiratory depression
risk of severe respiratory depression, hypotension, cardiac arrest when given IV
Interactions: significant respiratory depression if combines with other CNS depressants (opioids, alcohol, barbiturates)
Dosing and Administration of BZD
Insomnia: single oral dose at bedtime
Anxiety: orally 3-4 times daily
- SL faster onset
- little tolerance to anxiolytic/hypnotic effects
- can develop tolerance for seizure
- some physical dependence, GRADUAL WITHDRAWAL
Zopiclone (Imovane)
TREAT INSOMNIA
- non-benzodiazepine agonist
- rapid onset, half life about 5 hours
- side effect: bitter taste, daytime impairment
- some tolerance/dependence with long-term use
OTC Drugs for Insomnia
Antihistamines
- less effective than BCD, tolerance develops quickly
- safe for occasional use but anticholinergic effects
Valerian
- may help with falling asleep but not staying asleep
- effects take at least 1 week to develop
Melatonin
- effective for falling asleep and maintaining sleep
- high dose can cause hangover, headache, nightmares
