CNS Drugs 1 Flashcards
Triazolam
Benzodiazepine
Diazepam
Sedative-hypnotic, benzodiazepine
*PROTOTYPICAL
“valium” “mother’s little helper”
Lorazepam
Benzodiazepine, Sedative hypnotic/anxiolytic
Estazolam
Benzodiazepine, sedative-hypnotic/anxiolytic
Flumazenil
Benzodiazepine Antagonist
*Mainly used in combined EtOH/BZD OD.
MOA: direct acting competitive antagonist that binds to the BZD receptor site on GABAa receptors, prevents increase in GABA activity.
Pentobarbital
Barbituate
Phenobarbital
Barbituate
Benzodiazepines (BZDs)
Long acting (Anxiety disorders and waking frequently at night): Diazepam
Intermediate acting (Long-term sedation and cannot stay asleep): Estazolam, Lorazepam
Short acting (For difficulty falling asleep, assoc. with retrograde amnesia): Triazolam
MOA: Increases the affinity of GABA for the GABA-A receptor which increases the FREQUENCY at which the Cl- channel opens in response to GABA. Binds to benzodiazepine receptor site on GABAa between alpha and gamma-2 subunit– changes tertiary structure
Effects: Increases Cl- conductance which shunts depolarization = CNS depression. Since they are agonist at the site, but inhibit NT effect, they are INVERSE AGONISTS
“State-dependent action”: BZD action dependent on the status of GABA release. As the drug depresses CNS fxn, GABA release is reduced. Therefore BZDs have a ceiling effect, = little respiratory depression.
Toxicity: Very hard to kill a patient by OD = ceiling effect through CNS depression/GABA release reduction. IV use can have significant respiratory depression at very high doses. *Characteristic signs of CNS depression. Dirrahea, epigastric distress, bitter taste, nausea, vomitting, rare hallucination.
Withdrawal is mild, can have rebound insomnia, anxiety, increased reflexes, excessive motor activity, headache.
Can induce drug hang-over (reduced alertness, groggy feeling)
Benzodiazepine antagonist
Flumazenil
Barbituates
Pentobarbital (induces coma in status epilepticus)
Phenobarbital (Managing generalized seizures)
*Risk of respiratory depression HIGH
“drug automatism”: patient awakens, takes another pill, and this cycles until fatal consequences occur, originated with this drug class.
Commonly causes drug hangover.
MOA: binds to the Cl ionophore site independent of GABA binding site.
Increases time the gate is open in presence of GABA. *Opposite of BZDs, barbs can open Cl gate in ABSENCE of GABA (at high dose)
*no ceiling effect, dose-dependent increase in Cl conductance.
Toxicity: Easily produce coma/death, at high dose, can block Ca channels No ceiling effect. *potent CYP450 enzyme inducers, biotransformation increased = complication of therapy w/ other drugs
*Differential rates of tolerance, respiratory depression=antiepileptic efficacy in tolerance, «sedation tolerance
Other sedatives/hypnotics
Zolpidem (least likely to produce rebound insomnia with little muscle relaxant effects)
Meprobromate (older agent with greater potential for toxicity in OD)
Eszopiclone (For chronic use sedation with less tolerance)
Remelteon (Melatonin agonist with no adverse side effects seen with other drugs in same class. Not as good of a sedative)
MOA: all work on Cl channel.
Sedative/Anxiolytics
Buspirone (no dependence, no sedation, no anti-epileptic activity)
Propranolol
*All have anxiolytics, but are not anxioselective
Situational Anxiety drugs
Propranolol
Anti-spastic Drugs
Baclofen
Propranolol
Sedative-hypnotic and Antitremor drug
MOA: beta adrenergic non-specific antagonist
Anxiolytic may be due to increased activity of the locus ceruleus, blocking the action of NE reduces locus ceruleus activation of central nucleus of the amygdala
Use: preferred for situational anxiety– stage fright *can also use for essential tremor
Buspirone
Anxiolytic
Use: reduced anxiety with absence of sedation w/ few other actions
MOA: 5HT-1A partial agonist with small anti-dopaminergic component, reduces firing of raphe nucleus
Effects: do not have typical sedative-hypnotic effects, are without tolerance/cross-tolerance with BZDs
Toxicity: headache, dizziness, and nervousness
*not effective in management of panic attacks, where SSRIs are.
Baclofen
Anti-spastic drug
MOA: works on presynaptic terminals in spinal cord to ease spasticity. inhibits transmission of both monosynaptic and polysynaptic reflexes, possibly by hyperpolarization of primary afferent fiber terminals = antagonism of the release of excitatory NTs. *Hence, reduces the afferent reflexes that mediate spasticity. B/c of GABAb specificity, it produces less sedation than BZDs at doses that = anti-spasticity effects.
Toxicity: High doses can still be sedating, withdrawal can = hyper-spastic symptoms and seizure.
*For high doses that would = sedation, pumps are used intrathecally, allows for high levels of baclofen in spine w/o significant sedation
Eszopiclone
Other sedative/hypnotic “Lunesta”
BZD-like agent, “safe for chronic use”
Remelteon
Other sedative/hypnotic
New type of sedative, works at melatonin agonist at MT-1 receptor
Zeleplon
Other sedative/hypnotic “Sonata”
Short duration effect for those who have problems falling asleep, but not used for staying asleep.
*clears system rapidly, no drug hangover
Drugs for Parkinson’s
Carbidopa/Levadopa (indirect-acting DA agonists)
Indirect-acting DA Agonists
Benztropine Selegiline Rasagiline Tolcapone Entacapone Stalevo
Anti-muscarinic agents
Trihexyphenidyl
Benztropine
Direct-acting DA Agonists
Pramipexole
Ropinirole
Other drugs used
Clozapine
Huntington’s and Tourette’s Drugs
Haloperidol
Antitremor Drugs
Propranolol
Ethanol
Dystonia Drugs
Antimuscarinics
Benzodiazepines
BoTox
AD/HD Drugs
Methylphenidate
Adderall
Atomoxetine
Benztropine
Indirect-acting DA agonist/Antimuscarinic, Antipsychotic
DAT inhibitor and ACh antagonist
Use: other PD drug also Antipsychotic
Effects: Dual action- DA uptake inhibitor (DAT) and antimuscarinic mixes actions and enhances effect, both effectively overcome the deficiency of DA in the striatum at two locations in the pathway
Toxicity: produces unwanted side effects when used to treat PD, secondary to treatment with antipsychotic drugs anticholinergic properties produce sedation and other antimuscarinic effects including memory clouding/constipation
Selegiline
Indirect-acting DA agonist
converted to amphetamine and methamphetamine
MOA: MAO-B selective at normal doses, reuptake inhibitor. Contributes to effects by inducing DA release. Increases synaptic DA pool, and overall DA tone. *Normal DA release, extends duration
Toxicity: Can be a problem in working PD patients due to conversion to amphetamine (drug testing) Blocks MAO-A at high doses, but no tyramine effect.
Rasagiline
Indirect-acting DA agonist
MOA: MAO-B preferring with MAO-A blocking at normal doses, higher concentrations (pressor amine effect).
*Does not convert to amphetamine
Toxicity: MAO-A1 effect at high dose (NE neurons)
Tolcapone
Indirect-acting DA agonist
MOA: blocks COMT in peripheral and central CNS
Effect: increases bioavailability of levodopa to brain, and increases duration of levodopa action (reduced catabolism) *Crosses BBB
Toxicity: liver toxic!
Entacapone
Indirect-acting DA agonist
MOA: Block COMT in periphery only. *Does not cross BBB
Use: increases the bioavailability of Levodopa
Trihexyphenidyl
Antimuscarinic / Antipsychotic
Clean antimuscarinic, with typical anticholinergic side effects
MOA: very little inhibition of DAT, primarily antimuscarinic
Pramipexole
Direct-acting DA agonist
Use: used in early stage monotherapy, delays the requirement of levadopa.
MOA: Synthetic full intrinsic activity agonist (D2 and D3 agonist) with no D1 activity.
Effects: neuroprotective: may slow progression of PD. Similar efficacy to levadopa in early stage, but not as effective in late stage. Antidepressant action work against “amotivational” stage.
Toxicity: more hallucination, less dyskinesias. Associated with sleep attacks (all DA agonists), associated with OCDs (gambling, hypersexuality, risk taking
Ropinirole
Direct-acting DA agonist
effects: neuroprotective
Toxicity: more hallucinations, less dyskinesias
Clozapine
Other drug (PD) and 2nd generation Antipsychotic (atypical)
Use: drug of choice for hallucinations in PD patients, Antipsychotic
MOA: has little affinity for D-2 receptors in striatum, more potent D4 antagonists. Also potent antimuscarinic
Effects: produces agranulocytosis, peridoxical wet pillow due to high antimuscarinic activity,
Toxicity: Very low EPSE, no TDs, high sedation and orthostasis. High weight gain
Haloperidol
Use: HD and Tourette’s
High TI
Effects: decreases DA = treatment for movement disorder AND psychosis
Antimuscarinic drugs
Uses: generalized dystonia
Benzodiazepines
Uses: generalized dystonia
BoTox
Uses: Focal dystonia
MOA: inhibits release of ACh by interfering with release mechanism.
*long duration
Methylphenidate
Use: ADHD management
MOA: Indirect-acting DA agonist. DA selective slightly greater than NE, with fewer NE side effects than amphetamines
Effects: decreased hyperactivity, increased focus
Toxicity: psychomotor stimulation, headaches, appetite suppression, insomnia, nausea
Adderall
Use: ADHD management
MOA: Longer duration of action, greater dependence liability. Combination of amphetamine and dextroamphetamine –replaces DA in DAT and MAOI
Slightly prefers NE over DA.
Toxicity: increased insomnia
Atomoxetine
Use: ADHD management
MOA: NE»>DA, no dependence liability. Works on ventral attention system (many have dorsal deficits)
*non-amphetamine
Toxicity: fewer side effects
Levodopa
Indirect-acting DA agonist
*PROTOTYPICAL drug for PD treatment
Use: late stage PD treatment
MOA: immediate precursor to DA converted by aromatic amino acid decarboxylase (AAAD). “precursor load strategy” DATs and recycling of DA by terminals extend the effective duration of levadopa.
Effects: Increases precursor for DA production, as PD progresses, fewer DA terminals exist, there will be less recycling of DA thereby decreasing the effective duration of levadopa. “End of dose wearing of Effect”
*Does not occur at non-target sites, which decreases the TI as PD progresses. Thus frontal cortex terminals are significantly less damaged and as levodopa dosage is increased to compensate for striatal DA terminal loss, frontal cortex become hyperstimulated = psychosis.
Carbidopa
Indirect-acting DA antagonist (periphery)
Use: administered with Levodopa in the treatment of PD
MOA: Inhibits AAAD in the periphery (does not cross BBB). Decreased conversion of levodopa to DA in periphery reduces peripheral side effects of increased DA. Also results in increased bioavailability and availability to brain and increases CNS side effects (epigastric distress, nausea vomiting, orthostasis, +inotropy)
Toxicity: CNS side effects. Dyskinesias, dystonia, psychosis/hallucinations, hypoprolactinemia, hyperthermia, myoclonus
Stalevo
PD treatment, combination of Levodopa, Carbidopa, and Entacapone
First Generation Antipsychotics
Chlorpromazine*
Thioridazine
Fluphenazine
Haloperidol
Second Generation Antipsychotics
Clozapine Risperidone Olanzapine Quetiapine Aripiprazole Ziprasidone
Antimuscarinic Antipsychotics
Benztropine
Trihexyphenidyl
Other Antipsychotic
(usually for dyskinesias)
Reserpine
Chlorpromazine
Antipsychotic 1st gen
*PROTOTYPICAL
Toxicity: Orthostasis, weight gain, moderate EPSE, sedation, moderate TD.
Thioridazine
Antipsychotic 1st gen
Original Atypical drug choice (no longer considered atypical)
MOA: Antimuscarinic activity breaks the pattern of depolarization blockade = reduced EPSEs
Effects: potent antimuscarinic effect and DA antagonist
Toxicity: less TD, low EPSE,
Fluphenazine
Antipsychotic 1st gen
Toxicity: High EPSE, low weight gain, sedation, orthostasis, and low antimuscarinic effect. High TD
Haloperidol
Antipsychotic 1st gen
*High TI
Toxicity: high EPSE, low orthostasis and antimuscarinic effect, low weight gain, not sedating. High TD
Risperidone
Antipsychotic 2nd gen (atypical)
MOA: some DA receptor affinity, potent 5HT antagonist
Toxicity: Moderate EPSE, and less TD. Moderate orthostasis and sedation
Olanzapine
Antipsychotic 2nd gen/ Other drug (PD)
Use: used for treatment of PD hallucinations
Effects: Does have some D-2 blocking effects, more potent D4 antagonist and can aggravate PD symptoms but reduces hallucinations. Potent antimuscarinic
Toxicity: Low EPSE and TD, high weight gain and sedation, low orthostasis
Quetiapine
Antipsychotic 2nd gen
Toxicity: Low EPSE and TD, high weight gain, orthostasis, and sedation
Aripiprazole
Antipsychotic 2nd gen (atypical)
Use: rapid cycle bipolar disorder and antipsychotic
MOA: high levels of occupation of the D2 receptors. (partial agonist)
Toxicity: Low EPSE and TD, low weight gain, not sedating with little orthostasis.
Ziprasidone
Antipsychotic 2nd Gen (atypical)
MOA: potent antagonist at D2, D3, 5HT-1D, 5HT-2A, 5HT-2C, and 5HT-7. 5HT-1A agonist may alleviate anxiety and depression. Has moderate inhibitory effects on neuronal transport inactivation of 5HT similar to SSRIs (antidepressant)
Toxicity: Low EPSE and TD, CONTRAINDICATED in patients with history of arrhythmias.
Reserpine
Other antipsychotic
Use: treats dyskinesias
SSRIs
Fluoxetine*
(paroxetine, sertraline, fluvoxamine, citalopram)
-All can produce 5HT syndrome, when used with another drug (meperidine, tramadol, or MAOIs) or St. John’s Wort
Some weight gain, sexual dysfunction, nausea/vomiting, insomnia
5HT and NE reuptake inhibitors (SNRIs)
Venlafaxine* NE>5HT
(Desvenlafaxine - metabolite of venlafaxine NE=5HT, Duloxetine - DAT inhibition and NE/5HT)
- Nausea, constipation, somnolence, anorexia, abnormal ejaculation/orgasm, dose-dependent increase in diastolic BP.
Tricyclic antidepressants (TCAs)
Imipramine* - NE=5HT
(Amitriptyline -5HT>NE, Desipramine - almost pure NET inhibitor, Clomipramine - 5HT>NE)
-Some alpha antagonism (orthostasis), antimuscarinic action (sedation, increased HR, dry mouth, constipation, blurred vision, urinary retention)
weight gain, nausea, and highly toxic in OD (arrhythmias)
5HT-2A Antagonists
Trazodone*
(Nefazodone)
-Paradoxical antidepressant due to 5HT antagonism, down regulate 5HT-1A autoreceptors which increases 5HT release, mild alpha-1 antagonism (some orthostasis), potent H-1 antagonism (somnolence), priapism
Atypical Antidepressants (uni/heterocyclics)
Bupropion* -DAT and NET inhibitor, also used in craving reduction
(Mirtazapine (similar to trazodone), Maprotiline, Amoxipine
Monoamine Oxidase Inhibitors (MAOIs)
Phenelzine*
(Isocarboxazid, Tranylcypromine)
-Hypertensive crisis with foods high in tyramine (protein high), Orthostatic hypotension chronically from DA-beta-hydroxylase inhibition and false NT octopamine, Blurred vision, constipation
Lithium
Myo-inositol-1 phosphatase inhibitor
Toxicity: headache, diarrhea, dose-dependent tremor, confusion, polyuria, polydipsia, ataxia, slurred speech
Other drugs for Bipolar disorder
Carbamazepine
Valproate
Aripiprazole
Fluoxetine
Selective Serotonin Reuptake Inhibitor (SSRI)
*PROTOTYPICAL
MOA: heterocyclic that binds to allosteric regulatory site on the SERT and reduces binding of 5HT to SERT. 5HT»>NE
Venlafaxine
5HT and NE Reuptake Inhibitor (SNRI)
*PROTOTYPICAL
NE>5HT
Toxicity: Nausea, constipation, somnolence, anorexia, abnormal ejaculation/orgasm, dose-dependent increase in diastolic BP
Imipramine
Tricyclic Antidepressant
*PROTOTYPICAL
NE=5HT
MOA: competitive reuptake inhibitor, also have affinity for other receptors, muscarinic, alpha, and histamine
Toxicity: Some alpha antagonism, orthostasis, antimuscarinic: sedation, dry mouth, constipation, blurred vision, urinary retention
weight gain, nausea, Toxic due to arrhythmias
Trazodone
5HT-2A Antagonist
*PROTOTYPICAL
MOA: bind 5HT-2A receptors (apical dendrites of pyramidal cells in layer V of cortex) *Modulate cognitive processes by enhancing glutamate release. Enhancing glutamate release increases activity and reduces depression. *Weak, but selective SERT inhibitor, metabolite has high affinity for 5HT-2A receptors
Effects: paradoxical antidepressant due to 5HT antagonism, down regulation of 5HT-1a autoreceptor = increased 5HT release
Toxicity: alpha-1 antagonism: orthostasis, somnolence, priapism
Bupropion
Atypical antidepressants (Uni/hetero-cyclic)
*PROTOTYPICAL
MOA: DAT and NET inhibitor facilitates release of catecholamines
Use: craving reduction
Phenelzine
Monoamine Oxidase Inhibitor (MAOI)
*PROTOTYPICAL
MOA: pressor amines (tyramine) build up due to MAO-A inability to convert it to an inactive product and accumulation occurs = hypertensive crisis.
Toxicity: hypertensive crisis with food intake high in tyramine, orthostatic hypotension due to DA-beta-hydroxylase and false NT octopamine, blurred vision, constipation
Lithium
myo-inositol-1 phosphatase inhibitor
USE:
MOA: block myo-inositol-1 phosphatase and reduces the cycling of DAG and inositol-triphosphate. Stabilizes production of NTs 5HT and DA preventing mood swings. IP3 reduction = ^5HT release which resets circadian clock
Toxicity: headahe, dirrahea, dose-dependent tremor, confusion, polyuria, polydipsia, ataxia, slurred speech *increased with exercise (ADH unresponsiveness) –> diuresis, water loss, increased reabsorption. Can lead to diabetes insipidus
*Tremor is give away to lithium toxicity. Treated with dialysis
Carbamazepine
Anti-epileptic (treatment of bipolar) *PROTOTYPICAL
Use: bipolar *especially rapid-cycle
Valproate
Use: bipolar
Full Opioid Agonists
Morphine Codeine Heroin Hydromorphone Oxymorphone Hydrocodone Methadone Meperidine Fentanyl Oxycodone
Other Morphine-like drugs (no analgesic)
Dextromethorphan
Diphenoxylate
Loperamide
Partial Opioid agonist/antagonist
Pentazocine
Buprenorphine
Full Opioid Antagonist (non-analgesic)
Naloxone
Naltrexone
Morphine
Direct-acting agonist
*PROTOTYPICAL ANALGESIC
MOA: affect pain threshold at dosages that do not affect conciousness.
*inhibit the release of sub P in the substantia gelatinosa as well as activation of the descending pain suppressing pathways from PAG.
Acts through Mu system.
Effects: pain remains detectable, but affective component is reduced “don’t care about it”.
Toxicity (Side effects): Dependence (increase DA in n. accumbens), Euphoria, Respiratory Depression, Mild antitussive effect, nausea/vomiting, rigidity, increased ADH (increased smooth muscle contraction can make catheterization difficult), Constricted pupils, Histamine release (morphine flush), constipation,
Contraindications: closed head injury (increases cerebral pressure from respiratory depression which increases CO2 levels, induces vasodilation, which increases possibility of a brain bleed. Productive cough patients (antitussive). Reduced Renal Function (recirculated as metabolite if not excreted = toxicity RD
Naloxone
Opioid Antagonist
Use: treats respiratory depression (regardless of the cause – rules out opioid OD) IV or nasally, short acting
Naltrexone
Opioid Antagonist
*similar to Naloxone, not as widely used.
Orally available.
Toxicity: Can trigger withdrawal symptoms in dependent individuals, reduces pain threshold in normal individuals.
Clonidine
alpha-2 agonist
Use: treat anxiety and dysautonomia associated with opioid withdrawal.
Heroin-Diacetylmorphine
Effects: highly euphoric and analgesic
MOA: hydrolyzed to monacetylmorphine (MAM) and then to morphine
Crosses BBB (lipid soluble)
Toxicity: greater dependence and liability than morphine due to rapid CNS entry, withdrawal
Codeine
full, direct agonist
“methylmorphine”
MOA: same as morphine, analgesic effect is due to CYP2D6 conversion to morphine. Greater oral efficacy, renal excretion
Effects: less sedating and analgesic, but more antitussive.
Toxicity: same as morphine, less severe. Potent antitussive effect and HIGH constipation
Meperidine
Use: pre-anethetic, obstetric analgesic
Effects: analgesic, sedation, euphoria, respiratory depression, and others (morphine effects).
Toxicity: Constipation, urinary retention, increased biliary pressure (less than morphine) less miosis and antitussive power. W/ high dose or patient with decreased renal fxn, metabolites accumulate and excite CNS. *With MAOI can =serotonin syndrome b/c of effects on inhibiting serotonin transporter.
Fentanyl
*HIGHLY POTENT
Use: widely used in surgery as part of balance anesthesia
CONTRAINDICATED: in patients with no tolerance to opioid treatment quickly produces respiratory depression
Diphenoxylate
non-analgesic drug Meperidine congener *does not cross BBB no morphine-like effect at normal doses Use: anti-diarrheal. Formulated with atropine = lomotil. Atropine is anti-muscarinic (constipation)
Loperamide
non-analgesic
derivative of haloperidol *can cross BBB but generally does not due to p-glycoprotein
Toxicity: when consumed with large amounts of grapefruit juice (naringin) p-glycoprotein is inhibited and drug can enter CNS causing morphine-like effects.
Methadone
MOA: similar to morphine equi-effective by oral route
Use: analgesia, narcotic abstinence syndrome: reduces but elongated withdrawal symptoms from morphine dependence. Methadone treatment program: orally active and has easier withdrawal *switch from heroin to methadone and then ween off methadone.
Dextromethorphan
non-narcotic centrally active antitussive
MOA: glutamate antagonistic effects, increases the threshold for coughing
Rare drowsiness or GI disturbances
Toxicity: high doses= glutamate antagonist and PCP effects
Buprenorphine
semi-synthetic partial Mu agonist
Use: analgesic in non-tolerant patients, or as management of opioid-dependency
Tramadol
Synthetic
MOA: metabolite efficacy at Mu receptor (contributes to analgesia, and some respiratory depression). reuptake inhibitory properties at NE and 5HT terminals, potentiating pure opioid actions of drug.
Effects: reinstates dependence. drug interaction with SSRIs and MAOIs = serotonin syndrome
Pentazocine
Partial agonist
Use: can precipitate withdrawal in full agonist users. Formulated with naloxone to prevent IV abuse
Effects: respiratory ceiling, low dependence liability.
