Term
Diiferentiate between sedative and hypnotic. |
|
Definition
ØA Sedative drug decreases activity, moderates excitement, and calms the recipient
ØA Hypnoticdrug produces drowsiness and facilitates the onset & maintenance of a state of sleep that resembles natural sleep, and from which the patient can be easily roused not a good analgesic! |
|
|
Term
Drug classes used to treat OCD |
|
Definition
Clomipramine (TCA) and SSRIs |
|
|
Term
Describe monoamine neurotransmitters. |
|
Definition
ØSynthesized from aromatic amino acids.
Ø
ØForm a method of chemical communication in the brain.
Ø
ØTransmit signals from a neuron to another cell across a synapse.
Ø
ØForm the basis for drug discovery as structural scaffolds.
Ø
ØTargeting the enzymes associated with neurotransmitters is a treatment strategy in: depression, ADHD, psychiatric disorders and other CNS applications |
|
|
Term
What is dysthymia and hypomania |
|
Definition
DYSTHYMIA – Chronic depression, less severe but longer lasting symptoms.
HYPOMANIA – Patient experiences persistent and altering euphoric and irritable feelings along with all the associated emotions. May become very creative but lowers sense of risk. |
|
|
Term
WHat are the general mechanism of antidepressants? |
|
Definition
Blockade of:
ØSynaptic neuronal neurotransmitter reuptake transporters-
•Norepinephrine Transporter (NET)
•Serotonin Transporter (SERT)
ØSynaptic neurotransmitter catabolism - MOA
NE and 5HT Reuptake Transporters
|
|
|
Term
|
Definition
Tricyclic antidepressants inhibit transporters for amines (NE
& 5HT) which are located on the presynaptic plasma membrane & are responsible for reuptake of aminergic neurotransmitters from synaptic clefts into presynaptic cells.
Inhibition of synaptic reuptake leads to increased levels of NE
& 5-HT in the synaptic cleft, which leads to stimulation of postsynaptic receptors (increased NE & 5HT neurotransmission) |
|
|
Term
NE-selective compounds are more effective in treating ___. |
|
Definition
|
|
Term
5HT-selective compounds are more effective for treating ____ |
|
Definition
|
|
Term
Name the 4 NE-selective antidepressants |
|
Definition
Maprotilin
Desipramine
Protriptyline
Nortriptyline |
|
|
Term
Name the 3 non-selective antidepressent |
|
Definition
AMitriptyline
Clomipramine
Imipramine |
|
|
Term
Name the 5HT selective antidepressants |
|
Definition
Paroxetine (Paxil) Fluvoxamine (Luvox) Sertraline (Zoloft)
Fluoxetine (Prozac)
Venlafaxine (Effexor)
Citalopram (Celexa) |
|
|
Term
3 difference: tertiary amine and secondary amine antiDep |
|
Definition
Tertiary Amines
•Imipramine, doxepin, amitryptiline, clomipramine
•Inhibit 5-HT ≥ NE Reuptake Þmore mood-stabilizing (misery)
•Have a number of interactions with receptors
Secondary Amines
•Desipramine and nortryptiline
•Inhibit NE > 5-HT Reuptake Þ more activating (motivation)
•Less interactions with other receptors → less anticholinergic, sedative and hypotensive side effects |
|
|
Term
________ are responsible for functional negative feedback in serotoninergic terminal. |
|
Definition
5-HT1D & 1B Pre-synaptic Receptors |
|
|
Term
Do not combine TCA with ____ |
|
Definition
|
|
Term
At high (suicidal) Doses TCA‘s induce: |
|
Definition
•Excitation, delirium, convulsions Þ coma
•Cardiac arrhythmias (extrasystoles) Þ
ventricularfibrillations
•Used to be third leading cause of drug-
induced death (after heroin and cocaine)! |
|
|
Term
Give some PK parameters of TCAs |
|
Definition
•Highly lipophilic drugs with high plasma protein binding & high volume of distribution (Vd > 10 l/kg)
•Generally long half-lives (> 10 hrs)
•Extensive metabolism by P-450 (often by P450 2D6 Þpolymorphisms), plus conjugations
•Metabolites are often pharmacologically active (sometimes with slightly different specificities from parent drug):
Imipramine is partially metabolized todesipramine (below)
Amitryptiline is partially metabolized to nortryptiline |
|
|
Term
WHat is the MOA of MAOI agents? |
|
Definition
ØMAO enzymes oxidize and inactivate monoamines! Inhibition of MAO provides enhanced levels of NE and 5HT |
|
|
Term
ØAlmost all are substrate analogues of monoamine neurotransmitters containing the _____motif. |
|
Definition
|
|
Term
Give agents that irreversibly inhibit MAOI |
|
Definition
Phenelzine (Nardil)
Tranylcypromine (Parnate) |
|
|
Term
Give agents that reversibly inhibit MAOI |
|
Definition
Moclobemide (investigational drug; approved in Europe) Reversible competitive inhibitor |
|
|
Term
Antidepressive MAO-Is act mainly by inhibition of ___causing increases of ___ ≈ ___> ___ |
|
Definition
|
|
Term
In healthy people, MAO-Is cause immediate increase of _____ |
|
Definition
motor activity, and delayed euphoria & excitement |
|
|
Term
WHich works faster: TCA vs. MAOI |
|
Definition
|
|
Term
Give 2 benefits of MOAI over TCA |
|
Definition
1. MAOI works faster
2. Delayed downregulation of NE and 5-HT receptors - effect lasts longer |
|
|
Term
|
Definition
ØExcessive central stimulation:
ØMore common with tranylcypromine
ØHeadache (a warning sign for overdose)
ØExcitement, insomnia, tremor Þ convulsions
ØLethal dose is 5-10 times higher of the therapeutic dose
ØOrthostatichypotension
ØIncreased appetite and weightgain
ØAtropine-like effects (sometimes): constipation, dry mouth, blurredvision
ØSevere liver toxicity (rarely, phenelzine)
|
|
|
Term
Explain the interaction between MAOI and tyramine |
|
Definition
•Intake of tyramine-rich food (e.g., aged
cheese & red wine) can cause severe
increases of blood pressure,headache, etc.
Tyramine increases synaptic NE release,
which in the presence of MAO inhibition, is
not inactivated by MAO metabolism.
Enhanced synaptic NE leads to
vasoconstriction and hypertension!!
|
|
|
Term
Because of these problems MAO-Is are
2nd choice drugs for patients who do not
respond well to _____ |
|
Definition
|
|
Term
Explain drug interaction if MAOI +TCAs |
|
Definition
|
|
Term
Give examples of SSRI, SARI, SNRI, NDRI, NaSSA, NRI |
|
Definition
SSRIs: Serotonin SelectiveReuptakeInhibitors
(e.g., fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine)
SNRIs: Serotonin NorepiphrineReuptakeInhibitors
(e.g., duloxetine, venlafaxine)
NDRIs: NorepinephrineDopamineReuptakeInhibitors
(e.g., bupropion)
NRIs: NorepiphrineSelectiveReuptakeInhibitors
(e.g., atomoxetine, reboxetine)
SARIs: Serotonin Antagonist ReuptakeInhibitors
(e.g., trazodone, nefazodone)
NaSSA: NoradrenergicSpecificSerontonergicAntidpressants
(e.g., mirtazapine |
|
|
Term
Compare SSRI to MAOI and TCA |
|
Definition
Same efficacy but SSRI have better safety profile and no tyramine ("cheese syndrome) interaction.
Serotonin syndrome is higher in SSRI |
|
|
Term
T/F: SSRIs work well in patients with positive and negative affect
|
|
Definition
False: SSRIs work well in patients with negative affect
•SSRIs often fail to relieve symptoms ofdecreased “positive affect“or produce some of these symptoms as side effects, including loss of joy, happiness, enthusiasm, alertness, and self confidence.
•Apathetic recovery (Reduced negative affect but decreased positive affect)
|
|
|
Term
What are the ADR of SSRI? |
|
Definition
•Agitation, anxiety, panic attacks
•Restlessnes, psychomotor retardation, mild parkinsonian & dystonic movements
•Rapid muscle movements (myoclonus) during the night
•Inhibition of spinal reflexes of orgasm and ejaculation
•Increased bowel motility, GI cramps, and diarrhea
•Nausea & vomiting |
|
|
Term
Sexual side effects are common for SNRI than SSRI |
|
Definition
False: sexual side effects are very common for SSRIs |
|
|
Term
Rank these in order of most serotonin syndrome rate: MOAI, SSRI, TCA, lithium salts |
|
Definition
SSRI > MAOI > TCA > Lithium salts
Worst (potentially lethal) Combination: MAO inhibitors + SSRIs |
|
|
Term
Hyponatremia is a common ADR of ___ antidepressants |
|
Definition
SSRI
Mechanism: development of syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
ADH (= vasopressin) is over-secreted Þ Enhanced reabsorption of water and decreased serum
osmolality |
|
|
Term
•SERT Reuptake Blockade
•5HT 2C Antagonism
Net Result: Disinhibits NE and DA
Increased NE & DA in PFC
Activating:Leads to Energizing and
Fatigue reducing effect
Good for Depressed patients with
reduced positive effect
•5HT 2C Antagonism – Also leads to
anorexia and antibulimia therapeutic
actions at high doses
•Inhibition of NET at high doses and inhibition of CYP 2D6 and 3A4. Very long plasma t1/2 = 3 days |
|
Definition
|
|
Term
•DA Reuptake Blockade (weak)
May improve energy and motivation
Weakly “activating”
•Sigma 1 Antagonism =Creates anxiolytic effect
•Weak CYP 2D6 inhibition
•Long plasma t1/2 = 26 hrs |
|
Definition
|
|
Term
•More calming with ability to reduce anxiety symptoms
May be caused by weak M1
antagonism
•Weak NET inhibition
May contribute to efficacy
against depression
•Substrate and potent inhibitor of CYP 2D6
•Plasma t1/2 = 20 hrs
•Blockade of NOS may contribute to
sexual dysfunction in males
•Notorious for causing withdrawal reactions
(e.g., GI upset, akathisia, restlessness, dizziness, tingling) |
|
Definition
|
|
Term
•More used for treatment of OCD and anxiety
•Sigma 1 agonist – anxiolytic property
•Helpful in psychotic and delusional depression
•CYP 3A4 & 1A2 (induced in smokers)
•Plasma t1/2 = 15-20 hrs
•Controlled release formulation |
|
Definition
|
|
Term
•Contains two enantiomers: R and S as a racemic mixture
•S is active against SERT
•Mild H1 blocker (R)
•Generally one of better tolerated SSRIs
•Plasma t1/2 = 35 hrs
Mild CYP 2D6 inhibition(R) |
|
Definition
|
|
Term
•Pure active S enantiomer
•No Anti H1 activity
•No CYP 2D6 inhibition
•Plasma t1/2 = 28-32 hrs
•More or less pure SERT inhibitor or SSRI
•Possibly best tolerated SSRI with fewest CYP interaction |
|
Definition
S-Citalopram (Escitalopram) |
|
|
Term
Which SSRI has the longest half-life? |
|
Definition
|
|
Term
Problems with SSRI dosing. |
|
Definition
üDelayedantidepressant effect
üPoor correlation between plasma level & clinical effectiveness of these drugs
ü Most antidepressant drugs have long half-lives (12-36 hrs) and many have active metabolites
üDramatic (10-fold or more) interindividual variations in plasma levels of these drugs after intake of identical doses
ü Multiple interactions with cytochromes P-450 → many potential drug interactions
üContraindicated to combine with MAOIs!!!
|
|
|
Term
Dual Action Antidepressant Drugs |
|
Definition
SNRIs - VEnlafaxine (Effexor), Buproprion (Wellbutrin) and Duloxetin (Cymbalta) |
|
|
Term
Which SNRI has these properties:
ØBlocker of 5-HT (low dose) & NE uptake
(high dose)
ØVerycommonlyprescribed
ØSubstrate for 2D6 andprimarymetabolite
(desvenlafaxine) is also metaboliteof 2D6
Thus, variation in plasmalevels with dose
ØSide effects are SSRI-like(Nausea, sexual
dysfunction)
|
|
Definition
|
|
Term
Which SNRI has these properties:
- Has a poorly defined MOA
- Weak inhibitor of both NET and DAT
- Metabolites are more potent NET & DAT inhibitors and are more conentrated in brain
- Goldilocks drug solution
- CNS-activating & stimulating (proconvulsive in higher doses)
- - Is also marketed as an anti-smoking drug (Zyban)
- - Metabolism via CYP 2D6!
-
|
|
Definition
|
|
Term
Which SNRI has these properties:
ØBlocker of 5-HT & NE uptake
ØAlso activeagainstchronicpain, andpain
withdepression
ØCYP 2D6 inhibitor |
|
Definition
|
|
Term
NRI approved by FDA for ADHD |
|
Definition
|
|
Term
MOA of Serotonin Antagonist RIs |
|
Definition
SERT inhibition and 5HT 2A/2C blockade can have some beneficial properties |
|
|
Term
Novel atypical and sedative antidepressant (H1 and alpha 1 blocker)
Mostly inhibit 5-HT transport
substrate of CYP3A4
|
|
Definition
|
|
Term
Antidepressant with strong sedative (H1) properties
- Potent antagonist of a2 (presynaptic), receptors →
enhances NE neurotransmission
- Is an antagonist at H1, 5-HT2 & 5-HT3 receptors
- Weight gain is a typical adverse effect
|
|
Definition
– Noradrenergic-Specific Serotonergic Antidepressants (NaSSA) ex. Mirtazapine (Remeron) |
|
|
Term
- SSRI combined with 5HT 1A
partial agonist
- Improved mood within one
week
- No reduction in sexual
functioning
- Minimal or no weight gain |
|
Definition
|
|
Term
•Quite popular antidepressive OTC medication
•Strong placebo effect, however
•
•Hyperforin(extract constituent) has been shown to inhibit the uptake of biogenic amines
•
•Therapeutically useful for mild to moderate depression
•
•Unwanted effect: induction of P450 3A4 |
|
Definition
St John’s Wort (Hypericumperforatum) |
|
|
Term
•__________ are mood elevators in depressed patients but cause dysphoria in normal individuals |
|
Definition
|
|
Term
On NE neurons the pre-synaptic receptor is an ____; on 5-HT neurons the pre-synaptic receptor is a ____ |
|
Definition
α2 receptor /Gi coupled receptor;
5-HT1B/1D receptor /Gi coupled receptor |
|
|
Term
•Seizures are caused by _____ |
|
Definition
sudden, excessive firing of neurons |
|
|
Term
Explain the therapeutic targets for treatment of seizures |
|
Definition
Blockade of
Hyper-excitability by:
-Elevation of neuronal threshold to electrical & chemical stimuli
-Limitation of the propagation of seizure discharge from its origin
- Blockade of excitatory(glutamatergic) input
- Strengthening of inhibitory (GABAergic) input
- Blockade of Na+ channels
- Blockade of thalamic Ca2+ channels
|
|
|
Term
What is the effect of blocking Na+ channels in seizure therapy? |
|
Definition
•Reducing the ability of Na+ channels to recover from inactivation leads to inhibition of high-frequency neuron firing by increasing the threshold for action potentials |
|
|
Term
What is the effect of blocking Ca2+ channels in seizure therapy? |
|
Definition
•AED reduce the flow of calcium through T-type Ca2+ channels reducing the firing of thalamic neurons
–Thalamic neurons are involved in generation of cortical discharge (characteristic of absence seizures)
•Ca2+ channels are also important for NT release |
|
|
Term
•____ Ca2+ channels play a major role in generation of absence seizures |
|
Definition
|
|
Term
Describe the 2 main mechanisms of increasing GABA transmission to treat seizures. |
|
Definition
•pre- and post-synaptic:
–Activation of GABAA receptor increases the inflow of Cl- and inhibits the postsynaptic cell
–GABA transmission might be enhanced by blocking the GAT-1 GABA transporter and increasing GABA concentration in the synaptic cleft |
|
|
Term
Describe the mechanisms of decreasing glutamate transmission to treat seizures. |
|
Definition
•Glutamate is an excitatory NT often implicated in epilepsy
•Antagonists of NMDA and AMPA glutamate receptors possess anticonvulsant activity |
|
|
Term
Name the 6 classical anti-epileptic drugs |
|
Definition
•Phenytoin (Dilantin)
•Carbamazepine (Tegretol)
•Ethosuximide (Zarontin)
•Valproic acid (Depakote, Depakene)
•Phenobarbital
•Benzodiazepines |
|
|
Term
Pharmacodynamic Properties of Classical AEDs |
|
Definition
Narrow therapeutic index
CNS depression reflected in sleepiness, dizziness, ataxia
◦More prominent with phenobarbital and clonazepam
◦Less prominent but present with phenytoin and carbamazepine
◦Valproic acid – has the least sedation effects of these
Hypersensitivity reactions
◦Rare but present with most AED
◦Often manifest as skin reactions or hematotoxicity
Teratogenicity
◦Valproic acid, phenytoin, carbamazepine
◦In some cases due to their effects on CYP-3A4 classical AEDs can increasemetabolism of contraceptives => unplanned pregnancy
Decreased bone mineral density – interference with Vit D metabolism => increased osteoporosis |
|
|
Term
Pharmacokinetic Properties of Classical AEDs: – CYP Induction by ____, ___ and _____
– CYP Inhibition by _____ |
|
Definition
CYP induction: phenobarbital, phenytoin, carbamazepine
CYP inhibition by valproic acid |
|
|
Term
Pharmacokinetic problems of Classical AEDs |
|
Definition
•Long half-lives (>12hrs)
–Makes determining proper dose difficult/challenging
•Modulation of cytochrome P-450 (3A4, 2C19)
–Induction by phenobarbital, phenytoin, carbamazepine
–Inhibition by valproic acid
–Requires dose adjustments and causes interactions (warfarin, contraceptives)
•Poor compliance due to multiple doses/day
•Recommend Therapeutic Drug Monitoring (TDM)
–Both total and free drug levels for those with high protein binding kinetics |
|
|
Term
•A number of classical AEDs contain the ____structure |
|
Definition
|
|
Term
•MOA: slows the rate of recovery of Na+ channels from inactivation
•Widely used
•Effective for partial and tonic-clonic seizures
•Not effective for absence and myoclonic seizures
•Insoluble in water
•Not sedative in ordinary doses
|
|
Definition
|
|
Term
CYP interaction of phenytoin (Dilantin) |
|
Definition
•Metabolized by CYP2C9/10 and CYP2C19
Induces CYP |
|
|
Term
ADR of phenytoin (Dilantin) |
|
Definition
–CNS depression upon initiation of therapy (fatigue, blurred vision, incoordination, drowsiness)
–Gingival hyperplasia
–Osteomalacia
–Megaloblastic anemia
–Hirsutism
–Endocrine effects: inhibition of the release of antidiuretic hormone & insulin (leading to hyperglycemia and glycosuria)
–Teratogenic!
skeletal, CNS, limb and orofacial |
|
|
Term
Terotogenic classical AED |
|
Definition
◦Valproic acid, phenytoin, carbamazepine |
|
|
Term
•MOA: slows the rate of recovery of Na+ channels from inactivation
•First approved to treat trigeminal neuralgia
•Primary drug for partial and tonic-clonic seizures
•PK complex: induces its own metabolism (other AEDs can also induce carbamazepine’s metabolism)
–Decreased half life after chronic therapy (from ~35h to ~15h)
•Metabolized by CYP3A4 to 10,11-epoxide (active metabolite)
•Induces CYP2C, CYP3A and UGT
–Enhances degradation of drugs metabolized by these enzymes (oral contraceptives!!!) |
|
Definition
|
|
Term
AED causes Stevens Johnson syndrome and toxic epidermal necrolysis (life-threatening skin conditions), also acute intoxication and water retention in elderly |
|
Definition
|
|
Term
•MOA: blocs T-type Ca2+ channels in thalamus
–Thalamus plays an important role in generating spike-and-wave rhythms typical of absence seizures
–Blocking T-type current exhibited by thalamic neurons should stop the burst of action potential causing absence seizures
•First-line drug for absence seizures
–Narrow use spectrum; only this epilepsy form
•PK: metabolized in the liver (unknown if CYPs are involved)
–Plasma t1/2: 40-50 h in adults; 30 h in children
–few drug-drug interactions
•Adverse effects:
–GI problems: nausea, vomiting, anorexia
–CNS problems: drowsiness, lethargy, euphoria, headache (tolerance can develop to these) |
|
Definition
|
|
Term
•MOA poorly characterized with multiple actions:
–Na+ channel blocker (similar to phenytoin)
–Ca2+ channel blocker (similar to ethosuximide)
–Enhances GABA transmission
•Stimulates GABA synthesis & inhibits
GABA metabolism
•Useful for most types of partial and generalized
epilepsies including absence & myoclonic seizures
–Drug of choice for unclassified forms of seizure
–Also used as mood stabilizer
•
•Highly protein-bound
•Inhibits metabolism of drugs degraded by CYP2C9 (phenytoin, phenobarbital) and UGT (lamotrigine, lorazepam)
•Metabolized in the liver by UGT enzymes and b-oxidation |
|
Definition
|
|
Term
This AED causes:
–GI symptoms: nausea, vomiting, anorexia (most common & transient)
–Significant weight gain can also occur
–Temporary hair loss is common (in children)
–Tremor, rare pancreatitis
–Hepatotoxicity (especially in kids < age 2)
–Minimal sedation compared to other classical AED
–Allergic reactions possible (hematotoxicity)
••Teratogenic potential
–Spina bifida can be prevented by folic acid supplementation |
|
Definition
|
|
Term
•MOA: Allosteric modulator of GABAA receptors
•Drug of choice for neonatal
seizures
•Last resort drug for pts
unresponsive to other drugs
–May be used for refractory status epilepticus
•Used for generalized tonic-
clonic and partial seizures
•Plasma t1/2 2-6 days
•Induces CYP2C, CYP3A
–Increased degradation of drugs metabolized by these enzymes (oral contraceptives!!!)
•Adverse effects:
–Sedation (tolerance develops)
–Ataxia, nystagmus (involuntary rhythmic shaking)
–Irritability and hyperactivity in children
–Agitation and confusion in elderly |
|
Definition
|
|
Term
BZD used for status epilepticus |
|
Definition
Lorazepam (Ativan) and Diazepam (Valium) |
|
|
Term
BZD used for long-term treatment of certain seizure disorders |
|
Definition
Clonazepam (Klonopin) and Clorazepate (Tranxene) |
|
|
Term
•MOA: allosteric modulation at the GABAAreceptor
•Rarely used now in favor of other AED
•Adverse effects include:
•sedation (enhanced by other CNS depressants)
•lethargy, confusion
•muscular incoordination, ataxia
•children: aggression, hyperactivity, difficulty in concentration
–Tolerance to the side effects may develop
–Respiratory and cardiovascular depression can occur with intravenous administration; especially with other AEDs |
|
Definition
|
|
Term
•MOA: blocks Na+ channels
–Additionally modulates Ca2+ currents, and increases K conductance
•Can be effective in patients who did not respond to carbamepazine (CBZ).
•Pro-drug converted immediately to 10-hydroxy derivative
•Mono- or adjunctive therapy for partial seizures in adults and children 4 years and older
•Induces CYP3A4/5, inhibits CYP2C19
–Decreases plasma levels of ethinyl estradiol and levonorgestrel
–Less potent enzyme inducer than CBZ
•Adverse effects:
–Dizziness, headache
–Diarrhea, vomiting, nausea, constipation, dyspepsia
Ataxia, nervousness |
|
Definition
Oxcarbazepine (Trileptal) |
|
|
Term
•GABA molecule bound to a cyclohexane ring, but does not mimic GABA
•MOA: not well understood
–Binds to protein with sequence identical to that of the Ca2+ channel subunit α2δ-1
–Promotes release of GABA at synapse
•2nd line therapy for partial seizures (as adjunct)
•Very useful for neuropathic pain, migraine, spasticity (80% off-label use)
•PK: T½ 6-8 hrs; no metabolism, renal elimination
•No known interactions with other AEDs
•Overall well tolerated
–Sedative properties (often resolve after 2 weeks, less sedation than with other AEDs) |
|
Definition
|
|
Term
•MOA: delays recovery of Na+ channels from inactivation
•Used for partial seizure, absence and generalized tonic-clonic seizures; also used for drop attacks seen w/ Lennox-Gastaut syndrome
–Approved for monotherapy and add-on therapy
•Used as mood stabilizer and for mania
•Metabolized by liver, not an enzyme inducer
–Few drug interactions
•Adverse effects:
–Dizziness, ataxia, blurred or doubled vision
–Nausea, vomiting, rash
•Due to anti-folate activity; risk for oral clefts doubled |
|
Definition
|
|
Term
•MOA: multiple
Antagonizes AMPA / kainate glutamate receptors
Blocks Na+channels
Activates hyperpolarizing K+channel
Approved for monotherapy (> 10 y.o) and adjunctive therapy (> 2 y.o) for partial onset or primary generalized seizures, Lennox-Gastaut syndrome and migraine prophylaxis
Mainly renal elimination, little liver metabolism
Adverse effects:
Cognitive impairmentusually with too fast titration
Somnolence, fatigue, nervousness, weight loss (chronic use)
Kidney stones (1.5%) and vision changes
Due to mild inhibition of carbonic anhydrase
Teratogenic (pregnancy category D) |
|
Definition
|
|
Term
•MOA: novel, unknown (binds to synaptic vesicle protein SVZA)
•Approved for myoclonic, partial onset, and generalized tonic-clonic seizures in adults and children over 4 years of age
•Eliminated renally (mostly unchanged)
–Does not inhibit or induce hepatic enzymes
•Well tolerated, modest side effects:
–Sedation, fatigue, coordination problems
–Agitation, irritability or somnolence in children
•Limited evidence for anti-epileptogenic properties |
|
Definition
|
|
Term
•MOA: blocks Na+ and T-type Ca2+ channels
•Approved for adjunctive therapy of partial seizures in adults
•85% renal elimination of unchanged drug
•Long half-life = 63 hrs; no drug interactions
•Adverse effects:
–Somnolence, ataxia, anorexia, nervousness, fatigue
–Possible kidney stones
–Modest and reversible decline in renal function
–Allergies due to sulfonamide structure |
|
Definition
|
|
Term
Which new gen AED are approved for monotherapy? |
|
Definition
Topiramate
Oxcarbazepine
Lamotrigine
Felbamate |
|
|
Term
Compare new AED to old AED |
|
Definition
•Effectiveness
–Effective to a similar extent
–Only topiramate, lamotrigine, oxcarbazepine, and felbamate are approved for monotherapy
•Side effects
–Less sedative properties
–Many of newer AED are well tolerated
•Pharmacokinetic profile
–Improved PK profile
–Few P-450 and drug-drug interactions
•Little to no teratogenicity
–Exception: topiramate (category D)
–Safer AEDs for women on contraceptives |
|
|
Term
3 Alternative therapies for seizures |
|
Definition
•Surgery (only about 50% seizure freedom)
•Vagus nerve or cortical stimulation
•Children: Ketogenic diet - high fat, low carb and protein
- modified Atkins diet
- low glycemic index diet |
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Term
Major inhibitory neurotransmitter in anxiety |
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Definition
GABA (γ-aminobutyric acid) |
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Term
}GABA - ____receptor is a ligand-operated ion channel üPermeable for anions: chloride (hyperpolarization!) –tive potential üFive subunits & various subtypes of subunits
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Definition
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Term
}GABA - ___ receptor is a metabotropic receptor with presynaptic location (abundant in the spine) üinhibits adenylate cyclase, P/Q-type calcium channels, reduces neurotransmitter release
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Definition
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Term
T/F: Benzodiazepines (BZ) directly activate the GABA(A) receptor |
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Definition
False: Benzodiazepines (BZ) do not directly activate the GABA(A) receptor.
BZs potentiate the action of GABA → increase flux of Cl- (GABA-A receptors) → more pronounced hyperpolarization → less excitable neurons |
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Term
Name 3 class of drugs anxiolytics that affect GABA-A receptor and increase influx of Cl - ion magnitude and duration |
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Definition
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Term
Difference between BZD abd alcohol |
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Definition
Benzodiazepines are allosteric activators of GABA(A) receptors containing a1, a2, a3 or a5 subunits; they do not bind to a4 & a6 subunits.
ØGABA(A) receptors with a6 subunit are abundant in the cerebellum – an area involved in motor & balance coordination Ø Ethanol binds well to the GABA(A) receptors with a4/6 subunits. ØBenzodiazepines do not have much effect on motor coordination and balance! but ethanol does.
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Term
GABA ____subunits are most responsible for anxiolysis
GABA ____subunits are most responsible for hypnotic/sedative & anticonvulsant action, and anterograde amnesia
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Definition
a2 = anxiolytic
a1 = sedative/hypnotic/anticonvulsant/anterograde amnesia |
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Term
Combinationsof benzodiazepines & alcohol can be lethal by causing _____ |
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Definition
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Term
ØBenzodiazepines are strictly ____modulators of the GABA(A) receptor |
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Definition
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Term
Antidote for BZD overdose is ____ |
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Definition
flumazenil = competitive antagonist at benzodiazepine (not ethanol) binding site |
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Term
WHich BZD is used for status epilepticus? |
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Definition
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Term
Pharmacological effets of BZDs |
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Definition
}Reduction of anxiety and aggression }Sedation and sleep induction (little suppression of REM sleep) }Reduction of muscle tone and coordination (“central relaxants”) }Anticonvulsant effects (diazepam useful for status epilepticus) }Anterograde amnesia }Paradoxical effects (e.g. excitation) in rare cases (usually in elderly) }Effects of all benzodiazepines are basically the same; the main difference is in their pharmacokinetic properties!
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Term
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Definition
ØLipophilic (high logP/logD values) (Cross membranes easily)
ØExtensively metabolized in liver |
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Term
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Definition
}Daytime sedation (especially with long half-life drugs)
}Reduction of reaction time (traffic!)
}Ataxia, falls in elderly people; cognitive deficits
}Addictive properties (especially the short-acting ones) |
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Term
____ are used by heroin/cocaine addicts to fight withdrawal symptoms |
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Definition
Benzodiazepines --> flunitrazepam (Rohypnol) |
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Term
Zolpidem (Ambien) is a ___ drug that is selective for GABA alpha-__ subunit |
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Definition
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Term
Oldest sedative drug class |
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Definition
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Term
Barbiturates used for induction of anesthesia by IV injection |
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Definition
Methohexital (Brevital)
Thiopental (Pentothal) |
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Term
Barbiturates used for pre-operation sedation and insomnia |
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Definition
Amobarbital (Amytal)
Pentobarbital (Nembutal)
Secobarbital (Seconal) |
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Term
Barbiturate used as an anti-convulsant |
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Definition
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Term
BZDs and barbiturates are ____modulators of GABA-A receptors |
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Definition
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Term
Difference in MOA of BZD abd Barbiturates |
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Definition
BZDs do not open the ion channel directly while barbiturates open them directly
üAt high doses, open the channel directly → barbiturate overdose is lethal!
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Term
Difference in PK of BZDs and barbiturates |
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Definition
Barbiturates have strong CYP450 induction and BZDs does not |
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Term
Acute pharmacological effects of barbiturates |
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Definition
- ØAcute central effects include strong sedation and some anticonvulsant properties
- ØNo useful anxiolytic action
- ØSleep-inducing, suppression of REM sleep (typically hangover)
- ØPeripheral effects: high doses induce respiratory and cardiovasculardepression (main reason for lethal outcome in overdoses)
- !
- ØParadoxical excitement can occur in elderly
- ØPossible euphoria & central stimulatory effects upon chronic abuse (weeks to months → main reason for abuse)
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Term
T/F: barbiturates are preferred over BZD |
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Definition
False:
Benzodiazepines as the drugs of choice
- ØHave a high therapeutic index
- ØHave few peripheral effects
- ØLow incidents of tolerance development
- ØLow potential of physical dependence
- ØFewer drug interactions
- ØNo respiratory depression
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Term
Explain the CYP induction in Ramelteon (Rozerem) |
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Definition
Ramelteon (Rozerem) is used to treat insomnia - MT1 and MT2 agonists
CYP1A2 in cigarette smokers |
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Term
Neurotransmitter most frequently implicated in Schizophrenia |
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Definition
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Term
all effective antipsychotic drugs are antagonists at the ____ receptor |
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Definition
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Term
-Pscychostimulants increase synaptic ____with each dose but cause psychosis only after prolonged high dose exposure. |
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Definition
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Term
positive Symptoms of schizophrenia |
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Definition
Positivesymx of schizophrenia: presence of abnormal behaviors
-Hallucinations
-Delusions
-Thought disorder
-Movement disorder |
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Term
Negative symptoms of schizophrenia |
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Definition
Negative syx : absence of normal behavior found in healthy individuals
-Loss of interest
-Lack of emotion
-Ability to plan and carrt out activities
-Neglect personal hygiene
-Social withdrawal
-Loss of motivation |
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Term
Cognitive symptoms of schizophrenia |
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Definition
Cognitive syx:
-Problems making sense of info
-Attention deficit
-Memory problems |
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Term
Actions of classical antipyschotics on mesolimbic dopaminergic pathways in schizophrenia is it improves ___symptoms |
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Definition
positive – reduces hallucinations
but
Little or No Improvement
in Negative & Cognitive
Symptoms |
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Term
side effects of D2 anatgionists antipyschotics include: |
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Definition
- extrapyramidal system - control of motions
- Tardive dyskinesia
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Term
Classical antipyschotics increases this hormone |
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Definition
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Term
Classical antipyschotics block these 4 receptors and what are the effects? |
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Definition
D2 blockage- antipsychotic, extrapyramidal sx; hyperprolactinemia
H1 blockage- weight gain; drowsiness
M1 blockage - constipation; blurred vision; dry mouth; drowsiness
and alpha-1 receptor blockage - hypotension; dizziness; drowsiness |
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Term
prototype 1st gen antipsychotic |
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Definition
Chlorpromazine (Thorazine |
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Term
This 1st gen antipyschotic can cause severe QT prolongation |
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Definition
Thioridazine (Mellaril)
ØMost Discontinued by Original Manufacturer - Blocks K+ channels, Possible arrhythmias, even TpD and Sudden Cardiac Death |
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Term
This 1st gen antipyschotic has a piperazine side chain, less sedative effects and can be administered as decanoates for chronic therapy |
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Definition
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Term
Explain the MOA of classical antipsychs in acute psychosis |
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Definition
a) D2 receptors are blocked & negative inhibitory feedback on presynaptic release is compromised
b) other DA receptors are ~stimulated
c) overall reduction in DA neurotransmission is blunted.
Only partially reduced or unchanged |
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Term
Explain the MOA of classical antipsychs in acute psychosis |
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Definition
a) D2 receptors are blocked & there is limited negative feedback
b) Eventually, DA storage & release overwhelmed or depolarization blockade comprises activity
c) DA neurotransmission is further decreased |
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Term
What are the effects of D2 receptor blockage by antipsychotics which block increase prolactin |
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Definition
Hyperprolactinemia = amenorrhea/Galactorrhea, male infertility and gynecomastia |
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Term
T/F: D2 receptor blockers have an antiemetic and anti-diarrhea properties. |
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Definition
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Term
List the EP syndromes of D2 antagonists |
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Definition
Pseudoparkinsonism
Bradykinesia, rigidity, tremor, face mask, shuffling gait
Dystonia
Spasm of muscles of face and neck
Akathesia
Subjective and objective restlessness; Inability to sit still
Tardive Dyskinesia
Stereotyped, repetitive abnormal
Other Adverse Effects
Dyslipidemia(Elevated TG, Chol), Diabetes, Metabolic Syndrome,
Dermatologic Reactions (Allergic, Photosensitivity, Skin Coloration),
Hematologic (Neutropenia, leukopenia), Thermoregulatory Problems,
Ophthalmologic problems (glaucoma, corneal deposits),
Urinary retention and Sexual Dysfunction |
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Term
ØQuite Safe Drugs (Lethal doses are usually quite high)
ØHave NoAddictive Potential
ØExhibit tight, long-lasting binding to Dopamine Receptors which helps lead to enhanced dopaminergic side effects (EPS/Tardive dyskinesia) |
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Definition
Classical Antipsychotic Drugs |
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Term
Antipyschotics and smokers |
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Definition
Induce CYP1A2 and eliminate drugs more rapidly |
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Term
Significant Antidopaminergic Side Effects in Striatal and Tuberoinfundibular Pathways |
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Definition
•>80% D2 Receptor Occupancy = Extrapyramidal effects
•Extrapyramidal symptoms, Hyperprolactinemia
•Tardive dyskinesia. Develops in 20-40% of patients after months or years of treatment. Disabling and often irreversible |
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Term
First generation antipsychotics have 60-80% brain striatal D2 receptor occupancy for therapeutic antipsychotic effect. With over 80% occupancy, ____becomes problem |
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Definition
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Term
First ‘Atypical’ 2nd Generation Antipsychotic.
•Weaker D2 antagonism
•Stronger 5HT2A antagonism
•Greater response (30% than 1st gen)
•Treats both positive and NEGATIVE symptoms and Good for improving cognitive functions, unlike 1st gen. •Beneficial for cognition (disorganization, disorientation) •Good anti-suicidal effect
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Definition
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Term
Compare 1st gen vs 2nd gen antipyschotics |
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Definition
2nd gen has:
Less ExtrapyramidalSide Effects or
Tardive Dyskinesia
Less Hyperprolactineamia
2nd gen has more 5HT2A/C antagonist activity |
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Term
Symptoms of Clozapin (Clozaril) |
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Definition
Hematotoxicity → 1% agranulocytosis
- IncreasedSeizurerisk (3-5%)
- WarningforMyocarditis
- Metabolicsyndrome, Weightgain (>7% Body Weight),
Impairedglycemiccontrol |
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Term
Why Might 5HT2A Blockade by 2nd gen antipyschotics be Helpful? |
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Definition
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Term
Developed from and similar to clozapine ØComparable 5HT2A and 2C affinity, but better 5x better affinity against D2 ØMuscarinic and H1 Receptor (+++), α1 (Less ++) ØGenerally does not cause EPS or raise prolactin ØBut, low incidenceof agranulocytosis ØMain adverse effects: wSomnolence (drowsiness), dizziness wWeight gain; Increased appetite ØBlockade of H1 receptors ØBlockade of 5-HT2A receptors wDry mouth, constipation (blockade of muscarinic receptors)
ØAlso useful for bipolar disorder
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Definition
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Term
Very High affinity for the 5-HT2A receptor
w10X better affinity for the D2 receptor than olanzipine
wNo affinity for muscarinic receptors
wH1 receptor (++) α1 (+++)
w Very effective against Positive symptoms
Low EPS & wt gain but can raise prolactin
Unwanted effects: Hypotension, Sedation, Muscle pain, Photosensitivity, possible Arrhythmias (long QT), Prolactin (++++) Metabolism: P-450 2D6 (polymorphism!)
Active metabolite = 9-Hydroxyl risperidone |
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Definition
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Term
w Causes little or no EPS or prolactin
w Short half life and rapid dissociation
w Can cause weight gain & sedation
w Norepinephrine reuptake inhibitor (NRI)
w 5HT1A partial agonist |
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Definition
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Term
More pronounced antagonist of the 5-HT2A
receptor; 5HT1A partial agonist
w Low EPS & prolactin elevation.
Little or no propensity for weight gain or
dyslipidemia or insulin resistance
w Parenteral form available |
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Definition
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Term
Common characteristics of Olanzapine, Risperidone, Ziprasidone, Quetiapine |
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Definition
•High affinity for the 5-HT2A receptor 4Little or no pronounced parkinsonism 4Generally little or no prolactin increase (except Risperidone) 4Co anti-emetic effect •Beneficial effects on the regulation of DA, ACh, and glutamate in forebrain •Cognitive improvement
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Term
Main ADR of Olanzapine, Risperidone, Ziprasidone, Quetiapine |
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Definition
–Sedation, increased appetite, weight gain
–Metabolic syndrome (Diabetes, Hyperlipidemia)
–QT interval prolongation
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Term
ØPartial agonist at D2 receptors
ØAntagonist (full) at 5-HT2A receptors
ØPartial agonist at 5-HT1Areceptors
(→ anxiolytic effect)
ØLow affinity to cholinergic, adrenergic & histaminergic receptors
ØLess EPS, weight gain, metabolic syndrome, low sedation
ØLong half-life (~75 hrs) |
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Definition
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Term
•Binds to all D2 receptors Þ
•Does not allow any other ligand to bind to that receptor (antagonist)
while bound to the receptor the drug also stimulates it (agonist), but to some extent: Partial Agonist & Partial Antagonist of D2! |
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Definition
Aripiprazole (Abilify) : D2 Partial Antagonist/Agonist |
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Term
–Sublingual tablets for acute treatment of schizophrenia and manic/mixed episodes of bipolar disorder in adults
–An antagonist for multiple receptors!!!
serotonin: 5-HT1A&B, 5-HT2A,B&C, 5-HT5, 5-HT6 & 5-HT7
dopamine: D1, D2, D3 & D4 histamine: H1 & H2
adrenergic: a1 & a2 muscarinic: noaffinity
–Side effects: Increased risk of death in elderly with dementia (cerebrovascular accidents & transient ischemic attacks)
Orthostatic hypotension Metabolic syndrome & weight gain QT prolongation Hematotoxicity (agranulocytosis!) EPS & hyperprolactinemia Increased seizure threshold |
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Definition
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