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Neuro quiz 2
neurology
150
Pharmacology
Professional
08/27/2013

Additional Pharmacology Flashcards

 


 

Cards

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
MOA of TCA
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
loss of motivation
Term
5HT-selective compounds are more effective for treating ____
Definition
misery and pessimism.
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
sympathomimetics
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
phenylethylamine 
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
MAO-A ; 5-HT; NE ; DA
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
MAOI
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
GIve ADR of MAOI
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
reuptake inhibitors!
Term
Explain drug interaction if MAOI +TCAs
Definition
Serotonin syndrome
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)

 

NaSSANoradrenergicSpecificSerontonergicAntidpressants

                 (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 3A4Very long plasma t1/2  =  3 days
Definition
Fluoxetine (Prozac)
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
Sertraline (Zoloft)
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
Paroxetine (Paxil)
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
Fluvoxamine (Luvox)
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
Citalopram (Cipramil)
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
Fluoxetine (Prozac)
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
Venlafaxine (Effexor)
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
Bupropion (Wellbutrin)
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
Atomoxetine (Strattera)
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
Trazadone (Dysrel)
Term

Antidepressant with strong sedative  (H1) properties


 

  - Potent antagonist of a(presynaptic), receptors →

enhances NE neurotransmission


- Is an antagonist at
H1, 5-HT
& 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
Vilazadone (Viibryd)
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
TCA/MAOIs
Term
On NE neurons the pre-synaptic receptor is an ____; on 5-HT neurons the pre-synaptic receptor is a ____
Definition

αreceptor /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

  1. Blockade of excitatory(glutamatergic) input
  2. Strengthening of inhibitory (GABAergic) input
  3. Blockade of Na+ channels
  4. 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
T-type
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
ureide 
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
Phenytoin (Dilantin)
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
Carbamazepine (Tegretol)
Term
AED causes Stevens Johnson syndrome and toxic epidermal necrolysis (life-threatening skin conditions), also acute intoxication and water retention in elderly
Definition
Carbamazepine (Tegretol)
Term
MOAblocs 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
Ethosuximide (Zarontin)
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
Valproic Acid (Depakene)
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
Valproic Acid (Depakene)
Term
MOAAllosteric 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
Phenobarbital (Luminal)
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
MOAallosteric 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
Benzodiazepines
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
Gabapentin (Neurontin)
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
Lamotrigine (Lamictal)
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
Topiramate (Topamax)
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
Levetiracetam (Keppra)
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
Zonisamide (Zonegran)
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

Term
Major inhibitory neurotransmitter in anxiety
Definition
GABA (γ-aminobutyric acid)
Term
}GABA - ____receptor is a ligand-operated ion channel
üPermeable for anions: chloride (hyperpolarization!) –tive potential
üFive subunits & various subtypes of subunits

 

Definition
GABA A
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

 

Definition
GABA B
Term
T/F: Benzodiazepines (BZ) directly activate the GABA(A) receptor
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

Term
Name 3 class of drugs anxiolytics that affect GABA-A receptor and increase influx of Cl - ion magnitude and duration
Definition

BZD

Barbiturates

Ethanol

Term
Difference between BZD abd alcohol
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.

 

Term
 GABA ____subunits are most responsible for anxiolysis

 GABA ____subunits are most responsible for hypnotic/sedative & anticonvulsant action, and anterograde amnesia
Definition

a2  = anxiolytic


a1  = sedative/hypnotic/anticonvulsant/anterograde amnesia

Term
Combinationsof benzodiazepines & alcohol can be lethal by causing _____
Definition
Respiratory depression
Term
ØBenzodiazepines are strictly ____modulators of the GABA(A) receptor
Definition
allosteric 
Term
Antidote for BZD overdose is ____
Definition

flumazenil = competitive antagonist at benzodiazepine (not ethanol) binding site

Term
WHich BZD is used for status epilepticus?
Definition
Diazepam (Valium)
Term
Pharmacological effets of BZDs
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!

 

 

 

 

 

 

 

Term
2 PK properties of BZD
Definition
ØLipophilic (high logP/logD values) (Cross membranes easily)

 

ØExtensively metabolized in liver
Term
4 ADRs of BZDs
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)
Term
____ are used by heroin/cocaine addicts to fight withdrawal symptoms
Definition
Benzodiazepines -->  flunitrazepam (Rohypnol)
Term
Zolpidem (Ambien) is a ___ drug that is selective for GABA alpha-__ subunit
Definition
hypnotic; alpha-1
Term
Oldest sedative drug class
Definition
Barbiturates
Term
Barbiturates used for induction of anesthesia by IV injection
Definition
Methohexital (Brevital)

 

 Thiopental (Pentothal) 

Term
Barbiturates used for pre-operation sedation and insomnia
Definition
Amobarbital (Amytal)

  Pentobarbital (Nembutal)

 

  Secobarbital (Seconal)

Term
Barbiturate used as an anti-convulsant
Definition
Phenobarbital (Luminal)
Term
BZDs and barbiturates are ____modulators of GABA-A receptors
Definition
Allosteric
Term
Difference in MOA of BZD abd Barbiturates
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!


Term
Difference in PK of BZDs and barbiturates
Definition
Barbiturates have strong CYP450 induction and BZDs does not
Term
Acute pharmacological effects of barbiturates
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)

 

 

 

 

 

 

Term
T/F: barbiturates are preferred over BZD
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

 

Term
Explain the CYP induction in Ramelteon (Rozerem)
Definition

Ramelteon (Rozerem) is used to treat insomnia - MT1 and MT2 agonists

 

CYP1A2 in cigarette smokers

Term
Neurotransmitter most frequently implicated in Schizophrenia 
Definition
Dopamine
Term
all effective antipsychotic drugs are antagonists at the ____ receptor
Definition
D2 dopamine  
Term
-Pscychostimulants increase synaptic ____with each dose but cause psychosis only after prolonged high dose exposure.
Definition
Dopamine
Term
positive Symptoms of schizophrenia
Definition

Positivesymx of schizophrenia: presence of abnormal behaviors

-Hallucinations
-Delusions
-Thought disorder

 

-Movement disorder
Term
Negative symptoms of schizophrenia
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
Term
Cognitive symptoms of schizophrenia
Definition

Cognitive syx:

-Problems making sense of info
-Attention deficit

 

-Memory problems
Term

Actions of classical antipyschotics on mesolimbic dopaminergic pathways in schizophrenia is it improves ___symptoms

Definition

positive  – reduces hallucinations

but  

Little or No Improvement

in Negative & Cognitive

 

Symptoms

Term
side effects of D2 anatgionists antipyschotics include:
Definition
  1. extrapyramidal system  - control of motions
  2. Tardive dyskinesia
Term
Classical antipyschotics increases this hormone
Definition
Prolactin
Term
Classical antipyschotics block these 4 receptors and what are the effects?
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

Term
prototype 1st gen  antipsychotic
Definition
Chlorpromazine  (Thorazine
Term
This 1st gen antipyschotic can cause severe QT prolongation
Definition

Thioridazine (Mellaril)

 

ØMost Discontinued by Original Manufacturer  Blocks K+ channels, Possible arrhythmias, even TpD and Sudden Cardiac Death 
Term
This 1st gen antipyschotic has a piperazine side chain, less sedative effects and can be administered as decanoates for chronic therapy
Definition

Fluphenazine (Prolixin)

Term
Explain the MOA of classical antipsychs in acute psychosis
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

Term
Explain the MOA of classical antipsychs in acute psychosis
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

Term
What are the effects of D2 receptor blockage by antipsychotics which block increase prolactin
Definition
Hyperprolactinemia = amenorrhea/Galactorrhea, male infertility and gynecomastia
Term
T/F: D2 receptor blockers have an antiemetic and anti-diarrhea properties.
Definition
False: only anti-emetic
Term
List the EP syndromes of D2 antagonists
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

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)
Definition
Classical Antipsychotic Drugs
Term
Antipyschotics and smokers
Definition
Induce CYP1A2 and eliminate drugs more rapidly
Term

Significant Antidopaminergic Side Effects in Striatal and Tuberoinfundibular Pathways

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
Term

First generation antipsychotics have 60-80% brain striatal D2 receptor occupancy for therapeutic antipsychotic effect.  With over 80% occupancy, ____becomes problem

Definition
EPS 
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
 
Definition
Clozapine (Clozaril)
Term
Compare 1st gen vs 2nd gen antipyschotics
Definition

2nd gen has:

Less ExtrapyramidalSide Effects or

Tardive Dyskinesia

 

Less Hyperprolactineamia


2nd gen has more 5HT2A/C antagonist activity 

Term
Symptoms of Clozapin (Clozaril)
Definition

Hematotoxicity1% agranulocytosis

  -  IncreasedSeizurerisk (3-5%)

    -  WarningforMyocarditis

  Metabolicsyndrome, Weightgain (>7% Body Weight),

 

         Impairedglycemiccontrol

Term
Why Might 5HT2A Blockade by 2nd gen antipyschotics be Helpful?
Definition
  • 5HT2A Neurons function as Dopaminergic “Brake”
  • Their activation reduces DA activity in some pathways
  • 5HT2A blockade can release brake and increase DA communication


    This means more dopamine release and less EPS (less Tardive symx) and less prolactinemia 

 

 

 

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

 

 

 

 

Definition

Olanzapine (Zyprexa)

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  

Definition
Risperidone (Risperdal)
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

Definition

Quetiapine (Seroquel)

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

Definition

Ziprasidone (Geodon)  

Term
Common characteristics of Olanzapine, Risperidone, Ziprasidone, Quetiapine
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

 

 

 

Term
Main ADR of OlanzapineRisperidoneZiprasidoneQuetiapine
Definition
Sedation, increased appetite, weight gain
 
Metabolic syndrome (Diabetes, Hyperlipidemia)

QT interval prolongation

 

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)
Definition
Aripiprazole (Abilify)
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 extentPartial Agonist  & Partial Antagonist of D2!

Definition
Aripiprazole (Abilify) : D2 Partial Antagonist/Agonist
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 & D histamine: H1 & H2

 

  adrenergic: a1 & a 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

Definition
Asenapine (Saphris)
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