7. Antipsychotics Flashcards
II. PHARMACOLOGICAL ACTIONS
Anti-Adrenergic: ____ Blockade
Anticholinergic: Blockade
____ [CNS], M-2 [CV] and M-3 [smooth muscle] sites
Antihistaminic: ____ Blockade
In LP phenothiazines (e.g., chlorpromazine)
____
____ Blockade
Dopamine Theory of Schizophrenia
Current evidence: schizophrenia due to ____ of central dopaminergic systems (especially mesolimbic).
Central DA —–> ____ in CSF.
Plasma HVA (pHVA) accumulates in part from central DA.
Elevated ____ levels:
Ø found in post-traumatic stress disorder (PTSD)
• one recent study:
control subjects = 0.48 ng/mL PTSD = 1.53 ng/mL
Ø may ____ response to antipsychotic treatment:
• in schizophrenia:
non-responders = < 12 ng/mL
responders: = > 14 ng/mL
alpha1
M1
H1
hypothermic
dopamine
hyperactivity
pHVA
predict
D-2 Sites
All effective ‘typical’ antipsychotic agents have good degree of binding.
Correlation of antipsychotic action to binding at ____ sites:
n as degree of binding (in vitro & in vivo) increases, antipsychotic efficacy ____ (fewer mg needed; HP)
<60 % - ____
<70% - ____
70-80% - ____
> 80% - ____ (more side effects)
D2 increase none/minimal some significant significant
D-1 Sites
Linked to ____ receptors (D-1 effects may occur via D-2 pathways).
‘____’ antipsychotics also block D-1 sites.
D2
atypical
• PET Scan
• For D2 receptors
• Control patients light up, but those are ____ (he calls it Haldol) does not light up
because they are blocked
o Haloperidol is a complete block of lighting up
• ____ barely lights up
haloprediol
cluzapine
III. USES
Psychosis
Symptoms likely to respond to therapy include:
____ combativeness delusions hallucinations hostility hyperactivity insomnia negativism
Not as effective in improving: ____
judgment
____
Acute: efficacy may occur within ____ days
Chronic: several weeks of drug administration may be required initial dose increased over several days)
anorexia
insight
memory
1-2
III. USES \_\_\_\_ mania (especially when starting lithium therapy)
Organic mental syndromes delirium
dementia
Severe ____ unresponsive to other drugs (e.g., anxiolytics)
Ballismus (continual flinging of extremities [usually arms])
Alcoholic ____
Antiemetic
PHENOTHIAZINES
____ PHENERGAN THORAZINE TORECAN TRILAFON VESPRIN
BUTYROPHENONE
____
INAPSINE (droperidol)
[injection only]
Gilles de la Tourettes Syndrome
____Disease
Intractable hiccough
Pruritus (following drugs are phenothiazines):
____ (promethazine)
TACARYL (methdilazine)
TEMARIL (trimeprazine)
acute anxiety hallucinosis compazine haldol huntingdon's phenergan
IV. ADRs
Antipsychotics: generally safe medications; ____ therap. index.
ANS
Anticholinergic actions greater with ____ agents.
____ vision Mydriasis
Dry mouth Constipation Urinary retention
____
high
lower potency (LP)
blurred
tachycardia
IV. ADRs
Endocrine Amenorrhea Galactorrhea Ø inc secretion of \_\_\_\_ (normally inhibited by DA) (contrast: bromocriptine [PARLODEL]; \_\_\_\_ used to dec lactation in women who do not want to breast-feed) Ø avoid in patients with \_\_\_\_
____
Ø probably also due to DA blockade
Inhibition of ____ (without interfering with erection);
Ø anticholinergic effect could also be a factor
____ gain
prolactin
DA agonist
breast CA
gynecomastia
ejaculation
weight
IV. ADRs
CV
More likely with ____ agents.
Hypotension, possibly orthostatic (related to alpha1-ABA)
Reflex ____ ECG abnormalities
Hypersensitivity
____ (dermatitis)
Skin discoloration (gray-blue pigmentation; rare)
Jaundice Photosensitivity
CNS
____, confusion, drowsiness (prob. due to anticholinergic action; greater in LP)
LP
tachycardia
skin rash
sedation
IV. ADRs (continued)
CNS (continued)
Extrapyramidal Reactions (EPRs)
Most frequent occurrence with ____ derivatives (e.g., piperazines [Stelazine]; butyrophenones [Haldol]).
Less frequent occurrence with low potency antipsychotics (e.g., CPZ) possibly because of strong ____ actions.
Minimal with ____
HP
anticholinergic
clozapine
IV. ADRs (continued)
CNS (continued)
Early onset (days to weeks)
Akathisia Ø \_\_\_\_ motor restlessness Ø primarily in lower extremities Ø does not represent agitation or \_\_\_\_ Ø treatment options include: • reduce dose • change to \_\_\_\_ agent • pharmacologic intervention -\_\_\_\_ (propranolol [INDERAL]) - anticholinergic (benztropine [COGENTIN]) - \_\_\_\_ (lorazepam [ATIVAN]) -alpha-adren.agonist (clonidine [CATAPRES])
Dystonia (Torticollis) Ø muscle spasms of \_\_\_\_, tongue, neck Ø trismus (lockjaw) Ø treatment options include • \_\_\_\_ [COGENTIN] (IM & then p.o.) • \_\_\_\_ [BENADRYL] (IM & then p.o.) Ø pt usually develops \_\_\_\_
uncontrollable anxiety LP beta-adrenergic antagonist benzodiazepine
face
benztropine
diphenhydramine
tolerance
IV. ADRs
Early onset (days to weeks)
Parkinson-like syndrome (Pseudoparkinsonism)
____-related
Usually develops early (days -weeks after therapy begins)
Characteristics: Ø \_\_\_\_ (immobility; rigidity) Ø bradykinesia (slow movements) Ø \_\_\_\_ gait Ø tremor at rest Usually observed in children and geriatric pts
Treatment options include: Ø reduce \_\_\_\_ Ø change to \_\_\_\_ agent Ø pharmacotherapy • \_\_\_\_ (benztropine [COGENTIN]) • \_\_\_\_ (amantadine [SYMMETREL])
Extrapyramidal Reactions (continued) Clinical evidence that \_\_\_\_ receptor occupancy is a major factor:
dose akinesia shuffling dose LP anticholinergic DA agonist D2
IV. ADRs
Late onset (months –> years)
Tardive Dyskinesia (TD)
Ø any type of ____ agent can induce TD
Ø occurs in 15-20% of patients on chronic therapy
Ø repetitive, involuntary movements of jaw, lips & tongue
Ø may involve ____: neck; trunk (esp. in young ♂)
Ø abnormal movements cease while patient sleeps
Ø possibly related to compensatory increases in ____ activity within CNS due to chronic blockade of DA receptors
Ø may remain even after drug is ____
Ø best preventative measures:
• ____ use of antipsychotics
• ____ therapy when TD appears
(TD may increase in intensity during ____)
neuroleptic extremities DA discontinued conservative terminate withdrawal
IV. ADRs
Neuroleptic Malignant Syndrome (NMS) Ø more likely with \_\_\_\_ antipsychotics Ø appears to be severe form of Parkinsonism Ø characterized by: • \_\_\_\_ • tremor • ANS instability (e.g, \_\_\_\_; unstable HR & BP) Ø in past: fatal in 10% of patients Ø currently: significantly dec chance of fatality due to: • more careful \_\_\_\_ • rapid \_\_\_\_ of offending drug • rapid initiation of treatment - \_\_\_\_ (PARLODEL) - \_\_\_\_ (DANTRIUM)
HP catatonia hyperthermia monitoring D/C bromocriptine dantrolene
IV. ADRs
Hematological Leukocytosis Leukopenia \_\_\_\_ 0.1% ( 1 per 1000) with \_\_\_\_ (THORAZINE) 1.0% - 2.0% (10 - 20 per 1000) with \_\_\_\_ (CLOZARIL)
Priapism Persistent abnormal erection of \_\_\_\_: Ø painful Ø prolonged: • congestion & swelling • increased intracavernous pressure (≈ 80-120 mm Hg) Ø does not result from sexual desire Ø due to failure of detumescence Should be considered a urologic emergency.
agranulocytosis
chlorpromazine
clozapine
penis
IV. ADRs
Priapism (continued)
If not treated within 4 - 6 hours may lead to:
Ø ____
Ø permanent ____
Etiology: Ø Primary (\_\_\_\_): ≈33% Ø Secondary causes include: • \_\_\_\_ injury (≈12%) • sickle-cell anemia (≈11%)
• intracavernous injection of vasoactive substances (e.g., ____; papaverine) for
diagnosis and treatment of impotence (≈6%)
• ____ abuse or drug therapy (≈21%)
® antihypertensive meds
® antipsychotics
fibrosis impotence idiopathic traumatic prostaglandin E1 alcohol
IV. ADRs
ØAntipsychotic-induced:
• ____% of all medication-induced cases
• apparently unrelated to ____ or duration of Tx other adverse effects of neuroleptics on sexual
function are dose-related)
• suggests dysregulation of ANS (cholinergic-adrenergic imbalance)
• higher rates with:
- thioridazine (MELLARIL) [____ piperidine phenothz] - chlorpromazine (THORAZINE) [____ aliphatic phenothz]
• may be due to ____ activity
• treatment options include: - \_\_\_\_ - \_\_\_\_ agonists (e.g., epinephrine; phenylephrine) - decompressive surgery (when duration >24 hours or failure of other procedures
20 dose LP LP alpha-1-ABA ice packs alpha-1-adrenergic
• Just an example case of IV promethazine that went into tissue area rather than blood stream
o Causes ____
gangrene
Clozapine
Newer agent which–at present–is employed only for patients who have ____ response to other antipsychotics.
Reason: higher incidence of ____.
Advantage: lower incidence of ____
Mechanism:
Weak blockade of ____ receptors but also blockade of other receptors, all of which are ____ than its D2 antagonism:
Similar to other antipsychotics: M1, M2 and M3 ____
alpha1 adrenergic ____
Different than most other antipsychotics:
____ antagonist
____ antagonist
poor agranulocytosis EPS D2 stronger antagonist antagonist D1 5-HT2
ADRs
Clozapine
Hematologic
Agranulocytosis: ____ must be performed once per week!
normal range: 4500-11000 WBC/mm3 mild leukopenia: 3000-3500 WBC/mm3 -----> CBC \_\_\_\_ a week leukopenia: <3000 WBC/mm3 OR -------------> IMMEDIATE \_\_\_\_ <1500 granulocytes/mm3 agranulocytosis: <1000 WBC/mm3 OR <500 granulocytes/mm3 * Average recovery time = \_\_\_\_ weeks
Pt who develops agranulocytosis can NOT receive ____ again.
CBC twice D/C 2 clozapine
Clozapine
CNS
Confusion, sedation
Seizures:
Ø higher rate than with other antipsychotics
Ø mostly ____ (tonic-clonic)
Ø ____ is effective
Psychotic relapse (prolonged) following abrupt ____
grand mal
carbamazepine
withdrawal
Paliperidone (INVEGA®)
Active metabolite of ____. Same pharmacological profile ____ and IM dosage forms.
Effectiveness in the acute Tx of ____ established in three 6-week, placebo-controlled trials conducted in North America, Europe and Asia.
1665 participating adults evaluated for full array of signs
and symptoms of schizophrenia. Doses ranged from 3 mg -> 15mg daily. Effectiveness of Invega at relieving symptoms of schizophrenia > placebo treatment. Recommended dose range is 3 mg to 12 mg daily.
Commonly reported ADRs include ____, extrapyramidal Symptoms, tachycardia, orthostatic hypotension, sleepiness.
Not approved for ____-related psychosis.
INVEGAR SUSTENNATM indicated for the ____ and maintenance Tx of schizophrenia in adults.
resperidone schizophrenia restlessness dementia acute
Paliperidone (INVEGA)
DOSAGE AND ADMINISTRATION
For patients who have never taken oral paliperidone or oral or injectable risperidone, tolerability should be established with oral ____ or oral risperidone prior to initiating Tx.
Initiate with dose of 234 mg on treatment day 1 and ____ mg one week later, both administered in the deltoid muscle.
Recommended monthly maintenance dose is 117 mg; some patients may benefit from lower or higher maintenance doses within the recommended range of 39 mg to 234 mg based on individual patient tolerability and/or efficacy.
Following second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle.
Administer by ____ injection only, using appropriate needle sizes. For deltoid injection, use 11⁄2-inch 22G needle for pts ≥ 90 kg (≥ 200 lb) or 1-inch 23G needle for pts < 90 kg (< 200 lb).
paliperidone
156
intramuscular
• We have clozirel/clozapine
o Has ability to cause ____ but cannot cause Parkinson’s
• We compare this to aripiprazole – we don’t have ____
o They figured out what part of the molecule was causing the agranulocytosis and altered it so it wouldn’t cause it anymore
• Mechanistically there is some blockage of ____receptors
o There is D2 blockage, but there is a greater blockage of ____
§ “This is where the atypicals live”
agranulocytosis
agranulocytosis
5HT-2A
5HT-2A
LONG-ACTING INJECTABLE ANTIPSYCHOTICS — Other antipsychotic medications currently available in the US as LA injections are.
Aripiprazole
Fluphenazine
Haloperidol
Olanzapine
• ____ blockade»_space;> D-2 Blockade; also FDA warning for rapid decline to 27% 12 hrs later
Aripipazole: ____ agonist
Quietapine: agonist at ____ ≈ sedation
Ziprasidone: blocks reuptake of ____ – useful in assoc. depression
Positive Symptoms incl: hallucinations; delusions;
reality distortions
Negative Symptoms incl: anhedonia; social withdrawal
Cognitive deficits incl: alterations of attention, working
memory & executive functions
5HT-2A
partial DA
H1
NE and DA
ANTIMANIC DRUGS
Lithium CIBALITH ESKALITH; ESKALITH CR (Controlled Release) LITHANE LITHOBID
Pharmacological Action
Lithium does not have any ____ CNS depressant effects; does not induce ____.
Has a ‘____’ effect.
Mechanism of action remains unknown:
Ø does not appear to affect post-synaptic ____ receptors
Ø may impair release of ____
specific
euphoria
mood-stabilizing
catecholamine
catecholamines
Lithium
Pharmacokinetics
T1⁄2: ____ hours.
Onset of therapeutic effect: ____ days
Safe therapeutic plasma range is approximately 0.75 - 1.25 mEq/L.
Ø usually achieved at dose of 900 mg daily
Ø blood sample drawn right before ____ dose: usually 12 hrs after ____ dose (plasma levels most stable before dosing)
Low therapeutic index: ____
Ø depletion of ____ (e.g., by diuretics [esp. thiazides], loss of ____ [e.g., diarrhea) can cause greater retention of Li+ and induce ADRs
Ø in heavy ____, however, Li+ may be secreted > Na+
20-24
6 to 10
AM
PM
2 or 3
Na+
fluid
sweating
Lithium
Uses
Best use: ____ of manic-depressive illness (bipolar)
Tricyclic antidepressants alone are not recommended in ____ disorder; may switch patient to mania.
Others:
Acute mania (severe cases [delusions; hallucinations] best
treated with neuroleptic) Prevention of mania
Prevention of depression (efficacy similar to TCAs) Alcoholism if 2° to primary mood disorder
Aggressive behavior (efficacy ____ of effect on mood)
prevention
bipolar
independent
Lithium
ADRs
Initiation of dosage: plasma levels ____ a week.
Stable patients: determine plasma levels every two ____. Toxic reactions can occur at levels below ____ mEq/L.
Mild Intoxication (> 1.5 mEq/L) Ataxia Abdominal pain Diarrhea Nausea/vomiting Small tremors \_\_\_\_ \_\_\_\_ (aspirin can also cause)
Mod. (1.5 ® 2.5 mEq/L) to Severe Intoxication (> 2.5 mEq/L) Confusion—> coma—> ____
Respiratory depression
Major tremors/EPS Seizures
CV
____
Hypotension
twice
months
1.0
sedation
tinnitus
death
arrhythmias
Lithium
ADRs
Other
____
Weight gain
Edema
Increased urination (polyuria): ____-dependent
____ (polydipsia)
Possible kidney damage:
Ø regular monitoring of serum ____ if > 1.6 mg/dL
____ taste
hypothyroidism dose thirst creatinine metallic
Lithium
Drug Interactions
Increased Li+ concentrations by:
____ diuretics > Loop diuretics (e.g., furosemide)
____ Inhibitors
____ (e.g., indomethacin) but apparently not by ASA or
acetaminophen
thiazide
ACE
NSAIDs
Anticonvulsants
All of the following anticonvulsants have been employed in treatment of ____ disorder.
It must be noted that–at present–these uses are ____.
ADRs will be given whenever anticonvulsants presented in course.
Carbamazepine (TEGRETOL)
Efficacy similar to ____ in both treatment of acute mania and prophylaxis of bipolar disorder.
Evidence that it is superior in:
Ø more ____ mania
Ø rapid ____ with more previous admissions
Ø pts ____ family history of mania
– ____ pain
Induces its own ____ + that of TCAs Ø may need to ____ dose after one week
manic unlabeled lithium severe cycling without biotransformation increase nerve
Anticonvulsants
Clonazepam (KLONOPIN)
Shown to have efficacy in ____ (first week) treatment of acute mania.
Less effective in ____ of bipolar disorder
Valproic Acid (DEPAKENE)
Depakote is the ____-release tablet.
Significant antimanic action occurs within ____ days following establishment of therapeutic serum levels (same as for ____: 8-12 ug/mL)
Gabapentin (NEURONTIN)
Lamotrigine (LAMICTAL)
early prophylaxis delayed 1 to 4 epilepsy
Anticonvulsants
Topiramate (TOPAMAX).
Clinical evidence for efficacy of these anticonvulsants is more impressive for ____ mania than for long-term maintenance of bipolar disorder.
Some investigations indicate particular effectiveness of lamotrigine in ____ depression.
Currently, other than for valproic acid, there is no FDA approval of anticonvulsant administration in bipolar disorder; this can limit ____ coverage for these meds.
acute
bipolar
insurance
