AntiPsychotics 11

What are three examples of High Potency (Piperazine substituted phenothiazine compounds) Antipsychotics

"Try to Fly High" Trifluoperazine, Fluphenazine, Haloperidol

What are two examples of low potency ( Aliphatic and piperidine substituted phenothiazine compounds) Antipsychotics

(Cheating Thieves are low) Chlorpromazine, thioridazine.

Phenothiazines endocrine effects

1. Increased prolactin secretion ( lactation in females, gynecomastia in men) 2. Decreased secretion of gonadotropin, growth hormone and ACTH

Although the role of conventional neuroleptics ( Antipsychotics) will continue to diminish, several situations presently require their utilization, including:

1. Parental administration for acute agitation 2. Lack of benefit or intolerance to novel 3. Special populations (pregnant patients) 4. Noncompliant patients, for whom depot medication may be indicated

Conventional Antipsychotics

1. Phenothizines like Chlorpromazine 2. Butyrophenones like haloperidol 3. Thioxanthenes like thiothixene 4. Miscellaneous oike loxapine

4 important Phenothiazine drug interactions

1. Potentiation of CNS depressants and Opiods 2. Inhibition of alcohol metabolism 3. Reduced therapeutic effectiveness of L-Dopa in PD 4. Inhibition of phenytoin metabolism

Concentration of Lithium above ____ are toxic.

2.0 mEq/L

The first atypical antipsychoitc agent approved in the U.S. was Clozapine in 1990. Other approved later. They produce significant action on ________.

5-HT2 and dopamine D2 receptors.

What does Quetiapine bind to ?

5HT2A, D1, D2, H1, Alpha 1 with low affinity, muscarinic receptors with low affintiy

BIG ADVERSE EFFECT OF CLOZAPINE

Agranulocytosis occurs in 1-2% of patients. Onset w/in first 6 months of treatment, but the cell count can drop abruptly. In some cases, agranulocytosis is reversible if the drug is stopped early. However, other patients who developed agranulocytosis died. It is necessary to get weekly white blood cell count monitoring

Which kind of substituted phenothiazine compounds may precipitate seizures for the first time?

Aliphatic and piperidine compounds

Coventional antipsychotic drugs are those approved through 1975. Appear to act primarily by _________.

Antagonizing dopamine receptors.

The delayed onset of Lithium due to time necessary to achieve effective brain levels (7-10 Days). Thus __________ are used to initially control acute sever mania.

Antipsychotic agents (haloperidol)

What is the mechanism by which you get EPS parkinsonian symptoms in phenothiazines ?

Antipsychotic drug antagonism of dopamine D2 receptors in nigrostriatal system.

Sertindole has low EPS, low incidence of akathisia, low incidence of tar dive dyskinesia, mild weight gain, not sedative, appears to have potent anti_____ effects.

Anxiety.

There is no proven difference in antipsychotic efficacy among congenital antipsychotic drugs. However, ______________ drugs may relieve symptoms in schizophrenic patients resistant to other agents and produce better quality of response.

Atypical antipsychoitc.

Treatment of EPS Acute Dystonia (Spasms involving head, neck, trunk, and extremities)

Benztropine, diphenhydramine

Phenothiazines achieve their antiemetic effect by _____.

Blockade of the chemoreceptor trigger zone.

Is risperidone effective on positive or negative symptoms?

Both.

_______ alternative to lithium in treatment of bipolar disorder. Effective in some patients who do not respond to lithium. At times, can be combined with lithium.

Carbamazepine

_____ is a dibenzodiazepine antipsychotic drug that blocks dopamine receptors in the mesolimbic-mesocortical system showing less dopamine D2 receptor blocking activity in the extrapyramidal system. An effective antipsychotic agent producing minimal EPS, and an apparent lack of tar dive dyskinesia. Patients w/tardive dyskinesia improve while taking _____ over the course of a few months.

Cloazapine

Clozapine has potent ________, which may partially explain the lack of EPS. It causes only minimal elevation of serum prolactin.

Clozapine has potent anticholinergic actinos in the caudate- may partially explain the lack of EPS. It causes only minimal election of serum prolactin concentration.

Clozapine is several time more potent in blocking ______ than D2 receptors. Clozapine also has a high affinity for _____ found in limbic areas.

Clozapine is several times more potent in blocking 5-HT2 than D2 receptors. Clozapine also has a high affinity for D4 receptors found in limbic areas.

What receptors does Olanzapine block?

D1 ,2 and 4, 5-HT2 and 3, alpha 1, muscarinic 1, H1

Haloperidol is a potent _______ receptor _____.

D2 receptor antagonist; 2 mg produces 70% d2 receptor occupancy and achieve plasma concentration of .6-1.5 ng/ml and achieve high clinical efficacy.

Phenothiazine agents w/ greater propensity to induce EPS produce higher _________.

D2 receptor occupancy

Phenothiazines have a high affinity for ______ and the degree of binding with __________ correlates 2/ clinical potency in alleviating schizophrenia.

D2 receptors

Respiridone blocks which receptors?

D2, 5HT2, alpha 1 receptors

In .5 - 1 % of patients who receive high-potency neuroleptics they will develop Neuroleptic Malignant Syndrome. What is death associated with? What are the symptoms? What is the mechanism

Death is from Respiratory or renal failure, cardiovascular collapse, arrhythmias. MUST STOP DRUG. Think FEVER Fever, Encephalopathy, Vitals unstable, Elevated enzymes, Rigidity of muscles Mechanism is a sudden decrease in dopaminergic activity.

Phenothiazines cardiac effects

Depressed T-wave, prolonged q-t interval, (local anesthetic, anticholinergic and quindine-like effects on the heart)

Temperature regulation effects of Phenothiazines

Depressino of temperature regulation. Poikilothermic (assume the temperature of your environment). Could be either hypo or hyperthermic

Mechanism by which you get Tardive Dyskinesia with use of Phenothiazines?

Development of supersensitivity of dopamine receptors as consequence of long term blockade.

What is the mechanism by which you get EPS Acute dystonia when using phenothiazines?

Dopamine receptor blockade by antipsychotic drugs

Phenothiazine mechanism of antipsychotic action

Dopamine receptor blockade in mesolimbic-mesocortical dopaminergic system. The primary therapeutic action of phenothiazines and haloperidol involve blockade of the the D2 receptor, which inhibits adenylyl cyclase.

Haloperidol is considered a high potency conventional antipsychotic drug ( among the recommended first-line drugs for treatment of schizophrenia). It's basic therapeutic effects similar to phenothiazines. What is more common and precipitated?

EPS common and more frequent than with aliphatic or piperidine phenothiazines ( chlorpromazine or thioridazine); precipitated NMS (neuroleptic malignant syndrome)

At clinically effective doses, clozapine and other atypical antipsychotics bind to only 20 -60% of stratal D2 receptors, but conventional compounds bind 70-85% of d2 receptors, this probably accounts for the lack of _____.

EPS in Atypical Antipsychotic agents

PET studies (phenothiazines) showed that less than 60% D2 DA receptor occupancy in the striatum is suboptimal whereas greater than 80% provides no further benefit but may increase risk of ______.

EPS.

Treatment of EPS Tardive Dyskinesia (stereotypical repetitive involuntary movements of the mouth, lips and tongue)

Gradual reduction of dose; avoid anticholinergic drugs; switch to atypical (clozapine)

For relief of panic reactions and psychosis associated w/ drug use, _______ preferred over phenothiazins due to less anticholinergic and hypotensive effects.

Haloperidol

For treating acute manic phase of bipolar disorder _______ is the preferred drug. Used to gain rapid controls due to slow onset of lithium action.

Haloperidol

Treatment of Tourette's disorder.

Haloperidol is effective and currently the most used; pimozide (orap) is specifically approved for Tourette's, and is effective in cases where haloperidol is not.

Piperazine substituted phenothiazine compounds are called ________.

High Potency Antipsychotics

What are the values that the most be dropped below in order for Clozapine therapy to be stopped.

If total white cell count falls below 3000/mm3 or the granulocyte count falls below 1500, treatment is interrupted. If the white cell count is less than 2000 or the granulocytes count is less than 100, then the drug will be discontinued permanently. Clozapine is very expensive. 5000 per year.

Lithium is distributed in the total body water, then eliminated by the ______.

Kidneys

Lithium side effects

LMNOP Lithium side effects- Movement (tremor) Nephrogenic diabetes insipidus (irreversible nephrotoxicity is possible if lithium concentration are not kept within the recommended range) hypOthyroidism Pregnancy problems ( generally contraindicated in pregnancy)

Drug of choice for management of mild to moderate mania.

Lithium

Aliphatic and piperidine substituted phenothiazine compounds are called_________.

Low potency antipsychoitcs.

Deposits in phenothiazines

Low potency is Cheating Thieves are low. So Chloropromazine has Corneal deposits and Thioridazine has reTinal deposits.

_______ is an alternative for patients refractory from other antipsychotics and has no proven superiority over other agents. Similar side effects, but higher likelihood of oculogyric crisis and seizures; hypertension rather than hypotension. A high potency drug.

Loxapine

The anitpsychotic drugs relieve the ________ of bipolar disorder.

Manic Phase

Rapid withdrawal of Clozapine may cause

Marked exacerbation of patient's psychosis, worsening of pre-existing tar dive dyskinesia, w/ prominent involuntary lingual movements, and somatic symptoms

An effective antipsychotic drug with actions similar to the piperazine phenothizaines; advantage unlikely to cause weight gain. Low potency.

Molindone

Which Antipsychotic seems to be the least troublesome for weight gain?

Molindone

Phenothiazine dry mouth, blurred vision, urinary retention and aggravation of glaucoma are due to ______.

Muscarinic receptor blockade.

Were there hematologic abnormalities reported with olanzapine?

No

_______, a clozapine analogue, effective in positive and negative symptoms, and has try low EPS effects compared to conventional agents.

Olanzapine

The ________ structure forms the basic nucleus of phenothiazine.

Phenothiazine

Hypersensitivity effects of Phenothiazines

Photosensitivity, allergic rashes, agranulocytosis, cholestatic jaundice

Thiothixene has similar pharmacology an side effects to the __________ substituted phenothiazines.

Piperazine

Piperazine compounds are less _____ but have excellent ______.

Piperazine compounds are less sedative, but have excellent antipsychotic activity.

Phenothiazines in general; not effective against motion sickness, but ____ is effective, probably due to potent anticholinergic effects.

Promethazin

Clozapine analogue; low potency antipsychotic

Quetiapine

Treatment for EPS Parkinsonian symptoms

Reduce dose or change drugs (atypical or clozapine if severe); anticholinergic antiparkinson drugs or amantadine.

Treatment of EPS Akathisia ( State of extreme motor restlessness and drive to move)

Reduce dose; switch to low potency or atypical; propranolol; benzodiazepines;amantidine

TI of Antipsychotics

Relatively large TI. Acute poisoning w/antipsychotic drugs is rarely fatal.

Potential clinical problem of renal excretion of lithium.

Renal excretion is markedly affected by sodium intake; in presence of sodium deficiency, lithium ion selectively reabsorbed in renal tubules (Sodium-depleting diuretics markedly increase serum lithium and toxicity, thiazides are especially troublesome) Also impaired renal function increases lithium retention and toxicity

Characterized as "Quantitatively atypical" antipsychotic with relatively low incidence of EPS when given in low doses.

Risperidone

Named as as first-line alternative to high-potency conventional antipsychotics

Risperidone

Piperazine compounds are are more likely to cause

These are high potency antipsychotics and they are more likely to cause EPS (parkinsonian symptoms) and have antiemetic activity, but cause less hypotension or sedation.

Aliphatic and piperidine compounds are more likely to cause ______.

These are low potency antipsychotics and they are more likely to cause sedation, orthostatic hypotension, hypersensitivity (jaundice, skin sensitization)

Why do Atypical antipsychotics cause less EPS and endocrine disturbance than typical psychotics?

They bind less avidly to D2 receptors in the stratum and hypothalamus than conventional antipsychotics and therefore produce less EPS and exocrine disturbance.

Side effect of phenothiazine compounds that is especially worrisome in the elderly

Toxic Confusional state

__________ is the best alternative to lithium for treatment of mania and/or maintenance of bipolar disorder

Valproic acid

Does weight gain occur in Olanzapine?

Yes

Hypotension in Phenothiazine compounds is associated more with the ______ substituted compounds.

aliphatic

Phenothiazine autonomic nervous system effects are a result of ?

alpha-adrenergic receptor blockade

Substitution at position 2 imparts ______ activity in phenothiazines.

antipsychotic activity

Treatment of NMS

dantrolene, D2 agonist (bromocriptine)

Atypical Antipsychotics

it's ATYPICAL for for OLd CLOSets to QUIEtly RISPER from A to Z SERTanly OLanzapine, CLOZapine, QUETIapine, RISPERidone, Aripiprazole, Ziprasidone, Sertindole

Haloperidol lacks anticholinergic effects and is particularly effective for acute ______.

mania

Antipsychotic=

neuroleptic

Substitution on the nitrogen position 10 alters ___________; principle substitutions are: aliphatic, piperidine and piperazine

potency and adverse effects

The atypical antipsychotics, especially ____, are viable first-line drugs.

risperidone

Because of Clozapines _______, it is recommended only for patients not responding adequately to standard anti-psychotic drugs.

toxicity.

Phenothiazines are antagonists where?

various Dopamine, adrenergic and muscarinic receptors.