Kk&s Ch.36 Biological Therapies Cholin

Front 1

List the Cholinesterase Inhibitors and their indication.

Back 1

Donepezil (Aricept),
rivastigmine (Exelon),
galantamine (Reminyl), and
tacrine (Cognex) are cholinesterase inhibitors used to treat
mild to moderate cognitive impairment in dementia of the Alzheimer's type

Front 2

AChI MOA?

Back 2

They reduce the inactivation of the neurotransmitter acetylcholine and, thus, potentiate cholinergic neurotransmission, which in turn produces a modest improvement in memory and goal-directed thought

Front 3

What is memantine? Key difference to AChI?

Back 3

Memantine (Namenda) is not a cholinesterase inhibitor, producing its effects through blockade of N-methyl-D-aspartate (NMDA) receptors. Unlike the cholinesterase inhibitors, which are indicated for the mild to moderate stages of Alzheimer's disease, memantine is indicated for the moderate to severe stages of the disease

Front 4

Which ACHI rarely used?

Back 4

Tacrine, the first cholinesterase inhibitor to be introduced, is rarely used because of its multiple daily dosing regimens, its potential for hepatotoxicity, and the consequent need for frequent laboratory monitoring.

Front 5

Donepezil half life?

Back 5

70 hours

Front 6

Rivastigmine half life?

Back 6

The half-life of rivastigmine is 1 hour, but because it remains bound to cholinesterases, a single dose is therapeutically active for 10 hours, and it is taken twice daily

Front 7

Galantamine half like?

Back 7

The elimination half-life of galantamine is approximately 6 hours.

Front 8

Give details of AChI MOA

Back 8

The primary mechanism of action of cholinesterase inhibitors is reversible, nonacylating inhibition of acetylcholinesterase and butyrylcholinesterase, the enzymes that catabolize acetylcholine in the central nervous system (CNS). The enzyme inhibition increases synaptic concentrations of acetylcholine, especially in the hippocampus and cerebral cortex.

Front 9

Compare side fx of tacrine, donepezil, rivastigmine

Back 9

Unlike tacrine, which is nonselective for all forms of acetylcholinesterase, donepezil appears to be selectively active within the CNS and to have little activity in the periphery. Donepezil's favorable side-effect profile appears to correlate with its lack of inhibition of cholinesterases in the GI tract. Rivastigmine appears to have somewhat more peripheral activity than donepezil and, thus, is more likely to cause GI adverse effects than is donepezil.

Front 10

ACHI ... what improves?

Back 10

In long-term use, they slow the progression of memory loss and diminish apathy, depression, hallucinations, anxiety, euphoria, and purposeless motor behaviors.

Functional autonomy is less well preserved.

Some persons note immediate improvement in memory, mood, psychotic symptoms, and interpersonal skills. Others note little initial benefit, but are able to retain their cognitive and adaptive faculties at a relatively stable level for many months. A practical benefit of cholinesterase inhibitor use is a delay or reduction of the need for nursing home placement.

Front 11

Idiosyncratic ACHI reaction?

Back 11

Occasionally, cholinesterase inhibitors elicit an idiosyncratic catastrophic reaction, with signs of grief and agitation, which is self-limited once the drug is discontinued

Front 12

Side fx of donepezil?

Back 12

Donepezil is generally well tolerated at recommended dosages. Less than 3 percent of persons taking donepezil experience nausea, diarrhea, and vomiting.

These mild symptoms are more common with a 10-mg dose than with a 5-mg dose and, when present, they tend to resolve after 3 weeks of continued use.

Donepezil can cause weight loss. Donepezil treatment has been infrequently associated with bradyarrhythmias, especially in persons with underlying cardiac disease.
A few persons experience syncope.

Front 13

Rivastigmine side fx?

Back 13

Rivastigmine is generally well tolerated, but recommended dosages may need to be scaled back in the initial period of treatment to limit GI and CNS adverse effects. These mild symptoms are more common at dosages above 6 mg a day and, when present, they tend to resolve once the dosage is lowered. The most common adverse effects associated with rivastigmine are nausea, vomiting, dizziness, headache, diarrhea, abdominal pain, anorexia, fatigue, and somnolence. Rivastigmine can cause weight loss, but it does not appear to cause hepatic, renal, hematologic, or electrolyte abnormalities.

Front 14

Galantamine side fx?

Back 14

The most common side effects of galantamine are dizziness, headache, nausea, vomiting, diarrhea, and anorexia. These side effects tend to be mild and transient.

Front 15

Tacrine side fx?

Back 15

Tacrine is the least used of the cholinesterase inhibitors, but its use requires more discussion with the patient than the others because it is cumbersome to titrate and use, and it poses the risk of potentially significant elevations in hepatic transaminase levels. These increases occur in 25 percent to 30 percent of persons. Aside from elevated transaminase levels, the most common specific adverse effects associated with tacrine treatment are nausea, vomiting, myalgia, anorexia, and rash, but only nausea, vomiting, and anorexia have been found to have a clear relation to the dosage. Transaminase elevations characteristically develop during the first 6 to 12 weeks of treatment and cholinergically mediated events are dosage related.

Front 16

Tacrine is associated with increases in the plasma activities of

Back 16

alanine aminotransferase (ALT) and aspartate aminotransferase (AST).

For routine monitoring of hepatic enzymes, AST and ALT activities should be measured weekly for the first 18 weeks, every month for the second 4 months, and every 3 months thereafter.

Front 17

For any patient with ???, tacrine treatment should be stopped, and the patient should not be given the drug again.

Back 17

elevated ALT activity and jaundice

Front 18

All cholinesterase inhibitors should be used cautiously with drugs that

Back 18

also possess cholinomimetic activity, such as succinylcholine (Anectine) or bethanechol (Urecholine).

The coadministration of cholinesterase inhibitors and drugs that have cholinergic antagonist activity (e.g., tricyclic drugs) is probably counterproductive

Front 19

Which antidepressant to avoid with ACHI?

Back 19

Paroxetine has the most marked anticholinergic effects of any of the newer antidepressant and anxiolytic drugs and should be avoided for that reason, as well as for its inhibiting effect on the metabolism of some of the cholinesterase inhibitors

Front 20

Donepezil undergoes extensive metabolism via isozymes

Back 20

both CYP 2D6 and 3A4

Front 21

Drug intx with donepezil?

Back 21

The metabolism of donepezil may be increased by phenytoin (Dilantin), carbamazepine (Tegretol), dexamethasone (Decadron), rifampin (Rifadin), or phenobarbital (Solfoton). Commonly used agents, such as paroxetine, ketoconazole, and erythromycin, can significantly increase donepezil concentrations. Donepezil is highly protein bound, but it does not displace other protein-bound drugs, such as furosemide (Lasix), digoxin (Lanoxin), or warfarin (Coumadin). Rivastigmine circulates mostly unbound to serum proteins and has no significant drug interactions.
As with donepezil, galantamine is metabolized by both CYP 2D6 and 3A4 isozymes and, thus, may interact with drugs that inhibit these pathways. Paroxetine and ketoconazole should be used with great caution

Front 22

Describe approach before starting donepezil and give dose:

Back 22

Before initiating cholinesterase inhibitor therapy, potentially treatable causes of dementia should be ruled out and the diagnosis of dementia of the Alzheimer's type established.

Donepezil is available in 5- and 10-mg tablets. Treatment should be initiated at 5 mg each night. If well tolerated and of some discernible benefit after 4 weeks, the dosage should be increased to a maintenance dosage of 10-mg each night. Donepezil absorption is unaffected by meals

Front 23

Rivastigmine dosing?

Back 23

The recommended initial dosage is 1.5 mg twice daily for a minimum of 2 weeks, after which increases of 1.5 mg a day can be made at intervals of at least 2 weeks to a target dosage of 6 mg a day, taken in two equal dosages. If tolerated, the dosage can be further titrated upward to a maximum of 6 mg twice daily. The risk of adverse GI events can be reduced by administration of rivastigmine with foodG

Front 24

Galantamine dosing?

Back 24

The initial dosage is 8 mg per day and, after a minimum of 4 weeks, the dose can be raised. All subsequent dosage increases should occur at 4-week intervals and should be based on tolerability.

Front 25

Memantine half life?

Back 25

Memantine has linear pharmacokinetics over the therapeutic dose range and has a terminal elimination half-life of about 60 to 80 hours.

Front 26

Memantine MOA?

Back 26

Memantine may protect cells against excess glutamate by partially blocking NMDA receptors associated with abnormal transmission of glutamate, while allowing for physiologic transmission associated with normal cell functioning.Memantine is the only approved therapy in the United States for moderate to severe Alzheimer's disease

Front 27

Memantine indication

Back 27

Memantine is the only approved therapy in the United States for moderate to severe Alzheimer's disease

Front 28

Memantine Side fx?

Back 28

The use of memantine in patients with severe renal impairment is not recommended.

Memantine is safe and well tolerated. The most common adverse effects are dizziness, headache, constipation, and confusion

Front 29

Memantine drug intx?

Back 29

alkaline urine conditions,

Front 30

Memantine dosing?

Back 30

It should be given twice per day for doses above 5 mg. The recommended dosage is 5 mg twice daily following a 4-week titration. There should be a minimal interval of 1 week between dose increases.

Front 31

Memantine ACHI combo evidence?

Back 31

Patients with mild to moderate disease receiving memantine in combination with a cholinesterase inhibitor have not been found to experience significantly greater benefit in cognition or overall function than those who receive a cholinesterase inhibitor alone

Front 32

What is Dantrolene?

Back 32

Dantrolene (Dantrium) is a direct-acting skeletal muscle relaxant, which is used to treat neuroleptic malignant syndrome

Front 33

What is key indication for dantrolene?

Back 33

The skeletal muscle relaxant effect is the basis of its efficacy in reducing the muscle destruction and hyperthermia associated with neuroleptic malignant syndrome.

Intravenous (IV) dantrolene reduces muscle spasm in about 80 percent of persons with neuroleptic malignant syndrome

Front 34

Dantrolene is almost always used in conjunction with ...

Back 34

appropriate supportive measures and a dopamine receptor antagonist (DRA).

Front 35

Dantrolene should not be given by IV in combination with

Back 35

calcium channel blockers

Front 36

Dantrolene dosing?

Back 36

dantrolene in doses of 1 mg/kg can be given orally four times daily, or 1 to 5 mg/kg can be given by IV to reduce muscle spasms in patients with neuroleptic malignant syndrome. Although some clinicians have recommended low dosages (2.5 mg/kg per day) because of the adverse effects, other clinicians indicate that daily dosages of 10 mg/kg are most likely to be effective. Dantrolene is supplied as 25-, 50-, and 100-mg capsules and in a 20-mg parenteral preparation for reconstitution with 60 mL of sterile water.

Front 37

Disulfram is used for what? use?

Back 37

to treat alcohol dependence. Disulfiram is an alcohol-sensitizing agent—it deters use of alcohol by producing a rapid and violently unpleasant reaction in a person who ingests even a small amount of alcohol. Many clinicians have stopped prescribing disulfiram because of the risk of severe and even fatal disulfiram–alcohol reactions.

Front 38

acamprosate

Back 38

to treat alcohol dependence

acamprosate does not produce aversive side effects when combined with alcohol, but it reduces the craving that is experienced by alcohol-dependent patients

Front 39

Disulfram MOA?

Back 39

Disulfiram is an aldehyde dehydrogenase inhibitor that interferes with the metabolism of alcohol by producing a marked increase in blood acetaldehyde concentration

The accumulation of acetaldehyde (to a level up to ten times higher than occurs in the normal metabolism of alcohol) produces a wide array of unpleasant reactions, called the disulfiram–alcohol reaction, characterized by nausea, throbbing headache, vomiting, hypertension, flushing, sweating, thirst, dyspnea, tachycardia, chest pain, vertigo, and blurred vision. The reaction occurs almost immediately after the ingestion of one alcoholic drink and can last from 30 minutes to 2 hours

Front 40

Disulfram side fx without alcohol use?

Back 40

The adverse effects of disulfiram in the absence of alcohol consumption include fatigue, dermatitis, impotence, optic neuritis, a variety of mental changes, and hepatic damage. A metabolite of disulfiram inhibits dopamine-β-hydroxylase, the enzyme that metabolizes dopamine into norepinephrine and epinephrine and, thus, may exacerbate psychosis in persons with psychotic disorders. Catatonic reactions can also occur.

Front 41

Disulfram + alcohol consumption?

Back 41

In extreme cases it is marked by respiratory depression, cardiovascular collapse, myocardial infarction, convulsions, and death

Front 42

Disulfram dosing?

Back 42

The usual initial dosage is 500 mg a day taken by mouth for the first 1 or 2 weeks, followed by a maintenance dosage of 250 mg a day. The dosage should not exceed 500 mg a day.

Front 43

Disulfram warnings?

Back 43

The person taking disulfiram must be instructed that the ingestion of even the smallest amount of alcohol will bring on a disulfiram–alcohol reaction, with all its unpleasant effects. In addition, the person should be warned against ingesting any alcohol-containing preparations, such as cough drops, tonics of any kind, and alcohol-containing foods and sauces. Some reactions have occurred in patients who used alcohol-based aftershave lotions, toilet water, colognes, or perfumes and inhaled the fumes; therefore, precautions must be explicit and should include any topically applied preparations containing alcohol, such as perfume.

Disulfiram should not be administered until the person has abstained from alcohol for at least 12 hours. Persons should be warned that the disulfiram–alcohol reaction can occur as long as 1 or 2 weeks after the last dose of disulfiram. Persons taking disulfiram should carry identification cards describing the disulfiram–alcohol reaction and listing the name and the telephone number of the physician to be called.

Front 44

Acamprosate MOA?

Back 44

Acamprosate's mechanism of action is not fully understood, but it is thought to antagonize neuronal overactivity related to the actions of the excitatory neurotransmitter glutamate. In part, this may result from antagonism of N-methyl- D-aspartate (NMDA) receptors.

Front 45

Acamprosate indication?

Back 45

Acamprosate is used for treating alcohol-dependent individuals seeking to continue to remain alcohol-free after they have stopped drinking.

Its efficacy in promoting abstinence has not been demonstrated in persons who have not undergone detoxification and who have not achieved alcohol abstinence before beginning treatment.

Front 46

Acamprosate adverse effects?

Back 46

Side effects, which are mostly seen early in treatment, are usually mild and transient in nature. The most common side effects are headache, diarrhea, flatulence, abdominal pain, paresthesias, and various skin reactions. No adverse events occur following abrupt withdrawal of acamprosate, even after long-term use. No evidence indicates addiction to the drug. Patients with severe renal impairment (creatinine clearance of <30 mL/min) should not be given acamprosate.

Front 47

Acamprosate key points?

Back 47

It is important to remember that acamprosate should not be used to treat alcohol withdrawal symptoms. It should only be started after the individual has been successfully weaned off the alcohol.

Front 48

Acamprosate dosing?

Back 48

Each tablet contains acamprosate calcium 333 mg, which is equivalent to 300 mg of acamprosate. The dose of acamprosate is different for different patients. The recommended dosage is two 333-mg tablets (each dose should total 666 mg) taken three times daily.

Front 49

Dopamine receptor agonists and precursors were developed to treat

Back 49

idiopathic Parkinson's diseas

Front 50

Psychiatric indications for DA receptor agonists?

Back 50

On occasion, they are used by psychiatrists to treat such adverse effects of antipsychotic drugs as (1) parkinsonism, (2) extrapyramidal symptoms, (3) akinesia, (4) focal perioral tremors, (5) hyperprolactinemia, (6) galactorrhea, and (7) neuroleptic malignant syndrome.

Front 51

List most common DA receptor agonists?

Back 51

The drugs in this class most commonly prescribed are bromocriptine (Parlodel), levodopa also called L-Dopa, (Larodopa), and carbidopa-levodopa (Sinemet). New dopamine receptor agonists include ropinirole (Requip), pramipexole (Mirapex), pergolide (Permax), and apomorphine (Apokyn).

Front 52

The drugs in this class most commonly prescribed are bromocriptine (Parlodel), levodopa also called L-Dopa, (Larodopa), and carbidopa-levodopa (Sinemet). New dopamine receptor agonists include ropinirole (Requip), pramipexole (Mirapex), pergolide (Permax), and apomorphine (Apokyn).
Describe each.

Back 52

Levodopa is the natural precursor of dopamine. The formulation of levodopa combined with carbidopa reduces the incidence of noncentral nervous system (non-CNS) adverse effects experienced with use of levodopa alone. Bromocriptine and pergolide are ergotamine derivatives. Pramipexole is a nonergot dopamine agonist. Apomorphine, also a nonergot dopamine agonist, has been used in medicine for more than a century. It has been available since the 1970s in Europe and Canada, but was only approved for use in the United States in 2004. It is indicated for the treatment of motor symptoms associated with late-stage Parkinson's disease. Apomorphine is structurally related to morphine and other opioids

Front 53

Once X? enters the dopaminergic neurons of the CNS, it is converted into the neurotransmitter dopamine. DRUGS? act directly on dopamine receptors

Back 53

L-Dopa.

Apomorphine, bromocriptine, pergolide, ropinirole, and pramipexole

Front 54

L-DOPA binding?

Back 54

Dopamine, pramipexole, and ropinirole bind about 20 times more selectively to dopamine D3 than D2 receptors

Front 55

Apomorphine binds selectively to ? receptors, with little affinity for ? receptors.

Back 55

Apomorphine binds selectively to D1 and D2 receptors, with little affinity for D3 and D4 receptors.

Front 56

L-Dopa, pramipexole, and ropinirole have no significant activity at ? receptors,

Back 56

L-Dopa, pramipexole, and ropinirole have no significant activity at nondopaminergic receptors,

Front 57

pergolide and bromocriptine bind to ? receptors

Back 57

serotonin 5-HT1 and 5-HT2, and α1-, α2-, and β-adrenergic receptors.

Front 58

List main indications for dopamine agonists

Back 58

Medication induced Movement ... Disorders ... including restless legs disorder
Mood Ds
Sexual Dysfxn

Front 59

For the treatment of medication-induced movement disorders, most clinicians rely on

Back 59

anticholinergics, amantadine (Symmetrel), and antihistamines because they are equally effective and have few adverse effects

Front 60

Drug? remains in use in the treatment of neuroleptic malignant syndrome

Back 60

Bromocriptine

Front 61

? has long been used to enhance response to antidepressant drugs in refractory patients

Back 61

Bromocriptine

Front 62

Side fx of DA agonists?

Back 62

Adverse effects, which are dosage dependent, include nausea, vomiting, orthostatic hypotension, headache, dizziness, and cardiac arrhythmias.

To reduce the risk of orthostatic hypotension, the initial dosage of all dopamine receptor agonists should be quite low, with incremental increases in dose at intervals of at least 1 week. These drugs should be used with caution in persons with hypertension, cardiovascular disease, and hepatic disease. After long-term use, persons, particularly elderly persons, may experience choreiform and dystonic movements and psychiatric disturbances—including hallucinations, delusions, confusion, depression, and mania—and other behavioral changes.

Front 63

In general, DRUGS? have a similar but much milder adverse effect profile than L-Dopa, bromocriptine, and pergolide.

Back 63

pramipexole and ropinirole

Front 64

How dose L-Dopa?

Back 64

For the treatment of antipsychotic-induced parkinsonism, the clinician should start with a 100-mg dose of levodopa three times a day, which may be increased until the person is functionally improved. The maximum dosage of L-Dopa is 2,000 mg a day, but most persons respond to dosages below 1,000 mg per day. The dosage of the carbidopa component of the L-Dopa-carbidopa formulation should total at least 75 mg a day.

Front 65

Bromocriptine dosing?

Back 65

The dosage of bromocriptine for mental disorders is uncertain, although it seems prudent to begin with low dosages (1.25 mg twice daily) and to increase the dosage gradually. Bromocriptine is usually taken with meals to help reduce the likelihood of nausea

Front 66

Dosing of pramipexole?

Back 66

The starting dosage of pramipexole is 0.125 mg three times daily, which is increased to 0.25 mg three times daily in the second week and then increased by 0.25 mg per dose each week until therapeutic benefit or adverse effects emerge. Persons with idiopathic Parkinson's disease usually experience benefit at total daily doses of 1.5 mg, and the maximal daily dose is 4.5 mg.

Front 67

, was the first drug that significantly and consistently reduced symptoms of psychosis.

Back 67

Chlorpromazine (Thorazine), which was introduced in the mid-1950s

Front 68

Antipsychotic activity was related to high-affinity antagonism of dopamine ? receptors

Back 68

D2

Front 69

Typical half-life, protein bindings, parenteral forms? metabolism?

Back 69

All the DRAs are well absorbed after oral administration, with liquid preparations being absorbed more efficiently than tablets or capsules. Peak plasma concentrations are usually reached 1 to 4 hours after oral administration and 30 to 60 minutes after parenteral administration. Smoking, coffee, antacids, and food interfere with absorption of these drugs. Steady-state levels are reached in approximately 3 to 5 days. The half-lives of these drugs are approximately 24 hours. All can be given in one daily oral dose, if tolerated, once the person is in a stable condition. Most DRAs are highly protein bound. Parenteral formulation of DRAs results in more rapid and more reliable onset of action. Bioavailability is also up to tenfold higher with parenteral administration. Most DRAs are metabolized by CYP 2D6 and 3A isozymes; however, differences exist among the specific agents

Front 70

What factors can influence pharmacokinetics of antipsychotics?

Back 70

Age (less clearance), GMC (less hepatic clearance), Enzyme inducers (carb, etoh derivates), Clearance inhibitors, Changes in protein binding (low albumin, hepatic failure)

Front 71

Describe depot use?

Back 71

Long-acting depot parenteral formulations of haloperidol (Haldol) and fluphenazine (Prolixin) are available in the United States. They are usually administered once every 1 to 4 weeks, depending on the dose and the person. It can take up to 6 months of treatment with depot formulations to reach steady-state plasma levels, indicating that oral therapy should be continued during the first month or so of depot antipsychotic treatment.

Front 72

What is range of DR antagonism?

Back 72

The DRAs are effective when approximately 60 percent of D2 receptors in the brain are occupied. At 80 percent one sees the beginning of extrapyramidial signs. The DRAs also block noradrenergic, cholinergic, and histaminergic receptors, with different drugs having different effects on these receptor systems

Front 73

Difference between low and high potency?

Back 73

Some generalizations can be made about the DRAs based on their potency. Potency refers to the amount of drug that is required to achieve therapeutic effects. Low-potency drugs, such as chlorpromazine and thioridazine, given in doses of several hundred milligrams per day, typically produce more weight gain and sedation than high-potency agents, such as haloperidol and fluphenazine, usually given in doses of less than 10 mg per day. High-potency agents are also more likely to cause extrapyramidal side effects.

Front 74

DRA on + sx? on negative sx?

Back 74

The DRAs produce their most dramatic effects against the positive symptoms of schizophrenia (e.g., hallucinations, delusions, and agitation).

Negative symptoms (e.g., emotional withdrawal and ambivalence) are less likely to improve significantly, and they may appear to worsen because these drugs produce constriction of facial expression and akinesia, side effects that mimic negative symptoms.

Front 75

Following a first episode of psychosis, patients should be maintained on medication for ?? years; after multiple episodes, for ?? years

Back 75

Following a first episode of psychosis, patients should be maintained on medication for 1 to 2 years; after multiple episodes, for 2 to 5 years

Front 76

Why are antipsychotics used in mania?

Back 76

Because antimanic agents (e.g., lithium) generally have a slower onset of action than do antipsychotics in the treatment of acute symptoms, it is standard practice initially to combine either a DRA or an SDA with lithium (Eskalith), lamotrigine (Lamictal), or carbamazepine (Tegretol) and then gradually withdraw the antipsychotic.

Front 77

DRA and Tourettes?

Back 77

Because antimanic agents (e.g., lithium) generally have a slower onset of action than do antipsychotics in the treatment of acute symptoms, it is standard practice initially to combine either a DRA or an SDA with lithium (Eskalith), lamotrigine (Lamictal), or carbamazepine (Tegretol) and then gradually withdraw the antipsychotic.

Some clinicians prefer to use clonidine (Catapres) for this disorder because of its lower risk of neurologic side effects. Pimozide is used less frequently because of adverse cardiac effects.

Front 78

Role for DRA's in Delirium?

Back 78

About two thirds of agitated, elderly patients with various forms of dementia improve when given a DRA. Low doses of high-potency drugs (e.g., 0.5 to 1 mg a day of haloperidol) are used. DRAs are also used to treat psychotic symptoms and agitation associated with delirium. The cause of the delirium needs to be determined, because toxic deliriums caused by anticholinergic agents can be exacerbated by low-potency DRAs, which often have significant antimuscarinic activity.

Front 79

Benzodiazepines should be used instead of DRAs in cases of ??? intoxication because of the anticholinergic effects of the DRAs

Back 79

phencyclidine

Front 80

Cautions in Substance inDuced Psychotic Ds treatment with DRA?

Back 80

In cases where patients are experiencing hallucinations or delusions as a result of alcohol withdrawal, DRAs may increase the risk of seizure.

Front 81

The DRAs reduce the chorea in the early stages of ?

Back 81

Huntington's disease

Front 82

In huntington's which type of antipsychotics usually recommended ... high or low potency?

Back 82

High-potency DRAs should be used

Front 83

The rare neurologic disorders ??? characterized by propulsive movements of the limbs away from the body, also respond to treatment with antipsychotic agents

Back 83

ballismus and hemiballismus (which affects only one side of the body),

Front 84

miscellaneous indications for the use of DRAs include the treatment of ?

Back 84

nausea,
emesis,
intractable hiccups, and
pruritus

Front 85

As a rule, low-potency drugs cause most ?? adverse effects, while the high-potency drugs cause most ?? adverse effects

Back 85

non-neurologic

neurologic

Front 86

Describe Neuroleptic Malignant Syndrome

Back 86

Symptoms include extreme hyperthermia, severe muscular rigidity and dystonia, akinesia, mutism, confusion, agitation, and increased pulse rate and blood pressure (BP) leading to cardiovascular collapse. Laboratory findings include increased white blood cell (WBC) count, creatinine phosphokinase, liver enzymes, plasma myoglobin, and myoglobinuria, occasionally associated with renal failure. The symptoms usually evolve over 24 to 72 hours, and the untreated syndrome lasts 10 to 14 days

Front 87

NMS: GENDER are affected more frequently than are GENDER, and AGE persons are affected more commonly than are AGE persons

Back 87

Men are affected more frequently than are women, and young persons are affected more commonly than are elderly persons

Front 88

Tx of NMS?

Back 88

If neuroleptic malignant syndrome is suspected, the DRA should be stopped immediately and the following done:
medical support to cool the person; monitoring of vital signs, electrolytes, fluid balance, and renal output; and symptomatic treatment of fever

Antiparkinsonian medications may reduce some of the muscle rigidity. Dantrolene (Dantrium), a skeletal muscle relaxant (0.8 to 2.5 mg/kg every 6 hours, up to a total dosage of 10 mg a day) may be useful in the treatment of this disorder. Once the person can take oral medications, dantrolene can be given in doses of 100 to 200 mg a day. Bromocriptine (20 to 30 mg a day in four divided doses) or amantadine can be added to the regimen. Treatment should usually be continued for 5 to 10 days. When drug treatment is restarted, the clinician should consider switching to a low-potency drug or an SDA, although these agents—including clozapine—can also cause neuroleptic malignant syndrome.

Front 89

List all neurologic side fx of DRA?

Back 89

Acute extrapyramidal syndromes
Akathisia
Acute dystonia
Drug-induced parkinsonism
Neuroleptic malignant syndrome
Chronic extrapyramidal syndromes
Tardive dyskinesia and dystonia
Perioral tremor

Front 90

Which DRAs most epileptogenic? Least?

Back 90

The DRAs may lower the seizure threshold. Chlorpromazine, thioridazine, and other low-potency drugs are thought to be more epileptogenic than are high-potency drugs. Molindone may be the least epileptogenic of the DRA drugs. The risk of inducing a seizure by drug administration warrants consideration when the person already has a seizure disorder or brain lesion.

Front 91

Blockade of?receptors is the usual cause of sedation associated with DRAs

Back 91

Blockade of histamine H1 receptors is the usual cause of sedation associated with DRAs

Front 92

?? is the most sedating typical antipsychotic.

Back 92

Chlorpromazine

Front 93

List categories of DRA side fx?

Back 93

NMS, Lower Seizure Threshold, Sedation, Anticholinergic effects, Cardiac, Sudden Death, Postural Hypotension, Hematology, Peripheral Anticholinergic effects, Endocrine, Sexual, Skin, Eye, Jaundice, Overdose,

Front 94

Anticholinergic tox sx?

Back 94

severe agitation; disorientation to time, person, and place; hallucinations; seizures; high fever; and dilated pupils. Stupor and coma may ensue.


The treatment of anticholinergic toxicity consists of discontinuing the causal agent or agents, close medical supervision, and physostigmine (Antilirium, Eserine), 2 mg by slow intravenous (IV) infusion, repeated within 1 hour as necessary. Too much physostigmine is dangerous, and symptoms of physostigmine toxicity include hypersalivation and sweating. Atropine sulfate (0.5 mg) can reverse the effects of physostigmine toxicity.

Front 95

DRAs and cardiac effects?

Back 95

The DRAs decrease cardiac contractility, disrupt enzyme contractility in cardiac cells, increase circulating levels of catecholamines, and prolong atrial and ventricular conduction time and refractory periods.

Low-potency DRAs are more cardiotoxic than are high-potency drugs.

Chlorpromazine causes prolongation of the QT and PR intervals, blunting of the T waves, and depression of the ST segment.

Thioridazine and mesoridazine, in particular, are associated with substantial QT prolongation and risk of torsade de pointes. These drugs, thus, are indicated only when other agents have been ineffective

Front 96

DRAs and sudden death?

Back 96

Occasional reports of sudden cardiac death during treatment with DRAs may be the result of cardiac arrhythmias. Other causes may include seizure, asphyxiation, malignant hyperthermia, heat stroke, and neuroleptic malignant syndrome. An overall increase in the incidence of sudden death linked to the use of antipsychotics does not appear to exist, however

Front 97

How manage antipsychotic induced hypotension?

Back 97

Hypotension can usually be managed by having patients lie down with their feet higher than their heads, and pump their legs as if bicycling. Volume expansion or vasopressor agents, such as norepinephrine (Levophed), may be indicated in severe cases. Because hypotension is produced by α-adrenergic blockade, the drugs also block the α-adrenergic stimulating properties of epinephrine, leaving the β-adrenergic stimulating effects untouched. Therefore, the administration of epinephrine results in a paradoxical worsening of hypotension and is contraindicated in cases of antipsychotic-induced hypotension. Pure α-adrenergic pressor agents, such as metaraminol (Aramine) and norepinephrine, are the drugs of choice in the treatment of the disorder

Front 98

DRAs and hemotologic effects?

Back 98

A temporary leukopenia with a WBC count of about 3,500 is a common, but not serious problem. Agranulocytosis, a life-threatening hematologic problem, occurs in about 1 of 10,000 persons treated with DRAs. Thrombocytopenic or nonthrombocytopenic purpura, hemolytic anemias, and pancytopenia may occur rarely in persons treated with DRAs. Although routine complete blood counts (CBCs) are not indicated, if a person reports a sore throat and fever, a CBC should be done immediately to check for the possibility. If the blood indexes are low, administration of DRAs should be stopped, and the person should be transferred to a medical facility. The mortality rate for the complication may be as high as 30 percent.

Front 99

Which DRAs least associated with weight gain?

Back 99

Molindone (Moban) and, perhaps, loxapine (Loxitane) appear to be least likely to cause weight gain.

Weight gain is associated with increased mortality and morbidity and with medication noncompliance. Low-potency DRAs can cause significant weight gain but not as much as is seen with the SDAs olanzapine (Zyprexa) and clozapine (Clozaril)

Front 100

DRA's and prolactin?

Back 100

Blockade of the dopamine receptors in the tuberoinfundibular tract results in the increased secretion of prolactin, which can result in breast enlargement, galactorrhea, amenorrhea, and inhibited orgasm in women and impotence in men. The SDAs, with the exception of risperidone, are not particularly associated with an increase in prolactin levels and may be the drugs of choice for persons experiencing disturbing side effects from increased prolactin release.

Front 101

Agent most associated with decreased libido and retrograde ejaculation?

Back 101

Both men and women taking DRAs can experience anorgasmia and decreased libido. As many as 50 percent of men taking antipsychotics report ejaculatory and erectile disturbances. Sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis) are often used to treat psychotropic-induced orgasmic dysfunction, but they have not been studied in combination with DRAs. Thioridazine is particularly associated with decreased libido and retrograde ejaculation in men. Priapism and reports of painful orgasms have also been described, both possibly resulting from α1-adrenergic antagonist activity

Front 102

Skin changes with DRAs?

Back 102

Allergic dermatitis and photosensitivity can occur, especially with low-potency agents. Urticarial, maculopapular, petechial, and edematous eruptions can occur early in treatment, generally in the first few weeks, and remit spontaneously. A photosensitivity reaction that resembles a severe sunburn also occurs in some persons taking chlorpromazine. Persons should be warned of this adverse effect, spend no more than 30 to 60 minutes in the sun, and use sunscreens. Long-term chlorpromazine use is associated with blue-gray discoloration of skin areas exposed to sunlight. The skin changes often begin with a tan or golden brown color and progress to such colors as slate gray, metallic blue, and purple. These discolorations resolve when the patient is switched to another medication

Front 103

Why is thioridazine dosage max 800mg/day?

Back 103

Irreversible retinal pigmentation is associated with use of thioridazine at dosages above 1,000 mg a day. An early symptom of the side effect can sometimes be nocturnal confusion related to difficulty with night vision. The pigmentation can progress even after thioridazine administration is stopped, finally resulting in blindness. It is for this reason that the maximal recommended dosage of thioridazine is 800 mg per day

Front 104

cpz and eye changes?

Back 104

Patients taking chlorpromazine can develop a relatively benign pigmentation of the eyes, characterized by whitish brown granular deposits concentrated in the anterior lens and posterior cornea and visible only by slit-lens examination. The deposits can progress to opaque white and yellow-brown granules, often stellate. Occasionally, the conjunctiva is discolored by a brown pigment. No retinal damage is seen, and vision is almost never impaired. This condition gradually resolves when the chlorpromazine is discontinued

Front 105

CPZ and liver ?

Back 105

if get jaundice stop rx

Front 106

DRAs overdose treatment?

Back 106

Overdoses typically consist of exaggerated DRA side effects. Symptoms and signs include central nervous system (CNS) depression, extrapyramidal symptoms, mydriasis, rigidity, restlessness, decreased deep tendon reflexes, tachycardia, and hypotension. The severe symptoms of overdose include delirium, coma, respiratory depression, and seizures. Haloperidol may be among the safest typical antipsychotics in overdose. After an overdose, the electroencephalogram (EEG) shows diffuse slowing and low voltage. Extreme overdose can lead to delirium and coma, with respiratory depression and hypotension. Life-threatening overdose usually involves ingestion of other CNS depressants, such as alcohol or benzodiazepines.

Activated charcoal, if possible, and gastric lavage should be administered if the overdose is recent. Emetics are not indicated, because the antiemetic actions of DRAs inhibit their efficacy. Seizures can be treated with IV diazepam (Valium) or phenytoin (Dilantin). Hypotension can be treated with either norepinephrine or dopamine, but not epinephrine.

Front 107

DRA's and pregnancy?

Back 107

A low correlation exists between the use of antipsychotics during pregnancy and congenital malformations. Nevertheless, antipsychotics should be avoided during pregnancy, particularly in the first trimester, unless the benefit outweighs the risk. High-potency drugs, particularly fluphenazine (Prolixon), are preferable to low-potency drugs, because the low-potency drugs are associated with hypotension.
The DRAs are secreted in the breast milk, although concentrations are low. Women taking these agents should be advised against breast-feeding.

Front 108

CYP ??? is the most common hepatic isozyme involved in DRA pharmacokinetic interactions

Back 108

2D6

Tricyclic drugs and selective serotonin reuptake inhibitors (SSRIs) that inhibit CYP 2D6—paroxetine, fluoxetine, and fluvoxamine—interact with DRAs, resulting in increased plasma concentrations of both drugs.

Front 109

Cigarette smoking may ? the plasma levels of typical antipsychotic drugs

Back 109

decrease

Front 110

Epinephrine has a ? effect in persons taking typical antipsychotics.

Back 110

paradoxical hypotensive

Front 111

DRA's may ? the blood concentration of warfarin (Coumadin), resulting in ? bleeding time

Back 111

decreased,
decreased

Front 112

Phenothiazines, thioridazine, and
pimozide should not be coadministered with other agents that

Back 112

prolong the QT interval

Front 113

Thioridazine is contraindicated in patients

Back 113

taking drugs that inhibit the cytochrome P450 (CYP) 2D6 isoenzyme or in patients with reduced levels of CYP 2D6.

Front 114

DRA + propranolol?

Back 114

Propranolol coadministration increases the blood concentrations of both drugs.

Front 115

Phenothiazines, especially thioridazine, can decrease the metabolism of, and cause toxic concentrations of,

Back 115

phenytoin

Front 116

Barbiturates can ? the metabolism of DRAs, and these drugs may ? the person's seizure threshold.

Back 116

Barbiturates can increase the metabolism of DRAs, and these drugs may lower the person's seizure threshold.

Front 117

Digoxin and steroids, both of which decrease gastric motility, can ? DRA absorption.

Back 117

Digoxin and steroids, both of which decrease gastric motility, can increase DRA absorption.

Front 118

Contraindications to the use of DRAs include

Back 118

(1) a history of a serious allergic response,
(2) the possible ingestion of a substance that will interact with the antipsychotic to induce CNS depression (e.g., alcohol, opioids, barbiturates, and benzodiazepines) or anticholinergic delirium (e.g., scopolamine and possibly phencyclidine [PCP]),
(3) the presence of a severe cardiac abnormality,
(4) a high risk for seizures,
(5) the presence of narrow-angle glaucoma or prostatic hypertrophy if a drug with high anticholinergic activity is to be used, and
(6) the presence or a history of tardive dyskinesia.

Front 119

It is important to remember that the maximal effects of a particular dosage of DRA may not be evident for

Back 119

4 to 6 weeks

Front 120

The administration of more than XX mg of chlorpromazine in one injection can result in serious hypotension

Back 120

25

Front 121

Administration of the antipsychotic IM results in peak plasma levels in about ? versus minutes using the oral route

Back 121

30 minutes, versus 90

Front 122

About ? mg of haloperidol or ??? mg of chlorpromazine is the usual effective daily dose.

Back 122

About 5 mg of haloperidol or 300 mg of chlorpromazine is the usual effective daily dose.

Front 123

A full X weeks may be necessary to evaluate the extent of the improvement in psychotic symptom

Back 123

6

Front 124

Psychotic symptoms, both positive and negative, usually continue to improve ? months after the initiation of treatment.

Back 124

3 to 12

Front 125

The sedative effects of typical antipsychotics last ?, in contrast to the antipsychotic effects, which last for ?

Back 125

The sedative effects of typical antipsychotics last only a few hours, in contrast to the antipsychotic effects, which last for 1 to 3 days.

Front 126

The first X months after a psychotic episode is usually considered a period of stabilization

Back 126

3 to 6months

Front 127

A person is usually maintained on antipsychotic medications for ?years after the first psychotic episode.

Back 127

A person is usually maintained on antipsychotic medications for 1 to 2 years after the first psychotic episode.

Front 128

Antipsychotic treatment is often continued for ? years after a second psychotic episode

Back 128

Antipsychotic treatment is often continued for 5 years after a second psychotic episode

Front 129

lifetime maintenance is considered after the ? psychotic

Back 129

3rd

Front 130

Decanoate preparations can be given ?(more or less) frequently than enanthate preparations because they are absorbed (more or less) slowly

Back 130

Decanoate preparations can be given less frequently than enanthate preparations because they are absorbed more slowly

Front 131

IM Decanoate dosing?

Back 131

It is reasonable to begin with either 12.5 mg (0.5 mL) of fluphenazine preparation or 25 mg (0.5 mL) of haloperidol decanoate. If symptoms emerge in the next 2 to 4 weeks, the person can be treated temporarily with additional oral medications or with additional small depot injections. After 3 to 4 weeks, the depot injection can be increased to a single dose equal to the total of the doses given during the initial period.

Front 132

If a person has not improved after 4 to 6 weeks of treatment, do what?

Back 132

he plasma concentration of the drug should be determined, if feasible.

Front 133

How do levels?

Back 133

After a patient has been on a particular dosage for at least five times the half-life of the drug and, thus, approaches steady-state concentrations, blood levels may be helpful. It is standard practice to obtain plasma samples at trough levels—just before the daily dose is given, usually at least 12 hours after the previous dose and most commonly 20 to 24 hours after the previous dose. In fact, most antipsychotics have no well-defined dose–response curve. The best-studied drug is haloperidol, which may have a therapeutic window ranging from 2 to 15 ng/mL. Other therapeutic ranges that have been reasonably well documented are 30 to 100 ng/mL for chlorpromazine and 0.8 to 2.4 ng/mL for perphenazine.

Front 134

Approximately ? percent of persons with schizophrenia, however, do not obtain significant benefit from the antipsychotic drugs

Back 134

Approximately 10 percent to 35 percent of persons with schizophrenia, however, do not obtain significant benefit from the antipsychotic drugs

Front 135

Define treatment resistance

Back 135

Treatment resistance is failure on at least two adequate trials of antipsychotics from two pharmacologic classes

Front 136

Major reason for not using 1st generation DRA?

Back 136

Concern about the development of DRA-induced tardive dyskinesia is the major deterrent to long-term use of these drugs, yet it is not clear that SDAs are completely risk free of this complication.

Front 137

How chose DRA?

Back 137

Choice of a particular DRA should be based on the known adverse-effect profile of the drugs. Other than a significant advantage in terms of medication cost, the choice currently would be an SDA.

Front 138

If chose DRA which type?

Back 138

If a DRA is felt to be preferable, a high-potency antipsychotic is favored even though it may be associated with more neurologic adverse effects, mainly because a higher incidence exists of other adverse effects (e.g., cardiac, hypotensive, epileptogenic, sexual, and allergic) with the low-potency drugs

If sedation is a desired goal, either a low-potency antipsychotic can be given in divided doses or a benzodiazepine can be coadministered.

Front 139

An unpleasant or dysphoric reaction (a subjective sense of restlessness, oversedation, and acute dystonia) to the first dose of an antipsychotic predicts

Back 139

future poor response and noncompliance.

Prophylactic use of antiparkinsonian medications may prevent this reaction