Anti-Psychotics Flashcards
Psychosisand
symptom of mental disease: anosognosis, cognitive deficit, major depression, apathy, aboulia, alogie, Malia with hallucinations, delusions, disorganized speaking and agitation
Substances involved in inducing psychosis
Amphetamine(increase presynaptic neurotransmitter release), Methyphenidate, cocaine, amphetamine (inhibit presynaptic dopamine reuptake, levodopa (increase dopamine availability)
Before 1950, psychosis therapy
sedation, shock therapy, brain surgery
First antipsychotic
chlorpromazine (anesthetic), neuroleptics due to dopamine overactivity, psychomotor slowing, emotional quieting, affective indifference,
Second generation
Serotonin importance, lower risk of extrapyramidal/prolactin, efficiency in treatment resistant patients but with metabolic adverse effects
First generation antipsychotics - low potency
chlorpromazine, chlorprothixene, levomepromazine, melperone, perazine, pipamperone, promazine, promethazine, sulpiride, thioridazine, zuclopenthixole
First generation antipsychotic - high potency
benperidol, flupenthixol, fluphenazine, haloperidol, perphenazine
Second generation antipsychotics
amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, zotepine
depot antipsychotics
fluphenthixol decanoate, fluphenazine decanoate, haloperidol decanoate, fluspirilen, perphenazine, enanate, zuclopethixole decanoate
First generation antipsychotics (classical, conventional, typical, neuroleptics, major tranquilizers)
block dopamine, cholinergic (muscarinic), alpha1, h1 receptors, bond tightly to dopaminergic receptors and produce neurological side effects. read more
Second generation antipsychotics (atypical_)Antipode
metabolic side effects, life shortened by one decade, block serotinergic (5HT2A) and dopaminergic receptors, equally effective for reducing positive symptoms (hallucinations, delusions), better at relieving negative symptoms (withdrawal, thinking problems, lack of energy),
Antiparkinson Drugs
one of most common neurological diseases, 40-60, two of three major symptoms: bradykinesia, hypertonia, and tremor. Only slows down progressive disability, does not stop the disease, usually after 10-15 years of treatment, drugs no longer effective.
Dopamine precursor
Levodopa
Inhibitors of dopamine degradation - MAO B inhibitors
Selegeline, rasagiline
Inhibitors of dopamine degradation - COMT inhibitors
entacapone, tolcapone
Dopamine receptor agonists
Bromocriptine, pramipexol, ropinirole
NMDA antagonist
amantadine
Muscarinic receptor antagonists
trihexyphenidyl, benztropinem, diphenhydramine
Parkinson mechanism off action
The GABAergic neurons are the most important efferents from the striatum (see figures); normally they are inhibited by the dopaminergic afferents from the substantia nigra and stimulated by the glutaminergic afferents (from the cerebral cortex and thalamus) and cholinergic striatal interneurons.
The dynamic balance between dopamine and acetylcholine is required for proper initiation and integration of motor patterns; the loss of dopamine neurons in Parkinson’s disease upsets this balance; the goal of the therapy is to return the system to a balanced state by:
increasing local dopamine levels (Levodopa, MAO B inhibitors, COMT inhibitors), stimulating dopamine receptors (dopamine receptor agonists);
inhibiting the effect of cholinergic afferents (anticholinergics);
inhibiting glutaminergic NMDA receptors (Amantadine).
Levadopa
Levodopa (L-3,4-dihydroxyphenylalanine), the most efficient antiparkinsonian drug, is an amino acid naturally occuring in the human body. It is the precursor of dopamine, by decarboxylation.
Mechanism of action
conversion to dopamine occcurs in the CNS and in the peripheral tissues, causing adverse effects.
Pharmacokinetics
Absorption: oral Levodopa is absorbed rapidly from the small bowel; the rate of absorption is influenced by: gastric emptying rate, local pH, meals (delays absorption);
Distribution: Levodopa crosses the BBB, but only 1-2% of the administered Levodopa reaches the brain;
Biotransformation and elimination: the t1/2 is 1-3 hours.
Interactions
Vitamine B6 increases extracerebral Levodopa metabolism;
administering Levodopa with MAO A inhibitors or within two weeks after discontinuation of these drugs increases the risk for HBP crisis;
foods rich in proteins compete with Levodopa for absorption, lowering it.
Indications
Parkinson’s disease;
dopamine-responsive dystonia.
Contraindications
psychosis;
angle-closure glaucoma;
history of melanome or suspicious undiagnosed skin lesions (Levodopa is a precursor of melanin);
first months of pregnancy.
Adverse effects
orthostatic hypotension (avoid antihypertensive drugs);
arrhythmias (low incidence);
nausea, vomiting;
confusion, anxiety, hallucinations, sleeping disturbances (insomnia in young patients, somnolence in older patients);
dyskinesias (choreoathetosis);
mydriasis;
„on/off phenomenon”.
Therapeutic notes
Levodopa is administered usually in association with a peripherally acting inhibitor of dopa-decarboxylase (synthetic catecholamines - Carbidopa, Benserazide) that does not penetrate into the CNS (see figure); this decreases the frequency of some adverse effects, because Levodopa is not converted to dopamine, noradrenaline or adrenaline in the peripheral tissue; furthermore, the quantity of Levodopa that reaches the CNS is increased from 1-2% to 10% and we can reduce the administered dose (to 25%) Levodopa does not stop the disease progression and after 5-10 years of treatment, we will encounter the „on-off phenomena”, which means sudden changes from periods of good symptom control (1 to 2 hours after the administration) to periods where symptoms (rigidity, akinesia) are less controlled; increasing the dose and frequency of administration will improve this situation.
Selegeline
selective (high doses it is lost), irreversible MAO type B inhibitor, slows central degradation of dopamine because MAO B is responsible of dopamine metabolization, should not be administered if patients take Meperidine, tricyclic antidepressants, SSRIs, I: Parkinson (association w Levadopa), depression, senile dementia AE: anxiety, insomnia, hallucinations, nausea, constipation, arrhythmia
adjunsctive treatment to Levadopa, allows reduction of dose and attenuates mild on off phenomenon and end of dose akinesias
Entacapomne
conjunction w levodopa - prevents Catechol-O-methyltrasnferase from metabolizing levadopa in periphery, I: Parkinson disease, same effect as Levadopa, entacapone administered at same time with each dose of Levodopa/carbidopa
Bromocriptine
ergot alkaloid, dopamine agonists directly activate dopamine receptors, inhibits prolactin synthesis, D2 and partial D1 agonist, read more
Trihexyphenidyl
I: early Parkinson’s, drug induced Parkinsonism in patients treated with antipsychotic agents; CI : prostatic hyperplasia, narrow angle glaucoma, obstructive GI disease; AE” sedation, confusion, hallucination, mood change, dyskinesia, dry mouth, urinary retention, blurred vision, increased ICP, arrhythmia, nausea, vomitting, less effective than Levodopa, improve rigidity and tremor but minor effect on bradykinesia, does not respond to anymuscarinic, may respond to another choice
Amantadine
antiviral that also alters dopamine release, has anticholinergic properties and blocks glutamate receptors, biotransformation and elimination, t 1/2 is 2-4 hours, urinary excreted mainly unchanged, I: initial therapy of mild Parkinson’s disease, CI: seizure history, congestive heart failure, AE: dizziness, sedation, confusion, hallucinations, sleep disturbances, nausea, vomiting, dry mouth, urinary retention, constipation, less potent than LEvadopa but improves rigidity, tremor, bradykinesia
First generation antipsychotics pharmacodynamic
neuroleptic: antipsychotic (decreases hallucinations, delirium, autism, agitation), major tranquilizing (reduce nervous tension, anxiety and hyperexcitability), extrapyramidal effects (undesired);
antiemetic;
sedation (Levomepromazine, Chlorpromazine, Thioridazine, Chlorprothixene, Flupenthixol);
central and peripheral depression of the vegetative nervous system (alfa 1 - adrenolytics) with orthostatic hypotension and hypothermia (Chlorpromazine, Haloperidol);
antimuscarinic action, with constipation, hyposalivation, visual disturbances (Thioridazine);
hyperprolactinemia;
hypothermia, due to thermoregulatory center inhibition and peripheral vasodilation;
antihystaminic H1 action (Chlorpromazine)
First generation antipsychotic indications
schizophrenia; maniacal psychosis; agitation; bipolar disorders; senile dementia; Huntington’s chorea; Tourette’s syndrome (Haloperidol); rare as antiemetics (in small doses).
First generation antipsychotics adverse effects
parkinsonism in more than 80% of the patients, with rigidity, bradykinesia, tremor; appear progressive, more often in older patients; the treatment includes Trihexyphenidyl;
decreased attention, memory impairment, sedation;
extrapyramidal reactions (more often after Haloperidol): dystonia in 4 hours after administration (more often in younger patients), akathisia might appear after 4 days and akinesia, after one month of treatment;
neuroleptic malignant syndrome, rare, but lifethreatning, with: confusion, hyperthermia, muscle rigidity and seizures; the treatment includes: stop the antipsychotic administration, Dantrolene (myorelaxant) and Bromocriptine (D2 dopaminergic agonist);
tardive dyskinesia, often irreversible, in more than 25% of the patients, after at least 7 years of administration;
anticholinergic side effects;
gynecomastia, galactorrhea, amenorrhea, because of increased prolactinemia;
hypotension;
corneal deposits (Chlorpromazine);
retinal deposits (Thioridazine).
Second generation Adverse effects
obesity (Olanzapine); diabetes; hyperlipidemia; sedation (Quetiapine); hyperprolactinemia (Risperidone); agranulocytosis (Clozapine, never first line), which might lead to death; increase in QT interval (Ziprasidone).
