Exam 2 ( Antipsychotics) Flashcards
A9 nigrostriatal DA neurons
originate in substantia nigra pars compacta dendrites extend into pars reticulata.
axons innervate corpus striatum
DA release in striatum essential for normal extrapyramidal motor function
A10 mesolimbic DA neurons
originate in midbrain ventral tegmental area (VTA)
axons innervate limbic portions of striatum (nucleus accumbens) and cortex
DA release from these neurons important for normal affect, orderly thinking, “drive” states, pleasure and reward
D1 vs D2 receptor
D1 = short 3rd intracellular loop, long carboxyl tail
D2 = long 3rd intracellular loop, short carboxyl tail
Epidemiology of schizophrenia
1st presents between ages 16 - 20 yr old
1-3% pop overall
genetic predisposition, genetic component probably affected by multiple genes
both neurochemical (nature) and environmental factors (nurture) likely to contribute to development of disease
Organic psychoses
cause is known, due to impaired cerebral tissue function; cognitive and intellectual decline
can be secondary to drug abuse, metabolic or toxic insult, trauma, infections, or structural disease of the nervous system
Dopamine theory of schizophrenia
cause is postulated to be excessive DA transmission, especially within the limbic striatum and limbic cortical areas innervated by A10 DA neurons (mesolimbic and mesocortical DA pathways)
Idiopathic psychoses
cause not known, may have a genetic component.
schizophrenia denotes a form of idiopathic psychosis
Positive symptoms
hallucinations, usually auditory (voices talking to patient) delusions (false beliefs), grandiosity, paranoia
disorganized thinking, speech; tangential thinking, “word salad” bizarre behavior, catatonia
Negative symptoms
affective (emotional) flattening withdrawal, depersonalization, asociality poverty of speech and thought anhedonia, loss of motivation
Cognitive symptoms
impaired attention, deficits in learning and memory
D2 like family
D2, D3, D4
D1 like family
D1 and D5
D1 receptors
lead to stimulation of adenylate cyclase and increase cAMP
Affinity for phenothiazines > butyrophenones
D2 receptor
not associated with stimulation of adenylate cyclase and may inhibit it.
Affinity for butyrophenones > phenothiazines
Typical
blockade at D2 receptors > 5-HT2A receptors; antipsychotic potency correlates strongly with D2 receptor blockade
Phenothiazine derivatives
Thioxanthene derivatives
Butyrophenone derivatives
Miscellaneous “typical” antipsychotic drugs
Atypical
blockade at 5-HT2A receptors > D2 receptors
Loxapine Clozapine Risperidone Quetiapine Olanzapine Ziprasidone Aripiprazole
Manifestation:
Loss of accommodation, dry mouth, difficulty urinating,
constipation
Mechanism:
Muscarinic cholinoreceptor blockade
ANS
Manifestation:
Parkinson’s syndrome, akathisia, dystonias
Mechanism:
Dopamine-receptor blockade
CNS
Manifestation:
Tardive dyskinesia
Mechanism:
Supersensitivity of dopamine receptors
CNS
Manifestation:
Orthostatic hypotension, impotence, failure to ejaculate
Mechanism:
α-Adrenoceptor blockade
ANS
Manifestation:
Toxic-confusional state
Mechanism:
Muscarinic blockade
CNS
Manifestation:
Amenorrhea-galactorrhea, infertility, impotence
Mechanism:
Dopamine-receptor blockade resilient in hyperprolactinemia
Endocrine System
Manifestation:
Weight Gain
Mechanism:
Possibly combined H1 and 5-HT2 blockade
Clozapine (dibenzodiazepine)
1st effective antipsychotic without extrapyramidal side-effects
may suppress tardive dyskinesia due to other agents
reduces positive and negative symptoms
blocks many receptors
most serious side effect: agranulocytosis
other side effects:
hypercholesterolemia, weight gain, diabetes
Risperidone (Benzisoxazole)
D2 and 5-HT2 receptor blocking properties
no blood toxicity of clozapine
lower incidence of extrapyramidal side effects and tar dive dyskinesia than classical antipsychotics
not as effective in drug resistance cases as clozapine
Olanzapine (Thienobenzodiazepine)
effective treating both positive and negative symptoms
low incidence of extrapyramidal effects
main side-effects = weight gain and associated with metabolic disorders…diabetes, hypertension, hyperlipidemia
Quetiapine (Dibenzothiazepine)
one of most widely used
D2> 5-HT2a
low incidence of extrapyramidal side effects
lesser chance of weight gain
effective positive and negative symptoms
Ziprasidone (dihydroindolone)
injectable form for acute treatment of very agitated or violent patients
may cause QTc segment prolongation and serious cardiac arrhythmias (ventricular tachycardia and sudden death)
Aripiprazole (Dihydrocarbostyril)
most widely prescribed
1st antipsychotic with partial agonist activity at D2
termed DA stabilizer due to blocking D2 receptor but also stimulating D2
considered 3rd gen antipsychotic
lower weight gain, little effect on prolactin levels, no extrapyramidal side effects
Asenapine
used for schizophrenia and acute manic episode associated with bipolar disorder
sublingual admin
limited weight gain, no hyperlipidemia, no change in prolactin
minor extrapyramidal effects
Lurasidone
schizophrenia, depressive episodes associated with bipolar
minimal weight gain
extrapyramidal effects may occur; especially akathisia
CNS effects and side effects of antipsychotic
sedation
mild anti anxiety
neuroleptic syndrome
Neuroleptic syndrome
common with typical antipsychotics
cause loss of pleasure and reward
Endocrine effects and side effects
increased prolactin secretion
increased female, decreased male libido
increase appetite
increased prolactin secretion
“typical” cause prominent prolactin elevating effects
“atypical” have minimal effects on prolactin release
Antiemetic effect
due to blockade of DA receptors at chemoreceptor trigger zone (CRTZ) in medulla
Other clinical uses of DA receptor antagonists
Treating Huntington’s Disease
Treatment of Gilles de la Tourette’s syndrome
As an antiemetic
In anesthesiology to produce neurolepanalgesia
treatment of intractable hiccoughs
Parkinson syndrome (EPS)
onset 5-30 days, bradykinesia, rigidity, tremor.
Treatable with anticholinergic drugs and amantidine
Acute dystonic reactions (EPS)
onset 1-5 days, spasm of tongue, neck, face, back muscles.
Treatable with anticholinergic drugs
Akathisia
Onset 5-6 days, motor restlessness and desire to be in constant motion
Treatable by reducing antipsychotic drug dose.
Neuroleptic malignant syndorme
Onset weeks, can persist for days after stopping, characterized by fever, unstable blood pressure, stupor, can be fatal
Treat by stop antipsychotic immediately
Tardive dyskinesia
late occurring movement disorder (Months to years)
characterized by repeated involuntary movements of mouth, tongue, lips, jaws
No effective therapy, crucial to use lowest effective dose to prevent development
Mechanism: chronic blockade of Da receptors causes increase in D2 like receptors in striatum….supersensitivity?
Skin Reactions
Especially with phenothiazines
hypersensitivity reactions - urticaria, itching
Contact dermatitis - those who handle drug
photosensitivity - resembles sunburn, use sun screen
Abnormal skin pigmentation - grey/blue patches
Problem with Dopamine Theory
- no evidence for increased DA cell activity or DA release, no increase in DA levels or metabolites in brain or CSF of schizophrenics
- Poor temporal correlation between DA receptor block and antipsychotic effect
- correlation may not imply causation: DA receptor blocking property of anti-psychotic drugs does not necessarily indicate a causative role of DA in psychosis
- other transmitter systems and brain areas are also likely involved in etiology of schizophrenia
Psychosis
Characterized by impaired behavior with inability to think coherently and comprehend reality
Support for DA theory
Drugs that block DA receptors reduce psychotic symptoms
Drugs that increase synaptic DA levels can cause psychotic symptoms
PET scans show increase D2 like receptors in caudate nucleus of untreated schizophrenics, suggest D@ up regulator is feature of disease
Strong correlation between D2-like receptor blockade and antipsychotic drug potency
