Intro to Neuropsychopharmacology Part 1 Flashcards
where are the neuron cell bodies containing norepinephrine located
neurons containing norepinephrine are located in the locus coeruleus and innervate nearly every part of the CNS
Where are neurons containing serotonin located
neurons containing serotonin are located in two groups of raphe nuclei and project to most of the brain
where are neurons containing dopamine located
- dopaminergic (DA) pathways in the brain are responsible for the beneficial and adverse effects of many antipsychotic drugs
- Mesolimbic and Mesocortical pathways
GABA localization in brain
- substantia nigra
- globus pallidus
- hippocampus
- limbic structures: Amgydala
- hypothalamus
- spinal cord
List the Bipolar and related disorders
- bipolar I
- Bipolar II
- cyclothymic disorder
List the depressive disorders
- disruptive mood dysregulation disorder
- major depressive disorder
- persistant depressive disorder
- premenstrual dysphoric disorder
Criteria for MDD
- depressed mood
- diminished interest or pleasure
- weight change
- insomnia/hypersomnia
- fatigue or loss of energy
- feelings of worthlessness
- inappropriate guilt
- agitation/retardation
- difficulty concentrating
- preoccupation with death/suicidal ideation
Describe the monoamine theory of depression and how we think of it today
- the theory results from functionally deficient monoamine (NE and or 5-HT) transmission in the CNS
- based on pharmacological evidence
- known antidepressant drugs (TCAs and MAO inhibitors) facilitate monoaminergic transmission
- drugs such as reserpine that depletes amines to cause depression
- however other pharmacological evidence fails to support eh traditional monoamine hypothesis (takes 2 weeks for drugs to work0)
- simple monoamine hypothesis is no longer tenable as an explanation of depression, BUT pharmacological manipulation of monoamine transmission remains the most successful approach to treating depression
Classical Biogenic amine theory of MDD
depression is due to a deficiency of NE and/or 5HT
Effect of tricyclic antidepressants on noradrenergic transmission
- blockade of neurotransmitter uptake NE and 5-HT
- or acts on receptors and second messengers
Current status of Monoamine Theory –
Depression is due to a biogeneic amine receptor or transmission imbalance. the various drugs that we are discussing today act to change the imbalance and restore a more normal affect
Serotonin Specific Reuptake Inhibitors
- Block SERT so serotonin isn’t taken up and there is more available in the cleft
- antidepressant actions are similar in efficacy and time course to those of CTAs
- acute toxicity is less than that of a TCA and monoamine oxidase inhibitor therefore overdose risk is reduced
- side effects include nausea, insomnia, and sexual dysfunction
- no food reactions, but dangerous “serotonin reaction” (hyperthermia, muscle rigidity, cardiovascular collapse) can occur if given with MAOIs
SSRI WIthdrawal
-dizziness
-ligt headedness
-vertigo/feeling faint
-shock-like sensations
-paresthesia
-anxiety
fatigue
-gait instability
-headache
-insomnia
-irritabilit
-nausea or vomiting
-tremor
-visual disturbances
-symptoms appear within 1-7 days after stopping an SSRI
SSRI approved uses
- Major depression
- OCD
- Panic disorder
- social anxiety disorder
- PTSD
- Generalized anxiety disorder
- PMS now PDD (premenstraul dysphoric disorder)
- hot flashes associated with menopause
Fluoxetine
-Frist SSRI on the market
effects on drug metabolism
-long half life active metabolite (7 days or more)
-now available as sustained release product for PDD
Sertraline
similar in action to fluoxetine with less effects on drug metabolism
- shorter half life
- OCD
- Panic attacks
SNRI drugs
- block both 5-HT and NE reuptake
- side effect profile is more SSRI like than TCA like
- ex: Duloxetine
Duloxetine
- 12-18 hour half life
- also approved for neuropathic pain syndromes, fibromyalgia, back pain and osteoarthritis pain
- use with caution in patients with liver disease
- can produce withdrawal symptoms
Norepinephrine synapse
- Tyr enters the cell and is converted to DOPA which is converted to Dopamine
- dopamine enters the vacuole and is converted to NE
- NE is released from the cell and can act on the alpha receptor or the B receptor
- NE is taken up by NAT into the axon.
SNRI Drugs
- mechanism of action
- inhibition of 5HT and NE reuptake
- treatment of neuropathic pain
- treatment of depressive disorders
TCA
- same stuff as SNRIs
- but also receptor blockade
- muscarinic receptors=blurred vision, xerostomia, urinary retention, constipation, narrow angle glaucoma
- histamine H1 receptors=sedation
- alpha adrenergic receptors=orthostatic hypotension, dissiness, reflex tahcycardia
Atypical antidepressants
- drugs without typical tricycli structure or SSRI or SNRI action. may or may not block catecholamine uptake
- Bupropion
- Mirtazapine
Bupropion
- atypical antidepressant
- also approved for nicotine withdrawal and seasonal affective disorder.
- weakly blocks NE and Dopamine uptake
- no weight gain or sexual dysfunction
Mirtazapine
- blocks presynaptic apha2 receptors in brain
- increase appetite for AIDS patients with AIDS wasting syndrome
Tricyclic antidepressants
- first highly effective drugs for the treatment of depression
- block NE and 5-HT reuptake
- now used secondarily to SSRIs and other newer compounds
- long plasma life
Pharmacological properties of TCAs
- produces elevation of mood in depressed patients after about 2 to 3 weeks
- decreases REM and increases stage 4 sleep
- prominent anticholinergic effects
- sedation
- cardiac abnormalities-due to anticholinergic effects and increased NE concentrations palpitations, tachycardia and arrhythmias
- overdoses-acute toxicity-symptoms include hyperpyrexia, hyper or hypotension, seizures, coma, and cardiac conduction defects
Drug interactions of TCAs
- sympathomimetic drugs-particularly indirect acting agents
- effects absorption and metabolism of other drugs
therapeutic uses of TCAs
- major depressive disorder
- enuresis in childhood-imipramine
- chronic pain: amitriptyline
MAO Inhibitors mechanism of action
- block the oxidative deamination of naturally occuring biogenic amines, such as NE, DA and 5-HT and ingested amines.
- monoamine oxidase is found in neurons and also in the liver, lungs and other organs
- two forms A, and B. antidepressant action is probably due to A
- irreversible inhibitor is Phenelzine
MAO Inhibitors function/use/side effect/how long does ti take to begin working
- antidepressant action takes 2 weeks or more
- produces mood elevation in depressed patients. May progress to hypomania particularly in bipolar disease
- coorrects sleep disorders in depressed patient
- may produce stimulation in normals
- acute toxicity can produce agitation, hallucinations, hyperpyrexia, convulsions and changes in blood pressure
MAO Inhibitors and food
if you eat tyramine then you can overwhelm the MAO inhibitors
Therapeutic uses of MAOI
Major depression-although not drug of first choice
Narcolepsy
MOA Amitriptyline
-nonspecific blockers of NE and 5-HT Reuptake
MOA Fluoxetine and Sertraline
SSRI
MOA Duloxetine
SNRI
MOA Phenelzine
MAOI
MOA Bupropion Mirtazapine
other monoamine mechanisms
Psychosis
- derangement of personality
- loss of contact with reality
- delusions
- hallucinations
Schizophrenia central criteria
two or more symptoms during a one month period, at least one must be a core positive symptom, and there are no subtypes
core positive symptoms of schizophrenia
- delusions
- hallucinations
- disorganized speech
other symptoms of schizophrenia
- grossly disorganized or catatonic behavior
- negative symptoms
- blunted affect
- lack of spontaneity
- poor abstract thinking
- poverty of thought
- social withdrawal
Dopamine hypothesis of schizophrenia
- schizophrenia results from hyperactivity of dopaminergic neurons or their receptors, particularly those with terminals in limbic areas of the brain
- abnormal dopamine neurotransmission in frontal cortical areas may be responsible for negative symptoms
- mechanism of action: All effective antipsychotics interact with dopamine systems
DA Mesolimbic tract
- originates in A10
- arousal, memory, stimulus processing, locomotor activity, motivational behavior
- dopamine hyperactivity results in positive symptoms of schizophrenia
mesocortical tract
- originates in A10
- cognition, communication, social activity,
- altered dopaminergic activity leads to negative symptoms of schizophrenia
Nigrostriatal pathway dopamine
- originates in A9
- dopamine blockade increase EPS
- blockade of 5HT2a decrease EPS, parkinsonism
Tuberoinfundibular tract
-dopamine blockade leads to increase in prolactin release
Dopamine receptors
D1 like family:
- subtypes D1 and D5
- activation is coupled to G alpha “s” receptor. which activates adenylate cyclase which leads to increase in concentration of cAMP
D2 like family:
- includes D2, D3, and D4
- activation is coupled to G alpha “i”, inhibits adenylyl cyclase leading to decrease in concentration of cAMP
Atypical Antipsychotics
- most of the newer drugs such as clozapine, risperidone etc have an additional neurochemical effect in addition to DA receptor blockade
- block 5-HT receptors in the forebrain. often with greater potency than for DA receptors
Actions of the Antipsychotic Drugs
- Decrease in psychotic behavior
- typical drugs differ only in potency
- the negative symptoms of schizophrenia are not well treated by the older typical agents
- Atypical drugs in addition to treating positive symptoms, may be more effective in treating negative symptoms
-sedation
- Extrapyramidal effects
- dystonias
- parkinsonism (early reactions more with typicals)
- akthisia
- tardive dyskinesia (late reaction may be frequent with atypicals
Acute dystonia
- onset is 1-5 days
- spasm of muscle of tongue, face neck, and back
- opisthotonus
Parkinsomism
- onset 5 to 30 days
- bradykinesia, mask-like facies, tremor, rigidity, shuffling gait, drooling, cogwheeling, stooped posture
Akathisia
- 5 to 60 days
- compulsive restless movemnts, symtoms of anxiety, agitation
Later reaction-tardive dyskinesia
- months to years
- oral-facial dyskinesias, choreoathetoid movements
Actions of antipsychotic drugs-neuroendocrine
result of dopamine receptor blcokade
Actions of antipsychotic drugs-anticholinergic
dry mouth, blurred vision, urinary retention
side effects of antipsychotic drugs
- neuroendocrine
- anticholinergic
- orthostatic hypotension
- decreased seizure threshold- particularly clozapine
- weight gain: diabetes related events are more common with atypicals particulary olanzapine, risperidone clozapine and quetiapine
Neuroleptic Malignant Syndrome
- a potentially lethal hypodopaminergic side effect of antipsychotic drugs
- hyperthermia, parkinson-like tremor symptoms (muscular rigidity and tremor) mutism and possible death
- treatment includes cooling and hydration, bromocriptine and dantrolene
Available typical antipsychotic drugs
- Phenothiazines
- Chlorpromazine: low to medium potency, sedative with pronounced anticholinergic actions (aiphatic side chain)
- Fluphenazine (piperazine side chain) - Thioxanthine Derivatives
- Butyrophenone
- Haloperidol: not chemically related to the phenothiazines but is pharmacologically similar to the high potency piperazine derivatives
List the 5 atypical antipsychotic drugs
- clozapine
- olanzapine
- risperidone
- quetiapine
- aripiprazole
advantages of atypical antipsychotics over typical antipsychotics
- lower incidence of extrapyramidal symptoms (better compliance)
- possible lower incidence of tardive dyskinesia
- helps with negative symptoms
- improve positive symptoms in many antipsychotic-resistant or refractory patients
- less impact on cognitive function
Clozapine
- Blocks D4 and 5-HT2 receptors
- little effect on D2
- muscarinic antagonist
- improves positive symptoms even in patients not helped by other drugs
- improves negative symptoms
- lowers seizure thresholds more than other antipsychotics (5-10% incidence)
- can cause fatal agranulocytosis: requires monitoring
Olanzapine
- related to clozapine
- potent 5-HT2 antagonist
- D1 and 2 antagonist some D4
- few extrapyramidal symptoms (5HT>D)
- less seizure incidence than clozapine
- no agranulocytosis
- weight gain and diabetes related adverse events
- reports of olanzapine abuse
risperidone
- combined D2 and 5-HT2 antagonist
- greater reduction in negative symptoms and less extrapyramidal symptoms than traditional antipsychotics
- less seizure activity and less antimuscarinic than clozapine
- paliperidone is the active metabolite of risperidone
- both are available as intramuscular depot preparations
Quetiapine
- structurally related to clozapine
- similar to risperidone and olanzapine in effects on schizophrenia symptoms and side effects
- shorter half life
- approved for augmentation in depression
Aripiprazole
- a paritial D2 agonist and 5 HT 2 antagonist also approved as an adjunct in depression (augmentation) and for bipolar I disorder
- long acting forms available (one month or more)
- brexpiprazole is a similar drug partial agonsit at D2 and 5 HT1 A receptors; 5 HT2 antagonist
uses of antipsychotic drugs
- acute psychotic episodes
- chronic schizophrenia
- manic episodes, bipolar disorder: apripiprazole, olanapine, quetiapine, ziprasidone, risperidone, asenapine, ,lurasidone, cariprazine
- schizoaffective disorder-paliperidone
- augmentation in depression-aripiprazole, olanzapine, quetiapine
- tourette’s syndorme-haloperidol, aripiprazole and pimozide
- antiemesis
