Hyperfunctioning (dopamine) in the mesolimbic pathway causes:
Hyperfunctioning (dopamine) in the mesocortical pathway causes:
Hyperfunctioning (dopamine) in the tuberoinfundibular pathway causes:
Parkinsonism is hypodopamine in what brain area?
What is the main theory behind high or low dopamine functioning?
If you inherit an abnormal gene (val substitution), then you have aggressive COMT (catechol-O-methyltransferase) and break down too much dopamine and develop symptoms
What is Levodopa?
- Precursor to DA
- Crosses BBB (and is converted to DA; improves nigrostriatal functioning)
- 1st line tx for Parkinson's unless pt young (want to delay as long as possible)
What drug is often used in combination with Levodopa, and why?
- b/c it prevents peripheral dopamine activity and lowers fatigue, dizziness, and nausea SEs
Give the side effects: Levodopa
- If too much dopamine --> psychosis, mania, dyskinesias (abnormal, involuntary movements)
- Hypotension, syncope, nausea, anxiety/agitation, fatigue
People with the T-allele for folate metabolism have less of what chemical that may contribute to depression?
- less dopamine
- T allele = faulty methylhydrofolate reductase enzyme (MTHFR) --> less DA
- "you don't want to have T (allele for MTHFR) with Val (substitution --> abn, aggressive COMT)"
What is the mechanism of action of Norepinephrine Dopamine Reuptake Inhibitors (NDRIs)?
- NDRIs block the dopamine transporter (aka dopamine reuptake inhibition)
- Leaves more DA in the synapse to increase to increase DA in the mesocortical pathway
- Can lower depression symptoms
- Buproprion is an example
Give the side effects of NDRIs.
Insomnia, jitteriness, hypervigilance, seizures, anxiety, dry mouth, palpitations, mild increases in BP, sweating think sympathetic stimulation (NE)
Give the class: dextroamphetamine lisdexamfetamine mixed amphetamine salts
Give the indication: dextroamphetamine lisdexamfetamine mixed amphetamine salts
What is the mechanism of action of the stimulant class?
Stimulants block the DAT like buproprion, and may even reverse it, and increase vesicular monoamine transport (VMAT2) , ejecting more DA from nerve terminals
What is the mechanism of action of methylphenidate?
block DA transporter less effective than the stimulants
Give the class: Modafinil; Armodafinil
Stimulants Different MOA than amphetamine
Give the indications: Modafinil; Armodafinil
Narcolepsy, Apnea, Shiftwork disorder NOT ADHD approved Less severe side effects
What are unique side effects of Modafinil; Armodafinil?
May lower birth control effectiveness bc may increase p450-3A4 enzymes
Give the mechanism of action: Modafinil, Armodafinil
Increases histamine activity in the tuberomammilary nucleus; may block DAT May increase orexin activity
What are side effects of stimulants?
Psychosis at high doses Addiction Weight loss DA and NE side effects at any dose
Monoamine Oxidase Enzymes A and B are responsible for breaking down:
Dopamine and other monoamines like NE and serotonin
Give the mechanism of action: MAOi
Block the breakdown of DA
Give the indication for Selegiline.
Parkinson's Depression MAO-B inhibitor at low dose, full MAO-A and B at higher dose (patch)
Give the indication for Rasagiline.
Parkinson's MAO-B inhibitor
Give the mechanism of action: Tranylcypromine (Parnate); Isocarboxazid (Marplan); Phenelzine (Nardil)
Irreversibly inhibit both MAO-A and MAO-B
Give the side effects: MAOi
Hypotension, dizziness, insomnia, weight gain Hypertensive crisis (with tyramine-rich foods); serotonin syndrome (MAOI + SSRI)
What things in combination with MAOi use can precipitate a hypertensive crisis?
Tyramine-rich foods such as cheeses, fava beans or fermented things; Nasal decongestants NE-based antidepressants
Give two examples of COMT inhibitors.
Entacapone (nausea and fatigue) Tolcapone (not used anymore bc of liver failure) Catechol-O-methyltransferanse inhibitors COMT is an enzyme that degrades monoamines. Inhibit this enzyme to increase DA or NE Used to help treat Parkinson's
D2 receptor agonism increases DA activity mainly in the nigrastriatal pathway. In this way, it is therapeutically indicated for what diagnosed?
Parkinson's Restless Leg Syndrome
Give the class: Bromocriptine
Ergot D2 receptor agonist
Give the class: Pramipexole (Mirapex); Ropinerole
Selective D2 receptor agonist
Give the class: Apomorphine
D2 receptor agonist
Give the class: Aripiprazole (Abilify)
D2 & D3 receptor (partial) agonist
Give the class: Amantadine
Bromocriptine, Pramipexole, Ropinerole and Apomorphine are all used to treat mild Parkinson's and RLS. What other diagnosis is indicated specifically for Bromocriptine?
Give the indication: Aripiprazole
Schizophrenia and depression Antipsychotic
Give the indication: Amantadine
Mild Parkinson's (2nd-line); influenza
Give the side effects: Amantadine
Nausea, dizziness, psychosis, insomnia, seizures
Give the side effects: Bromocriptine, Pramipexole, Ropinerole and Apomorphine
Mania, nausea, dizziness, fatigue
The goal in therapy for narcolepsy, RLS and ADHD is to ____ DA activity
increase same with Parkinson's and Depression
Give the class: Reserpine Tetrabenazine
Give the indication: Reserpine
HTN can be used for schizophrenia
Give the indication: Tetrabenazine
Give the mechanism of action: Reserpine Tetrabenazine
Blocks VMAT (no release of monoamines into synapses) Synapse depleters
Give the notable side effect: Reserpine Tetrabenazine
What is the mechanism of action of the first generation antipsychotic (FGA)?
D2 receptor antagonism Non-selective, occurs in all DA pathways can lead to induced Parkinsonism
Give the side effects of FGAs such as: Chlorpromazine (Thorazine); Thioridazine
EPS - extrapyramidal syndromes - when DA is too low akathisia (restlessness) from D2 blockade, dystonia (muscle spasm), Parkinsonism, NMS (neuroleptic malignant syndrome)
What is Neuroleptic Malignant Syndrome (NMS)?
Hyperthermia Muscle rigidity Vital sign instability Rhabdomyolisis (kidney failure) SE of FGAs such as Chlopromazine, Thioridazine, Fluphenazine, Thioxixine, Haloperidol
Give the side effects: Fluphenazine, Thioxixine, Haloperidol
Why were anticholinergics such as Benztropine, Trihexyphenadyl and diphenhydramine used for Parkinson's disease?
Inhibiting cholinergic tone in the basal ganglia improves dopaminergic flow/tone in the nigrostriatal pathway, thus lowering Parkinson's symptoms
Give the side effects: Benztropine, Trihexyphenadyl and diphenhydramine (anticholinergics)
Dry mouth Blurred vision Tachycardia Constipation Confusion Delirium Hallicinations
Chronic D2 receptor antagonism may cause what permanent disorder?
Tardive Dyskinesia (longer effects than EPS side effect)
Name the high affinity FGAs.
Haloperidol Fluphenazine Thiothixine
Name the low potency FGAs.
Serotonin 2a (5HT2a) antagonism has more or less risks for EPS than FGAs?
Less ie risperidone
How are SGAs different from FGAs?
SGAs have Greater blocking of DA in the mesolimbic system, while allowing better transmission in all other DA pathways
SGAs that agonize 5HT1a help to treat:
SGAs that antagonize 5HT2c, 3, 7 help to treat:
T/F: Some SGAs have SRI and NRI properties that treat depression.
D2 blockage lowers aggression in what diagnosis?
D2 blockade lowers mania in what diagnosis?
Give the class: Risperidone
Give the class: Paliperidone
Give the class: Ziprasidone
Give the class: Iloperidone
Give the class: Lurasidone
Give the mechanism of action: Risperidone; Ziprazidone; Paliperidone; Iloperidone; Lurasidone
SGA D2 receptor antagonist; but various other receptor agonism/antagonism
Give the indication: Risperidone; Ziprazidone; Paliperidone; Iloperidone; Lurasidone
Psychosis, mania, aggression
Give the side effects: Risperidone; Ziprazidone; Paliperidone; Iloperidone; Lurasidone
Suicide risk in ages
Give the class: Olanzapine (Zyprexa); Quetiapine (Seroquel); Asenapine (Saphris)
Give the mechanism of action: Olanzapine (Zyprexa); Quetiapine (Seroquel); Asenapine (Saphris)
D2 receptor antagonist, 5HT2a receptor antagonist
Give the indication: Olanzapine (Zyprexa); Quetiapine (Seroquel); Asenapine (Saphris)
Psychosis, mania, aggression
Give the class: Clozapine
Give the mechanism of action: Clozapine
D2 (& D1, D4) receptor antagonist; 5HT2a receptor antagonist
Give the indication: Clozapine
Give the side effects: Clozapine
Side effects similar to other "pines", but also agranulocytosis (inhibits bone marrow) (NMDA receptor antagonism?) Suicide risk in ages
Give the side effects: Olanzapine (Zyprexa); Quetiapine (Seroquel); Asenapine (Saphris)
Suicide risk in ages
What receptor antagonism in SGAs is responsible for weight gain?
Of the SGAs, which has the highest risk of developing metabolic syndrome?
Clozapine Developing diabetes is guaranteed
Expected side effects of a patient on high potency first generation antipsychotics:
EPS symptoms because DA is too low: akathisia (state of agitation, distress, and restlessness) dystonia (muscle spasm) parkansonianism
What are parkinsonian symptoms?
Decrease in facial expressions. Difficulty starting and controlling movement. Loss or weakness of movement (paralysis) Soft voice. Stiffness of the trunk, arms, or legs. Tremor.
Expected side effects of a patient on low potency first generation antipsychotics:
Less EPS symptoms (still more than SGAs) but also many other symptoms because interferes with other pathways Dry mouth blurred vision constipation Fatigue and increased appetite/weight Orthostasis (faint/dizzy)
If question asks what antipsychotics cause agranular anemia and Clozapine is not listed as answer choice which antipsychotic should you choose?
Chose the 2nd generation antipsychotic - always more likely to inhibit bone marrow than 1st gens
What are the D2 agonists?
Bromocriptine Pramipexole Ropinerole Apomorphine injections
What is a D3 receptor agonist?
What are the MAOi drugs used for depression?
Isocarboxazid, phenelzine, tranylcypromine, selegiline
What is Rasagiline? What is it used for?
MAO-B inhibitor for Parkinson’s
Which drugs inhibit COMT?
Entacapone- may cause nausea, fatigue side effects Tolcapone- liver failure too
COMT inhibiting drugs should be used to treat parkinson's disease or schizophrenia?
Which class of drugs can cause Hyperthermia Muscle rigidity Vital sign instability Rhabdomyolysis
high potency first generation antipsychotics (D2 antagonists): Haloperidol Fluphenazine Thiothixine
In addition to blocking D2 receptors, 2nd generation antipsychotics also block Serotonin 2a (5HT2a) receptors. The benefit is:
lessens risk of EPS symptoms (dystonia, irritability, restlessness, agitation, parkinsonianism)
Which 2nd generation antipsychotic is actually a partial agonist at D2 and D3 receptors?
Major side effect relating to 5HT2c antagonism?
Which drugs are synapse depleting drugs? What are they used for?
Reserpine - treats hypertension, it blocks VMAT so that vesicles with monoamines cannot be released into synapses Tetrabenazine - treats Huntington’s Chorea by inhibtiting VMAT
What drug would be used to control drooling in a Parkinson disease patient?
Benztropine - anticholinergic