Neuropsychopharmacology Flashcards
What is Alzheimer’s disease and its symptoms?
- neurodegenerative condition: the most common condition to lead to dementia
- Cognitive decline: loss of memory, aphasia, ataxia, disorientation
- Behavioural changes: hallucination, depression, sleep fragmentation, aggression
- Functional symptoms: inability to care for self and perform daily tasks
What are the types of AD?
- Sporadic AD: late onset (> 65 years)- APoE4 carriers
- Familial AD: early onset with rapid progression with dominant inheritance- APP, PS1/PS2 mutations)
What are the core pathological hallmarks for AD in the brain?
- Accumulation of extracellular plaques consisting of amyloid beta proteins
- Neurofibrillary tangles consisting of hyperphosphorylated tau
- Loss of cortical neurons
What is the pharmacological goal for the treatment of AD?
- Unable to alter the underlying neurodegenerative process
- Able to provide modest short-term benefits
- Support slowing down of symptom development
What drugs are commonly used to treat cognitive symptoms of AD?
- AchE inhibitors
- Galantamine, Donepezil & Rivastigmine: indicated for mild to moderate AD
- “GALanttly DOwn the RIVer”
What are the side effects of the AchE inhibitors used to treat mild-moderate AD?
- Nausea
- Vomiting
- Vertigo
- Diarrhea
- Tremors
- Bradycardia
- Muscle cramps
What drug is used for moderate to severe AD? Side effects
- NMDA antagonist: Memantine
- often may be used in combination with Donzepil
- Side effects: Nausea, vomiting, headache & confusion
What first-choice drugs may be used for the treatment of behavioural symptoms of AD?
First Choice:
- Agitation: citalopram and risperidone
- Apathy- Methylphenidate
- Depression: a higher dose of citalopram, sertraline
- Insomnia: Zolpidem, Zaleplon
What Second choice drugs may be used for treatment of the treatment of behavioural symptoms of AD?
Second Choice:
- Agitation: Apripiprazole, Olanzapine
- Apathy: Modafinil
- Depression: Aripiprazole, Paroxetine, Duloxetine
- Insomnia: Trazodone, Suvorexant
What is anxiety?
- an unpleasant state of worry, tension or uneasiness from fear of a known or unknown source
- symptoms are sympathetic: tachycardia, sweating, trembling and palpitations
Which drugs are used as anxiolytics?
- Benzodiazepines
- Antidepressants: SSRI, SNRI
- Buspirone
- Pregabalin
What are the MOA of Benzodiazepines?
-indirect GABA A receptor agonists; → ↑ GABA action → ↑ opening frequency of chloride channels → hyperpolarization of the postsynaptic neuronal membrane → ↓ neuronal excitability
- decrease the duration of N3 phase in NREM sleep, thereby reducing the occurrence of sleepwalking and night terrors
What are the pharmacological effects of Benzodiazepines?
- Anticonvulsant
- Muscle relaxant
- Reduce anxiety
- Sedation
- Anterograde amnesia
Can Benzodiazepines be used during pregnancy?
- No
- they can cross the placenta and caused CNS depression of newborn
- not to be given when pregnant or breastfeeding
What are some common benzodiazepines?
- Diazepam
- Lorazepam
- Alprazolam
- Flurazepam
- Clorazepate
- Triazolam
What are the adverse effects of benzodiazepines?
- drowsiness
- confusion
- ataxia
- possible cognitive deficits after short-acting Benzo’s
What happens if Benzodiazepines are increased in dosage for longer periods?
- Develop dependence
- Signs of dependence, cease medication, withdrawal symptoms
- Resume medication, fear of withdrawal symptoms, creates dependence (back to signs of dependence)
What are the symptoms of withdrawal from Benzodiazepines?
- Confusion
- Anxiety
- Agitation
- insomnia, restlessness
- rarely seizures
- shortly acting Benzo’s (e.g. triazolam) create more abrupt and severe withdrawal reactions
Which drug is a benzodiazepine antagonist?
- Flumazenil
- blocks GABA A receptor; reverse effects of Benzo’s
- rapid onset of action but short duration (half-life around 1 hour)
What antidepressants may be used as anxiolytic agents?
SSRI: Paroxetine, Escitalopram
SNRI: Venlafaxine, Duloxetine
- given in combo with Benzo’s during the first week of treatment
What is Buspirone?
- not given for short action or acute anxiety due to slow onset of action
- more for chronic generalised anxiety disorder (GAD)
- requires constant use for at least up 2 weeks for effects to take place
- partial agonist of pre and post-synaptic 5HT 1a receptors
- antagonist of D2 AND 5HT 2a receptors
What is pregabalin?
- treatment of GAD, epilepsy, neuropathic pain etc
- low riks for addiction development not tolerance
- increases expression of glutamic acid decarboxylase to convert glutamate to GABA
What is the pharmacological management of insomnia?
- Hypnotic agents: benz, melatonin receptor agonist, Z drugs etc
- Antidepressant with sedating properties
- Antihistamine drugs
What Z drugs are used for insomnia? MOA? Adverse effects?
- Zolpidem and Zaleplon
- MOA: bind to GABA A receptors to enhance neuronal hyperpolarization
- rapid onset of hypnosis with amnestic effects or day after somnolence
- Side effects: dizziness, dry mouth , headache etc
What Benzo’s are used to treat insomnia? Adverse effects?
- Triazolam, Flurazepam, Oxazepam, Midazolam
- Adverse effects: withdrawal, drowsiness, headache, attention deficiency, tremor, ataxia etc
What orexin receptor anatagonists are used for insomnia? MOA? Adverse effects?
- Suvorexant, lemborexant (both are hypnotics)
- Bind to specific ORX1 and ORX2 receptors in brain to promote sleep
- adverse effects: drowsiness, headache, driving impairment
What melatonin receptor agonists are used for insomnia? MOA? Side effects?
- Ramelteon, Tasimelteon
- selectively activate MT1 and MT2 receptors in suprachiasmatic nucleus in the brain to induce sleep
- adverse effects: withdrawal, headache, fatigue, drowsiness
Which antihistamines are used for insomnia? MOA? Side effects?
- Diphenhydramine, Doxylamine, Hydroxyzine
- mild insomnia, used via OTCP
- bind and block H1 receptors in the brain to promote sedation and sleep
- Side effects: dry mouth, hallucination, fatigue
Which antidepressants are used for insomnia? MOA? Side effects?
- Doxepin, Trazodone, Mirtazapine, Amitriptyline
- Antagonist of 5HT2 and 3, A1 and H1
- Reuptake inhibition of 5HT and NA
- Side effects: prolonged sedation, orthostatic HTN, dry mouth, headache, constipation
What is depression?
- Depression is a state of mood disorder, characterised by persistent feelings of sadness, hopelessness, and loss of interest in activities an individual once enjoyed
- a sense of fatigue, depressed mood, significant weight loss/gain without intention, lack of focus etc
What antidepressants are used for the management of depression?
- SSRI e.g. paroextine or fluoxetine (1st line)
- SNRI e.g. venlafaxine, duloxetine (1st line)
-NDRI e.g. Bupropion (1st line) - NA-specific serotonergic antidepressants (NaSSA) e.g. mirtazapine (1st line)
- TCA e.g. amitriptyline (2nd line)
- MAOI e.g. selegiline (3rd line)
What SSRIs are used for depression management? MOA? Adverse effects?
- Paroxetine, Fluoxetine, sertraline etc.
- Inhibition of 5HT reuptake in the synapse to increase serotonergic transmission
- indicated: major depression, PTSD, eating disorder, anxiety etc
- adverse effects: nausea, diarrhea, headache, insomnia, weight gain (paroxetine), discontinuation syndrome & serotonin syndrome
What is discontinuation and serotonin syndrome?
- discontinuation syndrome: abrupt cessation of SSRI leads to anxiety, headache, malaise and sleep disturbance
- serotonin syndrome: when used with MAOI- hyperthermia, diarrhoea, muscle rigidity. sweating, myoclonus, mood alteration
Which SNRIs are used for depression management MOA? Side effects?
- Venlafaxine, Duloxetine, Desvenlafaxine etc.
- Moderate blockade of SERT and NA transporters to acutely increase serotonergic and adrenergic transmissions
- Indicated in major depression, chronic pain, perimenopausal symptoms
- Side effects: sedation, XS sweating, nausea, headache, diarrhea, insomnia etc
What NDRI is used for depression management? MOA? Side effects?
- Bupropion
- Blockage of dopaminergic and NA reuptake transporters to increase dopaminergic and adrenergic neurotransmission
- Indication: major depression, cigarette smoking cessation
- Side effects: headache, tremors, dry mouth, XS sweating
Which NaSSA is used for depression management? MOA? Side effects?
- Mirtazapine
- antagonism of presynaptic A2 and post-synaptic 5HT2 & 3 receptors in CNS to increase serotonergic neurotransmission
- indicated in major depression, increased anxiety, insomnia
- side effects: dry mouth, headache, increased appetite, weight gain
*when given with MAOI: can induce HTN, hyperthermia and seizures
What atypical antidepressants are used for depression management? MOA? Side effects?
- Nefazodone Trazodone
- weak inhibition of SERT
- antagonist of post-synaptic 5HT 2a receptors, H1 & A1: increase serotonergic neurotransmission
- indicated in major depression, sedation and insomnia
- side effects: headache, dizziness, sedation, nausea, ortho. hypotension
What TCAs are used for depression management? MOA? Side effects?
- amitriptyline, imipramine, Nortryptiline etc.
- increase MAO-mediated neurotransmission by inhibition of NA and 5HT reuptake and blocking NA, 5HT, H and muscarinic receptors
- require 2 weeks or longer to show effects on mood elevation
- adverse effects: blurred vision, dry mouth, urinary retention, constipation, tachycardia etc.
What MAOI are used or the management of depression? MOA? Side effects?
- Selegiline (MAO-B selective), Phenelzine, Tranylcypromine etc.
- irreversibly/reversibly inactivate enzymes MAO-A & MAO-B, therefore NTs can accumulate in presynaptic neurons and synapse
- used in major depression and selegiline used in PD
- Side effects: blurred vision, dry mouth, constipation
*with serotonergic agent may induce serotonin syndrome
What is the treatment protocol for depression in elderly patients?
1st line: SSRI (except fluoxetine) or SNRI, Bupropion, Mirtazapine
2nd line: Fluoxetine, Trazodone
3rd line: TCAs Maprotiline
Common side effects: extrapyramidal symptoms especially with SSRIs
Drug dose should be slowly increased to an effective dose for the individual or until the first occurrence of adverse effects
What is Bipolar disorder (BD) ? Types?
Type 1: 1 or more manic or mixed episodes with altered mood, euphoria, increased energy, rapid speech, reduced need for sleep
- mixed rapid alteration of manic and depressive symptoms
Type 2: 1 or more hypomanic episodes, elevated mood with talkativeness, racing thoughts and reckless behaviour
Cyclothymia: persistent mood swings for at least 2 years with numerous periods of hypomania and depressive states
What mood stabilizers are used for BD?
- Lithium, Carbamazepine, Valproic acid and Lamotrigine
How is lithium used for BD mood stabilization? MOA? Side effects?
- inhibits Monoamine reuptake
- inhibits inositol phosphates
- increase GABAergic and decrease Glutaatergic signalling
- effective in treating patients with mania and hypomania
- side effects: headache, dry mouth, dizziness, fatigue, sedation, polyuria etc
Lithium is a maintenance drug known to lower risk of suicide
*prolonged use can be toxic to kidney, liver and thyroid function
How is carbamazepine used for BD mood stabilization? MOA? Side effects?
- used in outpatients for acute symptoms of mania (200-600mg/day) and hospitalized patients (800-100mg/day)
- adverse effects: fatigue, nausea, skin rash, ataxia etc
- inactivates Na channels
How is valproic acid used for BD mood stabilization? MOA? Side effects?
- inhibits GABA transaminase → ↑ GABA → ↓ neuronal excitability and Inactivates Na+ channels
- adverse effects: GI disturbances, fine tremors, sedation, hair shedding, increased appetite and weight gain
How is lamotrigine used for BD mood stabilization? MOA? Side effects?
- adverse effects: dry mouth, nausea, headache
- acute mania syndrome- start with 2mg for the first 2 weeks up to 50 mg onwards
What atypical anti-psychotics may be used for BD? MOA? Side effects?
- Risperidone, Cariprazine, Olanzapine etc
- D2 receptor antagonism and 5-HT2A receptor antagonism
- Interaction with several other receptors (i.e., D3, D4, α-adrenergic, and H1 receptors)
- Side effects: metabolic effects, prolonged QT, hyperprolactinemia etc.
How is BD managed in the acute phase with mania/hypomania or mixed episodes
- mood stabiliser or atypical anti-psychotics
How is BD managed in the maintenance phase with mania/hypomania or mixed episodes or depressive episodes?
- Quetipine and lithium/valporic acid
- Olanzapine monotherpay
or Lamotrigine and valproic acid/carbamazepine
How is BD managed in the acute phase with depressive episodes?
- Olanzapine/fluoxetine
- Quetipine
What is schizophrenia?
- strong form of psychosis
- delusions, hallucinations (often acoustic) and disorder thinking and behaviour
- Strong genetic component
What is the pharmacology of antipsychotic drugs?
- 1st and 2nd generation
- both inhibit dopaminergic D2 receptors in the brain
- 2nd generation block 5HT 2a receptors (interaction with receptors also e.g. H, A and D3)
What are the pharmacological effects of antipsychotic drugs?
- Antipsychotic effects: reduce hallucinations and delusions (clozapine can reduce impaired attention and cognition and apathy)
-extrapyramidal effects: PD like, dystonia, motor restlessness
-antiemetic effect: due to D2 receptor blockade in chemoreceptors trigger zone in medulla
- anti-Ch effect: blurred vision, dry mouth, confusion, constipation
Others: weight gain, ortho hypotension, increased prolactin release, sexual dysfunction, neuroleptic malignant syndrome
What are the therapeutic indications for antipsychotics?
- Schizophrenia
- nausea and vomiting prevention
- agitated and disruptive behaviour, secondary to other disorders
What are the guideline for treating Schizophrenia?
- First choice: 2nd generation antipsychotics (except Clozapine)
- Second choice: 1st generation antipyschotics
- Third choice: Clozapine
What are 1st and 2nd generation antipsychotics used for schizophrenia management?
1st Generation:
- Chlorpromazine: low D2 potency
- Haloperidol: high D2 potency
- Molindone: high D2 potency
- Fluphenazine: high D2 potency
2nd Generation:
- Clozapine
- Quetiapine
- Olanzapine
- Risperidone
*all 5HT 2a > D2 receptor antagonism - along with 5HT1a, D1, D4, M and A adrenergic interaction receptors
