Mania, Depression, Neurodegenerative disorders Flashcards
BDNF hypothesis
Brain derived Neurotrophic factor Level: 1. Increased: mania 2. Decreased: depression Bipolar disorder: fluctuation of BDNF Rapid cyclers: fluctuations > 4 times/year
BDNF synthesis
GPCR pathway
- Gq subtype receptor stimulates
- PIP2 production
- IP3 production
- BDNF production
PIP2 is formed again from inositol from IP and IP3
• neuroprotection
• neuroplasticity
BDNF synthesis
β catenin pathway
- Frizzle receptors
- 🔼 GSK-3
- 🔽 β-catenin entry into nucleus
- 🔽 release of BDNF
Lithium
mechanism
- Blocks Gq and inositol monophosphatase ➡️ anti-mania
Takes 2 weeks - Blocks GSK-3 enzyme ➡️ 🔼BDNF ➡️ anti-depression
So lithium is a mood stabilizer
Based on BDNF level, lithium chooses to act upon GPCR or β-catenin pathway
Lithium
uses
Related to BDNF 1. Used in prophylaxis in acute mania along with atypical anti-psychotics +/- benzodiazepines 2. DoC for mania prophylaxis 3. DoC BPD prophylaxis 4. Unipolar resistant depression 5. 🔽 suicidal tendency Not related to BDNF: 6. DoC treatment of hypnic headache 7. Leukopenia
Lithium
side effects
- 2 receptors similar to GPCR: TSH and vasopressin rp
➡️ hypothyroidism and diabetes insidious (amiloride DoC, thiazides) - Fine tremors in normal plasma concentration
- 🔼 PTH ➡️ hypercalcemia
- Alopecia, Weight gain, acne
- Worsens psoriasis
- ECG changes:
• T wave flattening
• U waves seen - Lithium in 🤰
Lithium in 🤰
Lithium is teratogenic
1. Floppy infant syndrome:
due to NMJ block
2. Ebstein’s anomaly (cardiac defect):
• right atrium becomes huge (atrialisation of ventricles)
• ventricles becomes small ➡️ right outflow track obstruction
Lithium is CI in 🤰
DoC for mania in pregnancy: atypical antipsychotic
Lithium drug interactions
Loss of Na ➡️ Li retention ➡️ precipitating toxicity
So take adequate Na intake and adequate hydration
1. Diuretics
2. NSAIDs/ACE inhibitors:
🔽 GFR ➡️ 🔼 retention ➡️ toxicity
3. Muscle relaxants: non-depolarising
Lithium blocks transmission at Nm junction ➡️ 🔼 effect of NDMR
So stop Li 24 hr before surgery
Early findings of Li toxicity
- Nausea 🤢, vomiting 🤮
- Ataxia
- Dysarthria
- Course tremor
Later stages of lithium toxicity
- Arrhythmia
- Hypotension
- Coma
Prevention of lithium toxicity
Therapeutic drug monitoring Aim: to maintain plasma concentration 0.6-1 mEq/L in prophylaxis of mania 1-1.5 mEq/L in acute mania If, lithium level >1.5 mEq/L ➡️ toxicity >4 mEq/L, dialysis should be done
Other drugs used in bipolar disorder
V. Valproate:
Acute mania, DoC in rapid cyclers
O. Oxcarbamazepine, carbamazepine ➡️ BPD, acute mania
L. Lamotrigine ➡️ BPD depressive phase
T. Topiramate
A. Atypical > typical antipsychotics preference
GE. Gabapentin
Monoamine hypothesis about depression
In depression, 🔽 in monoamines like serotonin 5HT and NE
They are metabolised by:
1. MAO A everywhere
2. MAO B in 🧠
They undergo reuptake into presynaptic neutron
Monoamines stimulate BDNF production
MAO inhibitors
classification
uses
1. Non-selective: Irreversible (hit & run) Eg., phenelzine, isocarboxazid, tranylcypromine 2. Selective MAO A inhibitors: Reversible Eg., Moclebemide, eprobemide Uses: Atypical depression (mood improved by pleasurable events)
MAO inhibitors
Side effects
- Hepatotoxic
- Cheese 🧀 reaction:
Hypertensive crisis - Serotonin syndrome:
If used with:
meperidine, tramadol,
SSRI, SNRI/TCA,
methyl-phenidate, amphetamine
Treatment of serotonin syndrome
Mild: benzodiazepine
Moderate/severe: Cyproheptadine/ Chlorpromazine
Tricyclic antidepressants
Mechanism
Use
Examples
They inhibit the reuptake of NE and 5HT
Use: metabolic depression
Eg.,
Clomipramine, Desipramine, Imipramine, Amitripyline, Nortriptyline, Doxepin, Amoxepin
TCA
Clomipramine
Desipramine
1. Clomipramine: Maximum 5HT reuptake Best TCA for OCD 2. Desipramine: Maximum NE/Dopamine reuptake inhibitor Treatment of cocaine dependence (Amitryptyline: Maximum Antimuscarinic action, best TCA for neuropathic pain, DoC for post-herpetic neuralgia)
Tricyclic antidepressants
Amitriptyline
Nortryptyline
3. Amitryptyline: Maximum antimuscarinic action Best TCA for neuropathic pain DoC for post-herpetic neuralgia 4. Nortryptyline: Neuropathic pain Smoking 🚬 dependence
Tricyclic antidepressants
Imipramine
Doxepin
Amoxapine
5. Imipramine: Nocturnal enuresis 6. Doxepin: Histamine 🅱️ Used as TCA 7. Amoxapine D2 🅱️ Used in psychotic depression Loxepine an antipsychotic is derived from it
Side effects of
TCA and antipsychotics (both typical and atypical)
Due to other receptor blockage M🅱️: constipation, dry mouth, arrhythmia H1 🅱️: sedation 5HT 🅱️: obesity due to 🔼 appetite α1 🅱️: postural hypotension
Serotonin norepinephrine reuptake receptor SNRI
Use and examples
Use: Melancholic depression Eg., 1. Venlafaxine 2. Desvenlafaxine: Longer acting ➡️ 🔽 withdrawal symptoms 3. Milnacipran: fibromyalgia 4. Duloxetine All can be used in depression
Venlafaxine
SNRI • PTSD, panic disorder • depression associated with bp S/E: • perinatal complication • diastolic hypertension CI: 🤰 Shortest acting SNRI: risk of withdrawal symptoms
Duloxetine
uses
Longest acting SNRI
- Fibromyalgia
- Peripheral neuropathy
- Stress incontinence
- Pre-menstrual syndrome
- Hot flashes
- Bulimia
- Autism
Duloxetine
side effects and contraindications
Longest acting SNRI ➡️ no withdrawal symptoms No side effects due to no other receptor blockers S/E: 1. Due to 🔼 5HT 2. Duloxetine and milnacipran: Anticholinergic S/E: mydriasis CI: Close angled glaucoma
Selective Serotonin Reuptake Inhibitors SSRIs
uses
DoC for: 1. all forms of depression 2. Premenstrual syndrome 3. Neurosis: • OCD, phobia • PTSD, generalised anxiety disorder GAD • anorexia, bulimia 4. It is used in hot flashes (DoC: hormone replacement therapy) 5. Premature ejaculation because delayed ejaculation S/E When used against anxiety, BZD for 1 month
SSRIs
examples
- Fluoxetine and Norfluoxetine
- Fluroxamine: OCD, anxiety disorders
- Paroxetine: 🔽 t1/2
- Citalopram and escitalopram
- Vilazodone:
major depression
Fluoxetine and Norfluoxetine
Fluoxetine: Very long acting SSRI t1/2 = 50 hr No withdrawal syndrome symptoms DoC for most uses of SSRIs Its prodrug is Norfluoxetine (t1/2 = 250 hr)
Paroxetine
Short acting SSRI Short t1/2 No active metabolite ➡️ max withdrawal symptoms Teratogenic Max: • enzyme inhibition • erectile dysfunction H1 🅱️ ➡️ sedation ➡️ used in depression associated with insomnia (night time dosing)
Sertraline
Short t1/2 SSRI
Allosterically 🅱️ transporter by building the SERT receptor at a site other than 5HT binding site
Use:
Major depressive disorder
Premenstrual dysphoric disorder
S/E:
Discontinuation syndrome on abrupt stoppage ➡️:
• initially dizziness, paresthesia,…
• 1-2 days later diminishes sexual function and interest for a few weeks
Citalopram
Escitalopram
Vilazodone
All are SSRIs 1. Citalopram: Used in premenstrual syndrome agitation 2. Escitalopram: derived from citalopram Most specific SSRI 3. Vilazodone: 5HT1A stimulant also Treatment of major depression
SSRI side effects
5HT2:
- 🧠: transient anxiety, insomnia, vivid dreams
- Spinal cord: ED, anorgasmia, delayed ejaculation
- 5HT3: 🤢 and 🤮
- 5HT4: loose stools
- Akathesia
- Bleeding: least with citalopram, sertraline
- QT prolongation: citalopram
- Withdrawal symptoms
SSRI
withdrawal symptoms
Maximum with Paroxetine Not seen in fluoxetine 1. 🤢 2. Paresthesia 3. Flu-like symptoms 4. Insomnia, fatigue
5HT3 blockers
Antidepressants
1. Trazadone:
S/E:
• Sedation: used with SSRI or SNRI to prevent insomnia
• Priapism: used in erectile dysfunction
DoC phenylephrine intracavernosal route at base
2. Nefazadone:
S/E: hepatotoxicNew antidepressant drugs
Mirtazapine (& mianserin) Mechanism: NaSSA drug • 5HT2 🅱️ • α2 🅱️ ➡️ 🔼NE • 5HT1A 🅱️ ➡️ 🔼 5HT • H2 🅱️➡️ sedation • 5HT3 🅱️ ➡️ anti emetic effect DoC hot depression with insomnia (night dose) Nor-Adrenergic Specific Serotonergic Antidepressants
Bupropion
mechanism and side effects
Mechanism: Reuptake 🅱️ 🔼 release of both dopamine and NE S/E: 1. Maximum anxiety: Not used for treatment of anxiety disorders 2. Seizure at high doses
Bupropion
uses
- Atypical depression
- Obesity
- ADHD
- Peripheral neuropathy
- Smoking 🚬 dependence
Esketamine
Recently approved antidepressant Mechanism: NMDA 🅱️ Route: intranasal Use: Major depression
Brexanolone
Recently approved antidepressant
Mechanism: GABA2 modulatory action
Use: postpartum depression
IV continuous infusion for 60 hours
📝: Progesterone metabolite (Allopregnolone) is an anxiolytic antidepressant
Postpartum 🔽 in progesterone ➡️ depression
Levodopa
Prodrug of dopamine
DoC in Parkinson’s disease
Always combined with carbidopa (peripheral decarboxylation 🅱️)
On-off phenomena present, reduced when used along with Entecapone (COMT 🅱️)
CI: psychosis, closed angle glaucoma
Levodopa
side effects
🔼 dopamine Stimulates: 1. D1 receptor: Renal vasodilation ➡️ hypotension 2. D2 receptor: • Limbic system: psychosis • Striatum: dyskinesia • CTZ area: 🤢,🤮 3. Mydriasis 4. Worsens melanoma and periodic ulcer disease Carbidopa affects the S/E differently
On-off phenomena of levodopa
Due to declining dopamine in 🧠 Wearing off phenomena Symptoms correspond to amount of dopamine loss Rx: 1. DoC: COMT inhibitors entecapone 2. MAO B 🅱️ 3. D2 receptor agonist
MAO B inhibitors
Rasagiline
Selegiline
Safinamide
Use:
1. Rx of on-off phenomena
2. DoC for young onset Parkinson’s disease
Inhibit neurodegeneration bcz antioxidant effect
MAO B inhibitors
Side effects
- Psychosis
- Dyskinesia
The above side effects are due to D2 stimulation in 🧠
Seligine metabolises to amphetamine
So its S/E: insomnia, agitation
COMT inhibitors
🔼 bioavailability of levodopa 1. Entecapone: only peripheral COMT 🅱️ 2. Tolcapone: Long acting central and peripheral 🅱️ Use: Entecapone along with levodopa against on-off phenomena
COMT inhibitors
side effects
S/E: 1. Diarrhea 2. 🔼 dopamine: • Entecapone has peripheral S/E - Mydriasis Worsens melanoma and periodic ulcer disease • Tolcapone has both central and peripheral S/E - 🤢,🤮, hypotension, psychosis,… 3. Tolcapone is hepatotoxic
D2 receptor agonist
examples
uses
- Pramiprexole: oral
- Ropinirole: oral
- Rotigotine: transcranial patch
Uses: - Young onset Parkinson’s disease
Longer acting than levodopa ➡️ 🔽 on-off phenomena - Rx off on-off phenomena along with levodopa
- DoC in restless leg syndrome
D2 receptor agonists
side effects
1. D2 agonist: • 🤢, 🤮 • Psychosis • Dyskinesia (< levodopa) 2. Fatigue 3. Somnolence 🥱 4. Peripheral edema 5. Impulse control disorder: gambling 🎰/ sexual
Apomorphine
uses, S/E,…
• D2 agonist Subcutaneous type
• Rescue therapy (last resort) in on-off phenomena
S/E: severe 🤢, 🤮
(Rx: trimetho benzamide, NOT ondansetron bcz 🔼 risk of severe hypotension)
Amantadine
Mechanism: • mainly NMDA 🅱️ • 🔼 dopamine levels Use: 1. Mild Parkinson’s disease 2. Levodopa induced dyskinesia S/E: 1. Ankle edema 2. Livedoreticularis: purple colored pigmentation over skin
Alzheimer’s disease
drugs used
- Cholinergics
- NMDA 🅱️:
Memantine - add on drug - Memory enhancers/Nootropic:
Not FDA approved
• Piracetam, • Piribedil
• Citicoline, • Cerebrolysin
Alzheimer’s disease
Cholinergics used
- Tacrine: hepatotoxic
- Rivastigmine: mild/moderate
- Galantamine: mild/ moderate
- Donepezil: severe (DoC)
Amyotrophic Lateral Sclerosis
drugs used
- Riluzole
- Edaravone: free radical scavenger
- Baclofen: muscle relaxant
Riluzole
Mechanism: 1. 🔽 glutamate release 2. Inhibit NMDA and Kainate 3. Inhibit Na+ channels Use: 🅱️ neurodegeneration to delay Alzheimer’s disease S/E: 1. Hepatotoxic 2. 🤢, diarrhea
Edaravone
Mechanism: Free radical scavenger ➡️ neurodegeneration Use: Rx of ALS, acute stroke S/E: 1. Hypersensitivity (due to sodium bisulphite in solution) 2. Headache 3. Contusion
Fetal alcohol syndrome
(1) intrauterine growth retardation, (2) microcephaly, (3) poor
coordination, (4) underdevelopment of midfacial region (appear-
ing as a flattened face), and (5) minor joint anomalies. More severe
cases may include congenital heart defects and mental retardation.
