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Pharmacology MBBS > Mania, Depression, Neurodegenerative disorders > Flashcards

Mania, Depression, Neurodegenerative disorders Flashcards

1
Q

BDNF hypothesis

A 
Brain derived Neurotrophic factor
Level:
1. Increased: mania
2. Decreased: depression
Bipolar disorder: fluctuation of BDNF
Rapid cyclers: fluctuations > 4 times/year
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2
Q

BDNF synthesis

GPCR pathway

A
  1. Gq subtype receptor stimulates
  2. PIP2 production
  3. IP3 production
  4. BDNF production
    PIP2 is formed again from inositol from IP and IP3
    • neuroprotection
    • neuroplasticity
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3
Q

BDNF synthesis

β catenin pathway

A
  1. Frizzle receptors
  2. 🔼 GSK-3
  3. 🔽 β-catenin entry into nucleus
  4. 🔽 release of BDNF
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4
Q

Lithium

mechanism

A
  1. Blocks Gq and inositol monophosphatase ➡️ anti-mania
    Takes 2 weeks
  2. 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
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5
Q

Lithium

uses

A 
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
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6
Q

Lithium

side effects

A
  1. 2 receptors similar to GPCR: TSH and vasopressin rp
    ➡️ hypothyroidism and diabetes insidious (amiloride DoC, thiazides)
  2. Fine tremors in normal plasma concentration
  3. 🔼 PTH ➡️ hypercalcemia
  4. Alopecia, Weight gain, acne
  5. Worsens psoriasis
  6. ECG changes:
    • T wave flattening
    • U waves seen
  7. Lithium in 🤰
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7
Q

Lithium in 🤰

A

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

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8
Q

Lithium drug interactions

A

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

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9
Q

Early findings of Li toxicity

A
  1. Nausea 🤢, vomiting 🤮
  2. Ataxia
  3. Dysarthria
  4. Course tremor
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10
Q

Later stages of lithium toxicity

A
  1. Arrhythmia
  2. Hypotension
  3. Coma
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11
Q

Prevention of lithium toxicity

A 
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
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12
Q

Other drugs used in bipolar disorder

A

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

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13
Q

Monoamine hypothesis about depression

A

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

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14
Q

MAO inhibitors
classification
uses

A 
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)
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15
Q

MAO inhibitors

Side effects

A
  1. Hepatotoxic
  2. Cheese 🧀 reaction:
    Hypertensive crisis
  3. Serotonin syndrome:
    If used with:
    meperidine, tramadol,
    SSRI, SNRI/TCA,
    methyl-phenidate, amphetamine
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16
Q

Treatment of serotonin syndrome

A

Mild: benzodiazepine

Moderate/severe: Cyproheptadine/ Chlorpromazine

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17
Q

Tricyclic antidepressants
Mechanism
Use
Examples

A

They inhibit the reuptake of NE and 5HT
Use: metabolic depression
Eg.,
Clomipramine, Desipramine, Imipramine, Amitripyline, Nortriptyline, Doxepin, Amoxepin

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18
Q

TCA
Clomipramine
Desipramine

A 
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)
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19
Q

Tricyclic antidepressants
Amitriptyline
Nortryptyline

A 
3. Amitryptyline:
 Maximum antimuscarinic action
 Best TCA for neuropathic pain
 DoC for post-herpetic neuralgia
4. Nortryptyline:
 Neuropathic pain
 Smoking 🚬 dependence
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20
Q

Tricyclic antidepressants
Imipramine
Doxepin
Amoxapine

A 
5. Imipramine:
 Nocturnal enuresis
6. Doxepin:
 Histamine 🅱️
 Used as TCA
7. Amoxapine
 D2 🅱️
 Used in psychotic depression
 Loxepine an antipsychotic is derived from it
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21
Q

Side effects of

TCA and antipsychotics (both typical and atypical)

A 
Due to other receptor blockage 
M🅱️: constipation, dry mouth, arrhythmia
H1 🅱️: sedation
5HT 🅱️: obesity due to 🔼 appetite
α1 🅱️: postural hypotension
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22
Q

Serotonin norepinephrine reuptake receptor SNRI

Use and examples

A 
Use:
 Melancholic depression
Eg.,
1. Venlafaxine
2. Desvenlafaxine: 
 Longer acting ➡️ 🔽 withdrawal symptoms
3. Milnacipran: fibromyalgia 
4. Duloxetine
All can be used in depression
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23
Q

Venlafaxine

A 
SNRI
• PTSD, panic disorder
• depression associated with bp
S/E: 
• perinatal complication
• diastolic hypertension
CI: 🤰
Shortest acting SNRI:
 risk of withdrawal symptoms
24
Q

Duloxetine

uses

A

Longest acting SNRI

  1. Fibromyalgia
  2. Peripheral neuropathy
  3. Stress incontinence
  4. Pre-menstrual syndrome
  5. Hot flashes
  6. Bulimia
  7. Autism
25
Q

Duloxetine

side effects and contraindications

A 
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
26
Q

Selective Serotonin Reuptake Inhibitors SSRIs

uses

A 
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
27
Q

SSRIs

examples

A
  1. Fluoxetine and Norfluoxetine
  2. Fluroxamine: OCD, anxiety disorders
  3. Paroxetine: 🔽 t1/2
  4. Citalopram and escitalopram
  5. Vilazodone:
    major depression
28
Q

Fluoxetine and Norfluoxetine

A 
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)
29
Q

Paroxetine

A 
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)
30
Q

Sertraline

A

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

31
Q

Citalopram
Escitalopram
Vilazodone

A 
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
32
Q

SSRI side effects

A

5HT2:

  1. 🧠: transient anxiety, insomnia, vivid dreams
  2. Spinal cord: ED, anorgasmia, delayed ejaculation
  3. 5HT3: 🤢 and 🤮
  4. 5HT4: loose stools
  5. Akathesia
  6. Bleeding: least with citalopram, sertraline
  7. QT prolongation: citalopram
  8. Withdrawal symptoms
33
Q

SSRI

withdrawal symptoms

A 
Maximum with Paroxetine 
Not seen in fluoxetine
1. 🤢
2. Paresthesia
3. Flu-like symptoms
4. Insomnia, fatigue
34
Q

5HT3 blockers

A 
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: hepatotoxic
35
Q

New antidepressant drugs

A 
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
36
Q

Bupropion

mechanism and side effects

A 
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
37
Q

Bupropion

uses

A
  1. Atypical depression
  2. Obesity
  3. ADHD
  4. Peripheral neuropathy
  5. Smoking 🚬 dependence
38
Q

Esketamine

A 
Recently approved antidepressant
Mechanism:
 NMDA 🅱️
Route: intranasal 
Use:
 Major depression
39
Q

Brexanolone

A

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

40
Q

Levodopa

A

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

41
Q

Levodopa

side effects

A 
🔼 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
42
Q

On-off phenomena of levodopa

A 
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
43
Q

MAO B inhibitors

A

Rasagiline
Selegiline
Safinamide
Use:
1. Rx of on-off phenomena
2. DoC for young onset Parkinson’s disease
Inhibit neurodegeneration bcz antioxidant effect

44
Q

MAO B inhibitors

Side effects

A
  1. Psychosis
  2. Dyskinesia
    The above side effects are due to D2 stimulation in 🧠
    Seligine metabolises to amphetamine
    So its S/E: insomnia, agitation
45
Q

COMT inhibitors

A 
🔼 bioavailability of levodopa
1. Entecapone: only peripheral COMT 🅱️
2. Tolcapone:
 Long acting central and peripheral 🅱️
Use: Entecapone along with levodopa against on-off phenomena
46
Q

COMT inhibitors

side effects

A 
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
47
Q

D2 receptor agonist
examples
uses

A
  1. Pramiprexole: oral
  2. Ropinirole: oral
  3. Rotigotine: transcranial patch
    Uses:
  4. Young onset Parkinson’s disease
    Longer acting than levodopa ➡️ 🔽 on-off phenomena
  5. Rx off on-off phenomena along with levodopa
  6. DoC in restless leg syndrome
48
Q

D2 receptor agonists

side effects

A 
1. D2 agonist:
• 🤢, 🤮
• Psychosis
• Dyskinesia (< levodopa)
2. Fatigue
3. Somnolence 🥱 
4. Peripheral edema
5. Impulse control disorder: gambling 🎰/ sexual
49
Q

Apomorphine

uses, S/E,…

A

• 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)

50
Q

Amantadine

A 
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
51
Q

Alzheimer’s disease

drugs used

A
  1. Cholinergics
  2. NMDA 🅱️:
    Memantine - add on drug
  3. Memory enhancers/Nootropic:
    Not FDA approved
    • Piracetam, • Piribedil
    • Citicoline, • Cerebrolysin
52
Q

Alzheimer’s disease

Cholinergics used

A
  1. Tacrine: hepatotoxic
  2. Rivastigmine: mild/moderate
  3. Galantamine: mild/ moderate
  4. Donepezil: severe (DoC)
53
Q

Amyotrophic Lateral Sclerosis

drugs used

A
  1. Riluzole
  2. Edaravone: free radical scavenger
  3. Baclofen: muscle relaxant
54
Q

Riluzole

A 
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
55
Q

Edaravone

A 
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
56
Q

Fetal alcohol syndrome

A

(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.

Pharmacology MBBS (19 decks)

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