Central Nervous System CNS Pharmac😍

Central Nervous System

NEURODEGENERATIVE DISEASES

• Occur due to age-related degeneration of neurons.

ALS

• Riluzole

• Edavarone

• Mnemonic:
• ALS padikkan poyapo edavazhiyil (edavarone) turi (riluzole))

ALZHEIMER’S DISEASE

• Cause: Age-related degeneration of:
• Cholinergic neurons in basal nucleus of Meynert.

• Underlying cause of neuronal degeneration: 
• Aβ-amyloid deposition.

• Characteristic feature: 
• Loss of memory (Dementia).

DRUGS USED

1. AChE inhibitors:
• Preferred:
• Lipid-soluble drugs → cross BBB.
• Drugs:
• Donepezil
• Rivastigmine:
• DOC for Alzheimer’s dementia.
• Gallantamine
• Mnemonic: DRG (DR Gobind)

2. NMDA receptor antagonist:
• Memantine
• Mnemonic:
• Memantine to improve Nammada memory
• Donna is galavanting near the river for a meme → Adukkaan (Aducanumab)

3. Monoclonal Antibody against Aβ-amyloid:



• Aducanumab:
• Targets the underlying cause (Aβ-amyloid).
• Mab against ADUC
• → Alzheimers ds → targetting underlying cause
• Adukkan (Aducanumab) Marannu Poi

PARKINSONISM

• Normal state: 
• Balance b/w Dopaminergic (DA) and cholinergic (ACh) neurons.

• Pathology: 
• ↓↓ dopaminergic and ↑↑ cholinergic activity
• Relative cholinergic excess
• In basal ganglia /substantia nigra of brain.
• Mnemonic: Parkil poyapo dopamine kittunilla

Two ways to treat Parkinsonism

• A. Increase dopamine

• B. Decrease Ach

A. DOPAMINERGIC DRUGS

• Elderly → Syndopa

• Young → Dopamine Agonists
• S/E: Pathological gambiling

1. Levo-dopa:

• If given alone:
• Peripheral DOPA decarboxylase converts L-dopa to Dopamine.
• Less efficacious due to less entry in brain.
• Peripheral side effects:
• D1 → Hypotension
• β1 → Arrhythmias
• α1 → Hypertension
• Vomiting

• Combination with
• Carbidopa
• Benserazide
• Action: ↓ Peripheral DOPA Decarboxylase inhibitors
• Result: ↑ Efficacy and ↓ Peripheral S/E.

• Central Side Effects
• Psychosis
• Dyskinesia
• Abnormal behaviour
• Due to excessive DA in brain.
• Central S/E of levodopa cannot be prevented by carbidopa

• Mnemonic: L Dopa in a parkinsonism guy → to avoid falling off anywhere → we get him a car (carbidopa) or benz (Benserazide) → But he still shows psychosis inside benz → Psychosis maran thadiyan (Amantidine) venam

Levodopa induced Dyskinesia

• when levels are high

• Rx: Amantidine

2. Amantadine:

• Mechanism: Releases DA from vesicle.

• Acts as an NMDA Antagonist.

• Side Effects:
• Ankle edema (reversible)
• Livedo reticularis (Pinkish pigmentation of skin in form of meshwork)

• Recent Approval: 
• For treating Levo-dopa induced Dyskinesia.
• Only anti Parkinsonian drug to treat dyskinesia.

• Mnemonic: Nammada (NMDA) Thadiyan (amantidine) → avante kaalil neeranu (ankle edema), avante Liver um poi (Livido)

On off phenomenon

• due to ↓ dose of Syndopa
• Rx
• Selegeline (MAO B⛔) > (addl neuroprotective)
• Entecapone (COMT ⛔)

3. Metabolism Inhibitors:

• Selective MAO-B Inhibitors: 
• Selegiline
• Rasagiline
• Mnemonic: Maavu (MAO) vach Rasavada (Rasagiline) undakki sell (selegiline) cheyyan

• COMT Inhibitors:
• Entacapone
• Tolcapone NOT USED → Hepatotoxicity
• Mnemonic:
• Comet (COMT) → vann ente (entacapone) Tholil (Tolcapone) irunna Capil veenu

4. Dopamine Agonists:

• Mechanism: Directly works on dopamine receptors.

• Drugs:
• Pramipexole
• Ropinirole

• S/E: Pathological gambling

• DOC for
• Parkinsonism.

• Used for
• Restless leg syndrome.
• DOC: Pregabalin/Gabapentin

• Premikkunnavare (pramiprexole) tie with rope (repinirole) → dopamine effect (agonist)

5. Istradefylline:

• Adenosine [A2A] receptor antagonist

6. Deep Brain stimulation

• Subthalamic nucleus > Globus Pallidus interna

B. ANTI-CHOLINERGIC DRUGS

Two groups:

1. Central Anti-cholinergics:

• Benzhexol [Trihexyphenidyl]
• DOC: For Drug Induced Parkinsonism.
• Mnemonic: Try Benz with 6 wheels → Trihexyphenidyl

2. First Generation Anti-histaminic drugs:

• Promethazine.

Extra pyramidal symptoms (EPS) S/E:

• Cause: Blockade of D2 receptors in Nigrostriatal Pathway

• More common in Typical > Atypical Antipsychotics.

• Mnemonic: ADAPT
• AD - Acute Dystonia
• A - Akathisia
• P - Drug-induced Parkinsonism
• T - Tardive Dyskinesia
• Night - Neuroleptic Malignant Syndrome

EPS	Symptom	Cause	DOC / Treatment
Akathisia (most common)	• Inner Restlessness • Rocking, pacing. Akathisia → Akath	Unknown	Beta-blockers (DOC), Benzodiazepines
Acute dystonia (earliest)	• Abnormal posturing, • Facial grimacing • Eyes rolling upwards: Oculogyric crisis. • Neck: Torticollis. • Jaw: Trismus. • Laryngospasm. Stonia → stone like abnormal posturing	• ↓ Dopamine, • Metoclopramide inj.	Anticholinergics (DOC): • Benzhexol [Trihexyphenidyl] • Benztropine, Biperiden • Diphenhydramine Antihistaminic: • Promethazine
Drug induced Parkinsonism/ Tremor predominant	• Tremor, Bradykinesia • Rabbit syndrome (perioral tremors)	• ↓ Dopamine, • Metoclopramide inj.	• Benztropine, • Diphenhydramine, • Trihexyphenidyl (benzhexol)
Tardive dyskinesia (most late)	Facial dyskinesia • tongue protrusion • lip smacking • choreiform hand movements, • pelvic thrusting Limb dyskinesia • piano finger movement • foot tapping	D2 hypersensitive → (due to prolonged downregulation) → upregulation Anticholinergics are contraindicated in TD	VMAT-2 inhibitors: • Valbenazine, • Deutetrabenazine Thaadi (Tardive) varumbo → Piano vayikkum() , tap dance () kalikum → but thaadi varan time edukkum (Late) Thaadiyum Vaalum (Valbenazine)
Neuroleptic malignant syndrome (most lethal)	Muscle rigidity, Hyperthermia, ANS instability	D2 Block	Dantrolene (DOC), (⛔ Ryr) Bromocriptine, Amantidine (Activate D2)

• VMAT ⛔ →Also used in chorea

 

 

MULTIPLE SCLEROSIS

• Type of disease: Demyelinating disease.

Condition	DOC
Acute Episode	IV Steroids
Primary Progressive	Ocrelizumab
Relapsing Remitting	β-IFN

Drugs in EPILEPSY

Seizure	First Line Drug(s)
GTCS	Valproate, Lamotrigine
Seizure in neonates	Phenobarbital Mnemonic: Neonate → Barbie
Absence [Mnemonic: A.A.M] EEG shows 3 spike / wave pattern Mnemonic: Absent anenn vicharichapo ethi (Ethosuximide)	Atypical Valproate Typical Ethosuximide (T type calcium inhibitor)> Valproate child < 5 years → ethosuximide
Focal seizure/ Temporal lobe epilepsy Mnemonic: fOCL → Oxcarb, Carb, Levi Leave (Levi) Elderly (DOC)	• Oxcarbazepine > Carbamazepine (DOC) ↳ S/E: Dilutional Hyponatremia Levetiracetam/Lamotrigine (DOC in elderly) ↳ No hyponatremia
Myoclonic Refractory and intractable rheumatic chorea	Valproate
Atonic	Valproate
Mixed seizure syndrome: • child presents with multiple types of seizures which can be like atypical absence seizures, atonic seizures or GTCS. • also have low IQ. Lennox Gastaut Syndrome (LGS); Dravet Syndrome (DS) Mnemonic: Top for top syndromes like LG and Dravet	Topiramate Valproate, Rufinamide
Febrile seizures	Diazepam
Status Epilepticus	Acute: Lorazepam, Diazepam, Midazolam 2nd-line: Phenytoin/ Fosphenytoin, Levetiracetam, Valproate; Refractory: Phenobarbital, Propofol, Midazolam
Infantile spasms Also called Salaam seizures Seen in West syndrome Act (ACTH) western (West syndrome)	Without tuberous sclerosis complex (TSC) / Salaam spasm (West syndrome) ACTH (DOC), INICET → Steroids With tuberous sclerosis complex (TSC) Vigabatrin Mnemonic: With - Viga
Eclamptic seizures	MgSO4 (DOC) First sign of toxicity: → loss of deep tendon reflexes like patellar reflex.
Epilepsy in pregnancy	Don’t change drug if female is already controlled on any AED and comes in 2nd or 3rd trimester Least teratogenic: Levetiracetam (DOC) > lamotrigine Maximum: Valproate (A/w neural tube defects)
Obesity/Tremors	Topiramate
Anxiety	Pregabalin
Migraine prophylaxis	Topiramate, Valproate
Post herpetic neuralgia	TCA > Pregabalin/gabapentin (Use: Peripheral neuropathy)
Spinal cord injury	Pregabalin/gabapentin > TCA
DOC diabetic neuropathy	Duloxetine OR Pregabalin
Trigeminal neuralgia	Carbamazepine
Induction of anasthesia	Midazolam
Alcohol withdrawal	Lorazepam
Liver Transaminases elevated	Lora > Oxazepam > Tema
Restless leg syndrome	Gabapentin (DOC), NOT Ropinirole Rotigotine → Dopamine Transdermal Patch (for refractory cases)
Arrhythmias	Phenytoin
Bipolar disorder	Carbamazepine, Valproate, Topiramate

Revise Epilepsy

Epilepsy	Characteristic EEG
GTCS	DOC • Phenytoin, Valproate
Absence / Petit mal	• Spike & wave (dome) pattern • 3 Hz spikes DOC • Ethosuximide, Valproate • Absent? → Ethuvo ? (Ethosuximide)
Infantile spasms	• Hypsarrhythmia Age • < 1 years DOC • without tuberous sclerosis: ACTH, Prednisolone • with tuberous sclerosis: Vigabatrin
Juvenile myoclonic Epilepsy (Janz)	• 4–6 Hz polyspikes & slow wave discharge • JME → JANZ S → 4-5 letters → 4 - 6 Hz polyspikes, slow Age • 10 - 19 years DOC • Valproate
Lennox Gastaut syndrome	• Slow (<3 Hz) spike wave complex • LGS → < 3Hz spike complex DOC • Valproate, Lamotrigine
Hepatic encephalopathy	• Triphasic wave {- wave → +ve wave → - wave}
1. SSPE → 8 years age 2. HIE 3 3. Comatose → (drug/severe hypothermia)	• Burst suppression
Prion disease (Kuru)	• Periodic sharp wave complexes Age • 35 years
HSV encephalitis	• Periodic lateralized epileptiform discharge • Affects temporal lobes • DOC: IV Acylovir • HSV → His Wife → Like temples (Period late)

SSLC / SCENE Genes

SCN/SLC	Disease	Features
SLC6A19	Hartnup’s Disease (Chr 5) 6 days Hearty trip	• Defect of tryptophan transporter • Cutaneous photosensitivity (m/c symptom) • Obermeyer test → indoxyl in urine Accumulation of tryptophan in intestine → bacterial decomposition → indoxyl compounds → Indoles absorbed → excreted in urine as indoxyl sulfate→ bluish discoloration of diaper
SLC2A1	GLUT 1 defect SSLC → 2 times → bcz brain hypoglycemia	↓ CSF glucose → seizures ↳ Rx: Pure ketogenic diet
SCN1A	Dravet syndrome ↳ defective Nav1.1 Na channel ↳ ⛔ GABA	Seizures ↳ DOC: Valproate
SCN5A (Loss of function)	Brugada syndrome ↳ defective Cardiac Na channel 1 Dragon drank 5 Bru	Brutal (Brugada) scene (SCN5A) guy like me (pseudo RBB) → drinking soda (Na channelopathy) → sudden seizure and death () Broad P wave → Long PQ seg → raised J point → coved ST → T inversion
SCNN1B/G genes	Liddle Syndrome ↳ Defect: ENaC channel	• AD inheritance • Hypertension + Pseudoaldosteronism • Hypokalemic metabolic alkalosis
Anti GM1 Antibody	Guillain Barre Syndrome (AIDP)	• Albumino-cytological dissociation • Earliest sign: Distal areflexia. • Bladder and bowel spared. • Bilateral ascending symmetrical flaccid paralysis. • Brighton Criteria for GBS
Anti GQ1 Antibody.	Miller Fisher Fish vangan Que nikkanam	Triad • Ophthalmoplegia (3rd nerve palsy). • Areflexia. • Ataxia.
anti P/Q antibody	Lambert Eaton Syndrome Eat 3, 4 Amino acid (3,4 aminopyridine) → gain strength → ↑↑ response	• Pre-junctional ↓↓ release of Ach at NMJ • Oat cell cancer lung → Paraneoplastic • Repetitive nerve stimulation test: ↳ Incremental response Treatment: • DOC: 3,4 aminopyridine • Pyridostigmine

Carbamazepine

• Causes leucopenia, aplastic anemia, hepatotoxicity as a side effect.

• Patient of liver damage
• oxcarbazepine > carbamazepine

Levetiracetam

• Best safety profile

• Preferred in elderly individuals and pregnancy

Lamotrigine

• DOC: For focal seizures in elderly (along with levetiracetam).

• Side effects:
• Steven Johnson Syndrome
• Toxic Epidermal Necrolysis
• These side effects can be avoided by gradually increasing the dose

• Slowly Leave (Leviteracetum) Lame (Lamotrigine) Elderly with lame skin (SJS, TEN)

GABA agonists

• BZDs

• Barbis

• Phenobarbis

• Topira

GABA reuptake ⛔

• Tiagabin

Gaba transaminase ⛔

• Valproate
• ALL ANTI EPILETICS ARE CYP INDUCERS EXCEPT Valproate
• Valproate → CYP ⛔

• Vigabatrin

Drug in Breast Milk / Drug in Serum

• For valproate it is 5%.

• Levetiracetam: 300%.

• Continue anti-epileptic drug in breast feeding also, but watch for drowsiness and lethargyness of baby.
• If it is excessive then decrease / modulate the dose.

Sodium VaLProate

• Pregnancy
• Neural tube defects.
• Pregnancy Category D
• (Teratogenic risk + Used in pregnancy, Benefit > Risk).
• Highly teratogenic (7-20%).

• Antidote
• El Carnitine

Eslicarbazepine

• Given as once/day.

Phenytoin

• Phenytoin has nonlinear pharmacokinetics.

• So, toxicity can develop very fast, hence it is less preferred.

• HHHHH → Hirsutism, Hypertrophy of gums, Hydantoin syndrome, Hyperglycemia, Hemorrhagic disease of Newborn

Adverse Effects	Details
H - Hirsutism, Hypertrophy of gums	ㅤ
O - Osteomalacia	ㅤ
T - Teratogenicity	Fetal Hydantoin syndrome, Facial clefts
M - Megaloblastic Anemia	↓ Folate
A - Arrhythmia	Only in overdose
L - Lymph node enlargement Pseudolymphoma	ㅤ
I - ↓ insulin	Avoided in DM
K - ↓ Vitamin K	Increased bleeding in the newborn due to ↓Vit K.
A - Ataxias, vertigo	Overdose

• Phenytoin, carbamazepine, and oxcarbazepine
• causes a decrease in vitamin K dependent clotting factors.
• This can increase the risk of hemorrhagic disease of the newborn.

Topiramate

• Sodium channel opener

• S/E: renal stone, Angle Closure Glaucoma

• Other uses (COMB):
• C - Craving of Alcohol
• O - Obesity
• M - Migraine prophylaxis
• B - Bipolar disorder
• Mnemonic: Top ira → is alcoholic, obese, bipolar guy → who has migraine

Vigabatrin

• GABA Transaminase INhibitor

• INfantile Spasms (USE)

• Visual field contraction (S/E)

• Mnemonic:
• Vi (Visual field) → Gaba → Tr (transaminase) → In (inhibitor)
• Sezire (Infantile spasm) ulla kuttiye Vegalandil (Vigabatrin) kondu poi → apo kazhcha poi (S/E)

Retigabine/ Ezogabine

• Potassium channel Opener
• Does not act on GABA.

• Used for Focal seizures.

• Can cause retinitis as side-effect.

• Mnemonic:
• Reti → retinitis
• Gab - Not GABA → No action on GABA

DRUG OF ABUSE

Opioids

For Post-op ileus & Opioid induced Constipation

• Naloxegol

• Naldemedine

Morphine:

• Acts on µ, K, δ Receptors.
• Cause – Analgesia.

• µ Receptor Functions:
• S - Sedation
• A – Analgesia
• C – Constipation
• R - Respiratory depression
• U - Euphoria
• Kappa receptors cause dysphoria.
• M – Miosis

• C/I
• Absolute →→ Head trauma
• Relative →→ Bronchial asthma

Morphine in Biliary Colic

• Morphine is used for pain relief

• Contraindicated in biliary colic due to:
• Spasm of sphincter of Oddi
• Increased intra-biliary pressure
• Risk of bile duct rupture

Pethidine

• Metabolism: 
• Metabolized to Norpethidine (Inactive) by CYP 2B6.
• 99% Norpethidine (Inactive)
• 1% Norpethidine (Very long acting)

• Side effect: Seizures [on chronic usage]

• Contraindication: 
• Along with MAO - Inhibitors
• ↑ toxicity
• ↑ risk of serotonin syndrome
• Renal failure

• Use: DOC for chills
• Post Operative chills
• Drug induced chills
• Mnemonic:
• Maavu (MaO) Pothi (Pethidine) vakaruth
• Chills varumbo pothi vakkanam

Fentanyl

• Highly lipid soluble drugs.

• Potency: 100x morphine

• Used for anesthesia.

• Cause Post operative muscle rigidity.
• aka Wooden chest syndrome.

Mixed Agonist/Antagonist:

μ & κ

---

• Morphine → More μ & κ + → Morphine more (μ & κ )

• Pentazocine → Partial μ & κ +

• Buprenorphine → bU → μ → Partial μ, Antagonist at κ

---

Generic Name	μ	κ
Morphine	++	++
Buprenorphine	±	-
Pentazocine	±	++

• +++: Strong agonist

• ±: Partial or weak agonist

• - : Antagonist

 

• Agonists at one opioid receptor subtype (κ) and

• partial agonists/antagonists at another (μ).
• Cause less respiratory depression than full opioid agonists.
• Can cause less opioid withdrawal symptoms than full opioid agonists.
• Not easily reversed with Naloxone.

Miscellaneous Opioids

• Methadone
• S/E: Qt prolongation
• Used for opioid withdrawal
• drug sequestrated into tissues → sustained effects → minimal withdrawal symptoms

• Alvimopan, Naloxegol, Methylnaltrexone
• Use: Post op ileus
• Cause MI

• Loperamide
• DOC in IBS - Diarrhea
• u Agonist:
• Don't cross BBB → Efflux by P-glycoprotein (MDR1 transporter) → No dependence

Drug	Indication	ㅤ
Plecanatide	Chronic Idiopathic Constipation (CIC) in adult	Pling → when constipated
Naldemedine	Opioid-induced constipation	Naltrexone → Opioid Similarly → Naldemedine
Tenapanor	Irritable bowel syndrome with constipation	Thampanoor poyapo IBS vannu
Telotristat	Severe diarrhea due to Carcinoid tumors	Tell to start the car (Telotristat → Carcinoid)

ANTAGONISTS

• Drugs:
• Naloxone
• Short acting, given IV.
• DOC for acute Opioid poisoning
• Naltrexone
• Long acting, given Orally
• Maintenance in opioid poisoning

Opioid Dependence

Tolerance

• Reduced effect with constant dose.
• MOA:
• Receptor desensitization
• Receptor downregulation

De-addiction

1. Acute toxicity
• Naloxone

2. Reduce Withdrawal Symptoms:
• Initial Step (for Mild Symptoms on Cessation):
• Buprenorphine
• Methadone
• Followed by:
• Symptomatic treatment (e.g., Beta-blockers, clonidine)

3. Prevent Relapse:
• Opioid receptor blocker: Oral naltrexone.
• Decreased euphoria → reduced desire for consumption.