CNS

1. PSYCHIATRICS

1.1. Antipsychotics based on mechanism of drug action

1.1.1. Typical - blocks d2 receptors

1.1.1.1. Phenothiazines

1.1.1.1.1. Aliphatic – “promazine”

1.1.1.1.2. Piperidine – “ridazine”

1.1.1.1.3. Piperazine – “phenazine” and “perazine”

1.1.1.2. Butyrophenone

1.1.1.2.1. "peridol"

1.1.1.3. Thioxanthene

1.1.1.3.1. "thixene"

1.1.1.4. Neuroleptic Malignant Syndrome

1.1.1.4.1. Caused by **D2 Blockers**

1.1.1.4.2. Higher potency = higher risk

1.1.1.4.3. Remedy: **Dantrolene** (1st Line) ; **DIazepam** (alternative)

1.1.2. Atypical - block d4 and 5-HT2 receptors

1.1.2.1. Dibenzoxazepine

1.1.2.1.1. Loxapine

1.1.2.2. Dibenzodiazepine

1.1.2.2.1. Clozapine (Leponex)

1.1.2.3. Dibenzothiazepine

1.1.2.3.1. Quetiapine

1.1.2.4. Benzisoxazole

1.1.2.4.1. Resperidone (Risperidol) and Paliperidone

1.1.2.5. Thiabenzodiazepine

1.1.2.5.1. Olanzapine (Zyprexa)

1.1.2.6. Fluorophenylindole

1.1.2.6.1. Sertindole

1.1.2.7. Dihydroindolone

1.1.2.7.1. Ziprasidone

1.1.2.8. Dihydrocarbostyril

1.1.2.8.1. Aripiprazole (Abilify)

1.1.2.9. Benzamide

1.1.2.9.1. Amisulpride (Solian)

1.1.3. Adverse effects

1.1.3.1. ANS Side Effectcs

1.1.3.1.1. a) Antimuscarinic ’ Drying, ’ Constipation, ’ Urinaryretention

1.1.3.1.2. b) Alpha-blocking effect: ’ Orthostatic hypotension ’ Failure to ejaculate

1.1.3.2. CNS Side Effects

1.1.3.2.1. D2 Blockade (Typical)

1.1.3.2.2. D2 Hypersensitivity (Typical)

1.1.3.3. Endocrine - due to D2 blockade

1.1.3.3.1. ’ Amenorrhea - absence of mestruation ’ Galactorhhea ’ Infertility ’ Impotence

1.1.3.4. Others

1.1.3.4.1. Cardiotoxicities

1.2. Drugs for Bipolar Disorders

1.2.1. Lithium Brand Name: Eskalith

1.2.1.1. **First-Line** therapy for the **treatment** and **prevention** of **bipolar disorders,** except for **mixed episodes or rapid cycling**, effective for **treatment of acute manic episodes**

1.2.1.2. MOA: Blocks recycling of Phosphoinositides leading to a decrease in the release of IP3 and DAG (Largely unknown)

1.2.1.3. **Decreased** Serum levels with:

1.2.1.3.1. ’Acetazolamide ’Xanthines ’Urine alkalinizers ’Osmotic Diuretic ’Sodium Supplements

1.2.1.4. **Increased** Serum Levels with:

1.2.1.4.1. ’ACEI (ACE Inhibitors) ’NSAIDS ’Thiazides ’Dehydration and Sodium loss ’Renal Dysfunction

1.2.1.5. Side Effects

1.2.1.5.1. ’Nausea and Vomiting ’Diabetes Insipidus (Polyuria and Polydipsia) ’Fine Tremors

1.2.1.6. Toxicity (more serious)

1.2.1.6.1. ’Coarse Tremors ’Seizures ’Hyperreflexia (increased sensitivity to external stimulus)

1.2.2. Valproic Acid

1.2.2.1. Effective in the treatment of rapid cycling (Shifting between extremes in mood spectrum frequently)

1.2.3. Carbamazepine

1.2.3.1. ’For acute management of mania ’Prophylactic (Preventive) therapy

1.2.4. Antipsychotic Drugs

1.3. Drugs for Mood DIsorder

1.3.1. Depression - **Low Serotonin** and **Norepinephrine** in the brain

1.3.1.1. Mechanisms at which Depression is managed: - Reuptake Inhibition - Inhibition of NT metabolism

1.3.1.1.1. Antidepressants **Mechanisms:** Increases **serotonin** (SSRI), Increases **Norepinephrine** (SNRI) or increase **both** (TCA)

1.4. Sedative Hypnotics and Anti-Anxiety Drugs

1.4.1. Sedative Hypnotics

1.4.1.1. Benzodiazepines

1.4.1.1.1. MOA: Binds to the CNS inhibitory Neurotransmitter Gamma-Hydroxybutyric acid (GABA)

1.4.1.1.2. Leads to an Increase in the **FREQUENCY** of Cl- Channel Opening

1.4.1.1.3. TYPES

1.4.1.1.4. Adverse Effects

1.4.1.2. Barbiturates

1.4.1.2.1. MOA: Binds to Barbiturate Receptors

1.4.1.2.2. Leads to an Increase in the **DURATION** of Cl- Channel Opening

1.4.1.2.3. TYPES

1.4.1.2.4. USES

1.4.1.2.5. ADVERSE EFFECTS

1.4.1.3. Miscellaneous Agents

1.4.1.3.1. Buspirone - **5HT1a agonist**, for anxiety

1.4.1.3.2. Propranolol

1.4.1.3.3. Ramelteon and Tasimelteon

1.4.1.3.4. Zolpidem (stilnox)

2. Neurologics

2.1. Antiseizure drugs

2.1.1. MOA

2.1.1.1. Sodium Channel Blockers

2.1.1.1.1.  Carbamazepine  Phenytoin  Lamotrigine  Zonisamide  Valproic acid – also blocks Calcium Channels  Topiramate

2.1.1.2. GABA-related Targets

2.1.1.2.1.  Benzodiazepines  Barbiturates  Primidone  Gabapentin,Pregabalin, Vigabatrin, Tiagebine

2.1.1.3. Calcium Channel Blockers

2.1.1.3.1.  Ethosuximide – DOC for Absence seizures

2.1.1.4. Others

2.1.1.4.1.  Felbamate – Blocks Glutamate (Excitatory) NMDA receptors

2.1.1.4.2.  Glutamate (excitatory) is the opposite of GABA (Inhibitory)

2.1.1.4.3.  Topiramate – Blocks sodium Channels; Increases GABA; Blocks Glutamate receptors

2.1.2. Drugs for Generalized Seizures

2.1.2.1. Drugs for Generalized Tonic Clonic/Grand Mal/Myoclonic Seizures o1st Line Drugs: Valproic Acid

2.1.2.1.1. Valproic Acid

2.1.3. Drugs for Partial Seizures

2.1.3.1.  1st Line Drugs: Carbamazepine (Tegretol) and Phenytoin (Dilantin)

2.1.3.1.1. Both Na+ Channel Blockers and Enzyme Inducers

2.1.3.1.2. Carbamazepine ADR – Dose-related ataxia and Diplopia; Aplastic Anemia; SJS

2.1.3.1.3. Phenytoin ADR – Nystagmus; Dose-related ataxia and diplopia; Fetal Hydantoin Syndrome; Sedation at higher dose; Gingival Hyperplasia; SJS

2.1.3.2. Alternative Drugs: Lamotrigine (Lamictal) – Na+ Channel Blocker Valproic Acid– Increases GABA neurotransmitter in the CNS

2.1.4. Drugs for Absence Seizures/Petit Mal

2.1.4.1.  Characterized by blank stares & Lip Smacking

2.1.4.1.1. 1st line Drug –Ethosuximide Alternative – Valproic acid

2.1.5. Drugs for Atonic Seizures

2.1.5.1.  Characterized by absence of muscle tone which causes frequent falls.

2.1.5.1.1.  1st Line Drug – Clonazepam  Alternative: Valproic Acid, Lamotrigine, Topiramate

2.1.6. Drugs for Status Epilepticus

2.1.6.1. Characterized by:Loss of Consciousness, Seizures in frequent intervals.

2.1.6.1.1. 1st line: Lorazepam (Diazepam: Obsolete)

2.1.6.2. Caused by Brain or Cerebral Injuries

2.1.7. Drugs for Acute Seizure

2.1.7.1.  Diazepam

2.1.8. Drug for Febrile Seizures

2.1.8.1.  Characterized by seizures induced by very high fever (Tx. APAP) in children >6 months to 5 years old

2.1.8.1.1.  Treated with Phenobarbital

2.2. Parkinsonism

2.2.1. Also known as “paralysis agitans”

2.2.1.1. Common movement and neurodegenerative disorder that involves dysfunction in the substantia nigra

2.2.1.1.1. Involves Tremor at rest, Rigidity of skeletal muscles, Akinesia, Postural Instability (TRAP)

2.2.1.2. Brought about by Low Dopamine and High Acetylcholine

2.2.2. Drugs Therapy for Parkinsonism

2.2.2.1. Dopaminergic Agents - Increase Dopaminergic activity in the brain (MAIN)

2.2.2.1.1. Dopamine Precursor (1st line)

2.2.2.1.2. Dopamine Agonists

2.2.2.1.3. MAOB Inhibitor

2.2.2.1.4. COMT(Catechol-o-methyltransferase) Inhibitors

2.2.2.1.5. Amantadine (Primarily an Antiviral)

2.2.2.2. Anticholinergic Agents - Decrease cholinergic activity in the brain (SUPPLEMENTARY)

2.2.2.2.1. Benztropine (Congentin)

2.2.2.2.2. Biperiden (Akineton)

2.2.2.2.3. Trihexyphenidyl (Artane)

2.2.2.2.4. Diphenhydramine (Benadryl)

2.2.2.2.5. Effect: Useful in controlling tremors brought about by high acetylcholine in the brain

2.3. Alzheimer’s

2.3.1. Manifests as dementia (memory loss)

2.3.2. Pathophysiology

2.3.2.1. Low Ach

2.3.2.2. High Glutamate

2.3.2.3. High Beta-amyloid plaque

2.3.3. Management

2.3.3.1. AchE inhibitors

2.3.3.1.1. Rivastigmine

2.3.3.1.2. Galantamine

2.3.3.1.3. Donepezil

2.3.3.2. Block Glutamate

2.3.3.2.1. NMDA receptor antagonist

2.3.3.3. Beta-amyloid protein antagonist

2.3.3.3.1. Lecanemab

3. Miscellaneous

3.1. General Anesthetics - State characterized by unconsciousness, analgesia, amnesia, skeletal muscle relaxation and loss of reflexes.

3.1.1. Inhaled

3.1.1.1. Gas

3.1.1.1.1. Nitrous Oxide (Laughing Gas)

3.1.1.2. Volatile liquids

3.1.1.2.1. Desflurane – Smooth and rapid induction of anesthesia; Relatively non-toxic

3.1.1.2.2. Sevoflurane – Less pungent than others and is therefore used in Children

3.1.1.2.3. Isoflurane – Preferred anesthetic in neurosurgery; Non-toxic

3.1.1.2.4. Enflurane - Preferred in asthmatic patients; Contraindicated in labor; Hepatotoxic

3.1.1.2.5. Halothane – Less pungent than others like sevoflurane; Most Hepatotoxic

3.1.1.2.6. Methoxyflurane – Most potent and is most preferred in labor.

3.1.1.3. Mechanism of Action: Increase neuronal threshold for firing leading to a decrease in neuronal activity and hyperpolarization of neurons via activation of K+ currents

3.1.1.4. Adverse effect: Malignant Hyperthermia (Tx. Dantrolene)

3.1.2. Intravenous

3.1.2.1. Ultra-short Barbiturates

3.1.2.1.1. Ex: Thiopental, Methohexital, Thiamytal

3.1.2.1.2. Pre-Anesthetic Agents – rapid onset (15-30 seconds) and duration

3.1.2.1.3. High lipid solubility (has Sulfur in its chemical structure)

3.1.2.2. Benzodiazepines

3.1.2.2.1. Short-acting Barbiturates are used for rapid onset but with longer duration of action than Thiopental.

3.1.2.2.2. Ex: Diazepam IV IV is a widely used adjunct to inhaled anesthetics

3.1.2.2.3. Toxicity: Anterograde Amnesia and Respiratory Depression (Tx: Flumazenil)

3.1.2.3. Opiods

3.1.2.3.1.  Morphine and Fentanyl are used

3.1.2.3.2.  Adjuncts with other CNS depressants in anesthesia regimens.  Toxicity: Opioid Triad (COMA, Pinpoint pupil, Respiratory Depression)  Combined usually with a neuroleptic agent

3.1.2.3.3. Opioid With Neuroleptic

3.1.2.4. Miscellaneous

3.1.2.4.1. Propofol

3.1.2.4.2. Ketamine

3.1.2.4.3. Etomidate

3.2. Local Anesthetics

3.2.1. Esters

3.2.1.1. “-caine” with one “i”; More susceptible to Hydrolysis,

3.2.1.1.1. ✓ Chlorprocaine – Para-aminobenzoic acid derivative ✓ Cocaine – easily abused ✓ Procaine – First local anesthetic; PABA derivative ✓ Tetracaine – PABA derivative

3.2.1.2. Short Acting

3.2.2. Amides

3.2.2.1. “-caine with two “i” ; More stable to Hydrolysis,

3.2.2.1.1. ✓Bupivacaine – More Cardiotoxic than Lidocaine ✓Etidocaine ✓Lidocaine(Xylocaine) – Causes Arrythmia (also an Anti- arrythmic drug); Most widely used local Anesthetic; Metabolized to xylidides ✓Mepivacaine ✓Prilocaine – causes methemoglobinemia due to its metabolite o-toluidine ✓Articaine – Has the fastest onset of any LA

3.2.2.2. Long-acting

3.2.3. Uses

3.2.3.1.  Used in minor surgical procedures topically (Dental procedures Lidocaine is used)  Usually applied with vasoconstrictors (Epinephrine) to prolong action of LA  Used as epidurals (Labor Pain) – Bupivacaine, Tetracaine, Chlorprocaine  Used as anti-arrhythmic: Lidocaine (Ib)

3.3. Opioid Analgesics and Antagonists

3.3.1. Natural Opium Alkaloids

3.3.1.1. Morphine

3.3.1.1.1. Poor Oral Bioavailability o Oral Dose 40 mg PO = 10 mg IV o Used for Severe Pain – Cancer, Labor, MI o Used for management of Pulmonary Edema – reduced HR , Cardiac contractility and Peripheral vasodilator o Metabolites: M3G – causes convulsion in renally impaired patients; M6G – Potent analgesic

3.3.1.2. Codeine

3.3.1.2.1. AKA Methylmorphine

3.3.1.2.2. o Less sedating/addicting o Antitussive and used for moderate pain o Metabolized by CYP2D6 through demethylation to morphine

3.3.1.3. Thebaine

3.3.1.3.1. Precursor substrate for naloxone

3.3.2. Semisynthetic Opioids

3.3.2.1. Heroin

3.3.2.1.1. AKA Diacetylmorphine

3.3.2.1.2. Drug of abuse

3.3.2.2. Apomorphine

3.3.2.2.1. Non-narcotic; Used as an emetic (SQ), and used in Parkinson’s disease

3.3.2.3. Hydromorphone and Oxymorphone

3.3.2.3.1. 8-12 times more potent than codeine

3.3.2.4. Hydrocodone and Oxycodone

3.3.3. Purely Synthetic Opioids

3.3.3.1. Methadone

3.3.3.1.1. ✓ Similar to MORPHINE but greater oral efficacy, duration in action and less rapid development of tolerance

3.3.3.2. Loperamide and Diphenoxylate

3.3.3.2.1. – Antidiarrheal and derived from Meperidine

3.3.3.3. Meperidine

3.3.3.3.1. o Readily enters the CNS o Chronic use may lead to convulsion o 8-10 times dose needed to equal morphine dose

3.3.3.4. Fentanyl

3.3.3.4.1. o Dermal Patch o 100x more potent than morphine o Related agents (IV): Alfentanil, Sulfentanil, Remifentanil

3.3.3.5. Tramadol

3.3.3.5.1. oWeak mu receptor agonist oLess Addictiing oUsed for Mild Pain

3.3.3.6. Pentazocine

3.3.3.6.1. oLess sedating oStrong Analgesic

3.3.4. Classification of Opioids

3.3.4.1. Pure agonist

3.3.4.1.1. Morphine

3.3.4.1.2. Codeine

3.3.4.1.3. Meperidine

3.3.4.1.4. Fentanyl

3.3.4.1.5. Remifentanil

3.3.4.1.6. Propoxyphene

3.3.4.1.7. Hydrocodone

3.3.4.1.8. Oxycodone

3.3.4.2. Agonist-antagonist

3.3.4.2.1. Nalbuphine

3.3.4.2.2. Butorphanol

3.3.4.2.3. Buprenorphine

3.3.4.3. Pure antagonist

3.3.4.3.1. Naloxone

3.3.4.3.2. Naltrexone

3.3.4.4. Partial agonist

3.3.4.4.1. Pentazocine

3.3.5. Classification Based on Strength

3.3.5.1. Strong Full Agonist

3.3.5.1.1. o Morphine o Methadone o Meperidine o Hydromorphone o Oxymorphone o Fentanyl

3.3.5.2. Mild to Moderate Agonist

3.3.5.2.1. o Codeine o Oxycodone o Hydrocodone o Diphenoxylate o Propoxyphene

3.3.5.3. Mixed Agonist and Antagonist

3.3.5.3.1. o Nalbuphine o Buprenorphine o Butorphanol o Pentazocine

3.3.5.4. Antagonist

3.3.5.4.1. o Naloxone(IV) o Nalorphine o Naltrexone(PO) o Levallorphan

3.3.6. Effects of Opioid Analgesics

3.3.7. Clinical Uses

3.3.7.1. Analgesia for moderate to severe pain – For Cancer, Labor, and Myocardial Infarction

3.3.7.2. Acute Pulmonary Edema – IV morphine

3.3.7.3. Antitussive - codeine and dextrometorphan and hydrocodone

3.3.7.4. Antidiarrheal - diphenoxylate and loperamide

3.3.7.5. Anesthetic - morphine and fentanyl

3.3.8. Side Effects

3.3.8.1. Tolerance after 2-3 weeks of use

3.3.8.2. Cross tolerance among full MU agonist but not PARTIAL AGONIST

3.3.8.3. Psychologic and Physical Dependence

3.3.8.3.1. Withdrawal syndrome

3.3.9. Contraindications

3.3.9.1. Use of partial agonist with full agonist

3.3.9.2. Patients with head injury

3.3.9.3. Avoided during pregnancy

3.3.9.4. Avoided in patients with bile stones, EXCEPT FOR MEPENIDINE

3.4. Others

3.4.1. ADHD

3.4.1.1. 1st Line - Methylphenidate

3.4.1.1.1. Reuptake inhibitor (NE, DOPA)

3.4.1.2. Alt : Amphetamine

3.4.1.2.1. Inc. release of NE

3.4.2. Neuromuscular Blockers (Nm Blockers)

3.4.2.1. Depolarizing

3.4.2.1.1. Succinylcholine

3.4.2.1.2. Toxicity: Malignant Hyperthermia

3.4.2.2. Non-depolarizing

3.4.2.2.1. Steroidal (-uronium)

3.4.2.2.2. Isoquinoline - derived from the alkaloid Tubacurarine

3.4.2.2.3. More commonly used

3.4.2.2.4. MOA: Block Nm - relaxation of skeletal muscles (IMMEDIATE)