/teach me CNS pharmacology

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CNS neurotransmitter pathways dopamine serotonin diagram

This educational infographic displays the neuroanatomical distribution of dopamine and serotonin pathways in the human and rat brains. The image is divided into two panels: Panel A focuses on Dopamine, showing its chemical structure alongside sagittal schematics of human and rat brains. Key pathways originate in the midbrain (specifically the ventral tegmental area and substantia nigra) and project to the striatum (mesostriatal), neocortex (mesocortical), and limbic structures like the hippocampus and amygdala. Panel B illustrates Serotonin, displaying its chemical structure and wide-ranging projections originating from the raphe nuclei in the brainstem. These serotonergic axons extend extensively to the neocortex, striatum, hippocampus, and downward toward the spinal cord. Both panels highlight comparative anatomy, illustrating similarities in basic circuitry between species while noting human-specific anatomical complexity. The diagram serves as a resource for understanding monoamine neurotransmitter systems, their localization, and their broad influence on CNS functions including reward, motor control, and mood regulation.

This anatomical diagram presents a sagittal view of the human brain, illustrating the major neurotransmitter pathways associated with the Brain Reward Cascade (BRC). The illustration distinguishes between the Dopamine and Serotonin systems using color-coded projections. The Dopamine pathways, highlighted in blue, originate in the Ventral Tegmental Area (VTA) and project to the Nucleus Accumbens and the Frontal Cortex. Labeled functions for this system include reward (motivation), pleasure, motor function, compulsion, and perseveration. The Serotonin pathways, highlighted in red, originate from the Raphe Nuclei and demonstrate a more diffuse distribution pattern, passing through the hippocampus, substantia nigra, and striatum before reaching the frontal cortex. Functional correlates for serotonin listed include mood, memory processing, sleep, and cognition. This educational graphic is designed to demonstrate the neuroanatomical circuitry underlying motivation and behavior, specifically highlighting the mesocorticolimbic system's role in reward and its interplay with wider serotonergic projections.

This medical illustration presents two sagittal sections of the human brain, side-by-side, detailing the central dopamine and serotonin neurotransmitter pathways involved in food intake regulation. The left panel depicts the Dopamine Pathways in red, showing projections originating from the Ventral Tegmental Area (VTA) and Substantia Nigra (SN) in the midbrain. Key innervated regions highlighted include the Dorsal Striatum, Nucleus Accumbens (NAc), and the Prefrontal Cortex (PFC), representing the mesolimbic and mesocortical reward circuits. The right panel illustrates the Serotonin Pathways in blue, originating from the Raphe Nuclei in the brainstem. This pathway shows a broader distribution, with projections reaching the Striatum, Thalamus, Amygdala, and the Ventromedial Prefrontal Cortex (vmPFC). Arrows indicate the directional flow of neural signaling. Both diagrams highlight the anatomical overlap in the striatum and prefrontal regions, emphasizing their integrated role in homeostatic and hedonic appetite control.

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antipsychotic drug dopamine receptor mechanism

A comparison panel of axial diagnostic neuroimaging scans illustrating striatal dopamine D2 receptor occupancy during antipsychotic treatment. Panel A presents structural T1-weighted MRI slices with anatomical segmentations of the basal ganglia from the Harvard-Oxford atlas, highlighting the caudate nucleus (light blue), putamen (red), and nucleus accumbens (dark blue). Panels B and C display co-registered Single-Photon Emission Computed Tomography (SPECT) and MRI fusion images. The color heat map (scale 0–3) represents the specific binding potential of a radioactive tracer to dopamine D2 receptors. Row B shows baseline binding potential (pre-treatment) with high intensity (red/yellow) in the striatum. Row C depicts the same patient after six weeks of treatment with 300 mg of the antipsychotic amisulpride, demonstrating a visible reduction in tracer binding (blue/green shift), corresponding to a mean receptor occupancy of 56%. This visual illustrates the pharmacological mechanism of competitive receptor blockade in psychiatric neuroimaging.

This diagnostic image displays two side-by-side transaxial Positron Emission Tomography (PET) brain scans using the radiotracer [11C]raclopride, which targets dopamine D2 receptors. The left image represents the 'Baseline' state, showing high radiotracer binding in the striatum (specifically the putamen and caudate nucleus), indicated by warm yellow and orange hues. The right image depicts the 'Drug challenge' state after the administration of 6 mg of aripiprazole. In this scan, there is a visible reduction in radiotracer uptake within the striatal regions, characterized by a shift toward cooler blue and green colors. This visual decrease represents competitive displacement of the radiotracer by aripiprazole, effectively illustrating dopamine D2 receptor occupancy by the antipsychotic medication. The comparison serves as a clinical demonstration of neuropharmacological activity and receptor binding dynamics in the human brain.

This diagnostic comparison image features three transversal [123I]IBZM SPECT slices at the level of the striatum, illustrating dopamine D2/3 receptor (D2/3R) availability across different clinical states. The panels represent a patient with treatment-resistant depression (TRD), a TRD patient receiving antipsychotic medication (TRD AP), and a healthy control (HC) subject. In the TRD and HC images, there is a prominent, bilateral, and symmetric high-intensity signal within the striatal regions (caudate and putamen), appearing as well-defined, bright orange-yellow structures against a darker background. In contrast, the TRD AP image demonstrates a marked reduction in signal intensity and distinctness in the striatum. This visual difference indicates high occupancy of D2/3 receptors by antipsychotic dopamine antagonists, which reduces the binding availability for the radiotracer. The comparison serves to illustrate that while TRD alone does not significantly alter striatal D2/3R availability compared to healthy controls, pharmacological intervention with antipsychotics causes a visible and quantifiable decrease in receptor availability.

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CNS Pharmacology - Full Teaching Guide

Sources: Katzung's Basic and Clinical Pharmacology 16e, Lippincott Illustrated Reviews: Pharmacology, Stahl's Essential Psychopharmacology, Adams and Victor's Principles of Neurology 12e, Goodman & Gilman's The Pharmacological Basis of Therapeutics

FOUNDATION: Key Neurotransmitters of the CNS

Before drugs make sense, you need a map of what they act on. Every CNS drug manipulates one or more of these systems:

Transmitter	Key Locations	Primary Function	Drugs Targeting It
GABA	Ubiquitous inhibitory	Neuronal inhibition	Benzodiazepines, barbiturates, valproate
Glutamate	Ubiquitous excitatory	Neuronal excitation, memory	Ketamine (NMDA blocker), memantine
Dopamine	Substantia nigra → striatum (nigrostriatal); VTA → limbic/cortex (mesolimbic/mesocortical)	Movement, reward, motivation, cognition	Antipsychotics, L-DOPA, stimulants
Serotonin (5-HT)	Raphe nuclei → cortex, limbic, spinal cord	Mood, sleep, appetite	SSRIs, SNRIs, MAOIs, antipsychotics
Norepinephrine (NE)	Locus coeruleus	Arousal, attention, fight-or-flight	TCAs, SNRIs, clonidine
Acetylcholine (ACh)	Basal nucleus of Meynert → cortex	Memory, cognition	AChEIs (donepezil), antimuscarinics

Mnemonic - "GAGNDS": GABA, Acetylcholine, Glutamate, Norepinephrine, Dopamine, Serotonin = the 6 major CNS neurotransmitter systems.

PART 1: SEDATIVES, HYPNOTICS & ANXIOLYTICS

The GABA-A Receptor - Master Switch

GABA-A is a ligand-gated Cl⁻ channel. When GABA binds, Cl⁻ flows in → hyperpolarization → neuronal inhibition. This is the molecular target for most sedative-hypnotics.

GABA-A receptor subunit complex:
  - Benzodiazepine site (α-subunit): allosteric modulator
  - Barbiturate site (β-subunit): separate binding pocket
  - GABA binding site: direct activation

Benzodiazepines (BZDs)

Mechanism: Bind at the BZD site on GABA-A receptor. They increase the FREQUENCY of Cl⁻ channel opening (they do NOT open channels on their own - they potentiate GABA). This is allosteric positive modulation.

Mnemonic - "BZD = Frequency, Barbiturate = Duration"

BZD → ↑ Frequency of channel opening
Barbiturate → ↑ Duration of channel opening

Drug	T½	Key Use	Notes
Diazepam	Long (20-100h)	Anxiety, status epilepticus, alcohol withdrawal	Active metabolite (desmethyldiazepam)
Lorazepam	Medium (10-20h)	Status epilepticus (IV), perioperative	No active metabolite - safer in liver disease
Midazolam	Short (1-4h)	Procedural sedation, anesthesia induction	Highly lipid-soluble, water-soluble at acidic pH
Alprazolam	Medium	Panic disorder	High abuse potential
Triazolam	Very short	Insomnia	Rebound anxiety on discontinuation
Clonazepam	Long	Seizures, panic disorder	Good oral bioavailability

Clinical Pearls:

Overdose: Supportive care is key. Flumazenil (BZD antagonist) can reverse but caution - precipitates seizures in chronic BZD users or if co-ingested TCA
Withdrawal: Life-threatening (like alcohol). Taper slowly or substitute phenobarbital
Tolerance develops to sedation but less so to anxiolytic effects

Adverse Effects: Sedation, anterograde amnesia, respiratory depression (especially with opioids), paradoxical agitation in elderly ("Ativan Rage"), physical dependence.

Barbiturates

Mechanism: Bind GABA-A at a separate site → increase DURATION of Cl⁻ channel opening. At high doses can directly open channels without GABA (this is why overdose is so dangerous).

Drug	Duration	Use
Phenobarbital	Long	Seizures, alcohol withdrawal
Thiopental	Ultra-short	IV anesthesia induction (historical)
Pentobarbital	Short	Sedation, refractory status epilepticus

Why barbiturates are more dangerous than BZDs: They have a narrow therapeutic index. High doses → respiratory depression and death (no ceiling effect). BZDs cannot open Cl⁻ channels without GABA.

Non-BZD Hypnotics ("Z-drugs")

These also act on GABA-A but are selective for α1-subunits (sedation, amnesia, less anxiolysis).

Drug	Notes
Zolpidem	Most widely used; can cause sleepwalking, sleep-eating; CYP3A4 substrate
Zaleplon	Shortest acting; good for sleep-onset (can take after waking)
Eszopiclone	Longer acting; approved for up to 6 months use

Mnemonic: "Z-Z-Z" for Z-drugs = sleep!

Buspirone - The Odd One Out

Mechanism: 5-HT1A partial agonist; NO GABA activity
Anxiolytic (not hypnotic, not anticonvulsant)
Onset: 1-2 weeks (unlike BZDs which work immediately)
No sedation, no dependence, no withdrawal - great for GAD in elderly
Does NOT cross-react with BZDs (cannot treat BZD withdrawal)

PART 2: ANTIDEPRESSANTS

Core concept: Depression involves reduced activity of monoamines (5-HT, NE, DA) in the synaptic cleft. All antidepressants work to increase monoamine activity, but by different mechanisms. Onset is 2-4 weeks for all - tell your patients this!

Class 1: SSRIs (Selective Serotonin Reuptake Inhibitors)

Mechanism: Block the serotonin transporter (SERT) → ↑ serotonin in synapse. No significant action on NE or DA transporters.

"Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, Fluvoxamine"

Mnemonic: "Five Sexy People Can Experience Fun" (Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, Fluvoxamine)

SSRI	Unique Feature	Extra Indications
Fluoxetine	Longest T½ (1-4 days + active metabolite norfluoxetine 4-16 days) - best if concerned about discontinuation syndrome	Bulimia, OCD, premenstrual dysphoric disorder
Sertraline	Most commonly used first-line; relatively safe in pregnancy	PTSD, panic disorder, OCD
Paroxetine	Most anticholinergic SSRI; most discontinuation syndrome	Panic disorder, GAD, PTSD, OCD; avoid in pregnancy
Citalopram	Dose-limited QT prolongation; maximum 40mg/day
Escitalopram	S-enantiomer of citalopram; fewest drug interactions
Fluvoxamine	Strong CYP1A2 inhibitor	OCD, social anxiety

Adverse effects (all SSRIs): Nausea (take with food), sexual dysfunction (most common), insomnia or hypersomnia, weight gain long-term, serotonin syndrome (with MAOIs, tramadol, linezolid), QT prolongation (citalopram), SSRI discontinuation syndrome (paroxetine worst - "FINISH": Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal).

Serotonin Syndrome triad: Altered mental status + Autonomic instability + Neuromuscular abnormalities (tremor, clonus, hyperreflexia). Treatment: cyproheptadine (5-HT antagonist).

Class 2: SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors)

Block both SERT and NET (norepinephrine transporter).

Drug	Notes
Venlafaxine	Dose-dependent: low dose = SSRI-like; high dose = adds NE. Can raise BP. Discontinuation syndrome
Duloxetine	Also approved for diabetic peripheral neuropathy, fibromyalgia, stress urinary incontinence
Desvenlafaxine	Active metabolite of venlafaxine
Levomilnacipran	Most NE-selective SNRI

Class 3: TCAs (Tricyclic Antidepressants)

Mechanism: Block SERT + NET (mainly) + muscarinic + H1 + α1 receptors.

Mnemonic - "TCA blocks 4 things: SHAM": SERT/NET (antidepressant), Histamine H1 (sedation), Alpha-1 (orthostatic hypotension), Muscarinic (anticholinergic effects).

Drug	Notes
Amitriptyline	Most sedating, most anticholinergic; used for chronic pain, migraine prophylaxis
Nortriptyline	Less anticholinergic; preferred in elderly
Desipramine	Least anticholinergic
Imipramine	Enuresis in children
Clomipramine	Most serotonergic TCA; OCD

Toxicity: Anticholinergic toxidrome (CANT SEE - Constipation, Anhydrosis, Nausea absent, Tachycardia, Sedation, Eyes dilated, Elevated temperature). Cardiotoxicity: QRS widening, arrhythmias (block Na⁺ channels). Treatment of overdose: Sodium bicarbonate (narrows QRS), supportive care.

Contraindication: Acute glaucoma (angle-closure), BPH, post-MI (arrhythmia risk). Avoid in elderly.

Class 4: MAOIs (Monoamine Oxidase Inhibitors)

Mechanism: Inhibit MAO-A (breaks down 5-HT, NE) and/or MAO-B (breaks down DA). → ↑ all monoamines.

Drug	Selectivity	Notes
Phenelzine	Irreversible, non-selective	Atypical depression, PTSD
Tranylcypromine	Irreversible, non-selective	Also inhibits DA reuptake
Selegiline	Selective MAO-B at low dose	Parkinson's disease; transdermal patch for depression
Moclobemide	Reversible MAO-A (RIMA)	Safer, less dietary restriction

Hypertensive Crisis ("Cheese Reaction"): MAOIs prevent breakdown of tyramine (found in aged cheese, wine, cured meats). Tyramine → releases NE → severe hypertension. Management: Phentolamine (α-blocker).

Drug-drug interaction: MAOIs + SSRIs/TCAs/meperidine/tramadol → Serotonin Syndrome. Must wash out SSRIs 2 weeks (fluoxetine 5 weeks) before starting MAOI.

Class 5: Atypical Antidepressants

Drug	Mechanism	Key Feature
Bupropion	NE + DA reuptake inhibitor (no serotonin!)	Smoking cessation, weight-neutral, no sexual dysfunction; lowers seizure threshold
Mirtazapine	α2 antagonist + 5-HT2 & 5-HT3 antagonist	↑ appetite, weight gain, sedating (useful in low-weight depressed patients); least sexual dysfunction
Trazodone	5-HT2 antagonist + weak SERT inhibitor	Mainly used for insomnia; rare priapism
Vortioxetine	SERT inhibitor + 5-HT receptor modulator	Cognitive benefits; multimodal
Esketamine	NMDA receptor antagonist	Intranasal; rapid-acting for treatment-resistant depression and suicidality
Brexanolone	GABA-A modulator (neurosteroid)	IV; postpartum depression only

PART 3: ANTIPSYCHOTICS

Core concept: Psychosis (positive symptoms - hallucinations, delusions) is driven by mesolimbic hyperdopaminergia. Cognitive/negative symptoms are driven by mesocortical hypodopaminergia. This dual-pathway model explains the limitations of dopamine blockade alone.

Aripiprazole D2 receptor PET scan showing dopamine occupancy

4 Dopamine Pathways - MUST KNOW

Pathway	Origin → Target	Function	If D2 blocked
Mesolimbic	VTA → nucleus accumbens	Reward, psychosis	↓ Positive symptoms ✓
Mesocortical	VTA → prefrontal cortex	Cognition, negative symptoms	Worsens negative symptoms ✗
Nigrostriatal	Substantia nigra → striatum	Movement	EPS (extrapyramidal symptoms) ✗
Tuberoinfundibular	Hypothalamus → pituitary	Inhibits prolactin	Hyperprolactinemia (galactorrhea, amenorrhea) ✗

First-Generation (Typical) Antipsychotics (FGAs)

Mechanism: Primarily D2 receptor blockade (high potency blockade).

Potency	Drug	Adverse Profile
High potency	Haloperidol, Fluphenazine	More EPS, less sedation/anticholinergic
Mid potency	Perphenazine	Intermediate
Low potency	Chlorpromazine, Thioridazine	More sedation, anticholinergic, orthostasis; less EPS

Mnemonic - "High potency = High EPS; Low potency = Low EPS but lots of other effects"

EPS (Extrapyramidal Symptoms) and Timing:

EPS	Timing	Treatment
Acute dystonia	Hours-days	Benztropine (anticholinergic) or diphenhydramine (IV)
Akathisia	Days-weeks	β-blockers (propranolol), benzodiazepines
Parkinsonism	Weeks	Benztropine, amantadine; reduce dose
Tardive dyskinesia (TD)	Months-years	Irreversible (if not caught early); use VMAT2 inhibitors (valbenazine, deutetrabenazine)

Mnemonic: "4 A's of EPS" (in order of onset): Acute dystonia, Akathisia, Akinesia/Parkinsonism, Abnormal movements (TD).

Neuroleptic Malignant Syndrome (NMS) - Life-threatening:

"FEVER": Fever, Encephalopathy, Vitals unstable, Elevated CK, Rigidity ("lead pipe")
Treatment: Stop antipsychotic, dantrolene (muscle relaxant), bromocriptine (DA agonist), ICU

Thioridazine: Highest risk of retinal pigmentation and QT prolongation. Reserved for refractory cases.

Second-Generation (Atypical) Antipsychotics (SGAs)

Mechanism: Block both D2 AND 5-HT2A receptors. 5-HT2A blockade → DA release in nigrostriatal pathway → less EPS. Better for negative symptoms and cognition.

Drug	Key Feature	Watch For
Clozapine	Most effective (treatment-resistant schizophrenia); lowers suicidality	Agranulocytosis (weekly CBC monitoring), seizures, metabolic syndrome
Olanzapine	Highly effective; strong metabolic effects	Weight gain, dyslipidemia, T2DM - most metabolic risk after clozapine
Risperidone	Most EPS of the atypicals (dose-dependent); most prolactin elevation	EPS, hyperprolactinemia
Quetiapine	Sedating; minimal EPS, minimal prolactin	Sedation, metabolic effects; used as sleep aid off-label
Aripiprazole	Partial D2 agonist (stabilizer) - unique mechanism!	Akathisia; weight-neutral; activating
Ziprasidone	QT prolongation; must take with food	Take with 500 kcal meal; weight-neutral
Lurasidone	Metabolically neutral; approved for bipolar depression	Take with food
Paliperidone	Active metabolite of risperidone	Long-acting injection available
Pimavanserin	5-HT2A inverse agonist (NO D2 blockade!)	Specifically for Parkinson's Disease Psychosis

Metabolic Risk Ranking (highest → lowest): Clozapine > Olanzapine > Quetiapine > Risperidone > Aripiprazole, Ziprasidone, Lurasidone

Clozapine Monitoring: CBC weekly for 6 months, then every 2 weeks for 6 months, then monthly. ANC must be checked before each refill.

PART 4: ANTIEPILEPTIC DRUGS (AEDs)

Core mechanisms that AEDs exploit:

Na⁺ channel blockade - stabilize inactivated state → limit repetitive firing
Ca²⁺ channel blockade - especially T-type (absence seizures)
GABA enhancement - ↑ inhibition
Glutamate blockade - ↓ excitation
SV2A binding - reduce vesicle release (levetiracetam)

Drug-by-Drug Breakdown

Drug	Mechanism	Seizure Types	Key Toxicity
Phenytoin	Na⁺ channel blocker	Partial, generalized tonic-clonic (GTC)	Zero-order kinetics at therapeutic doses, gingival hyperplasia, hirsutism, teratogen (fetal hydantoin syndrome), cerebellar ataxia, nystagmus
Carbamazepine	Na⁺ channel blocker	Partial, GTC, trigeminal neuralgia	Agranulocytosis, aplastic anemia, SIADH, teratogen; strong CYP inducer; *HLA-B1502 → Stevens-Johnson** in Asian patients
Valproate (VPA)	Na⁺ blockade + GABA ↑ + T-Ca²⁺ blockade	Broad spectrum (all types)	Teratogen (neural tube defects, valproate syndrome); hepatotoxicity, pancreatitis, tremor, weight gain, CYP inhibitor
Lamotrigine	Na⁺ channel blocker	Partial, GTC, absence, bipolar	Stevens-Johnson syndrome (slow titration prevents this); CYP2 interactions
Levetiracetam	SV2A binding (unique!)	Broad spectrum	Behavioral/psychiatric side effects ("Keppra rage"); no drug interactions
Ethosuximide	T-type Ca²⁺ channel blocker	Absence seizures ONLY	GI symptoms, Stevens-Johnson
Phenobarbital	↑ GABA-A duration	Broad spectrum	Sedation, tolerance, dependence, strong CYP inducer; safest in pregnancy for seizures
Gabapentin	α2δ subunit of Ca²⁺ channels	Partial, neuropathic pain, fibromyalgia	Sedation, dizziness; no drug interactions; renal elimination
Pregabalin	α2δ subunit of Ca²⁺ channels	Same as gabapentin	Similar to gabapentin; controlled substance (Schedule V)
Topiramate	Na⁺ block + GABA ↑ + Glu block	Partial, GTC, migraine prophylaxis	Cognitive dulling ("Dopamax"), nephrolithiasis, weight loss, metabolic acidosis, angle-closure glaucoma
Zonisamide	Na⁺ + T-Ca²⁺ block	Partial, GTC	Nephrolithiasis, sulfonamide allergy
Tiagabine	GABA reuptake inhibitor	Partial	Dizziness; non-convulsive SE at high doses
Vigabatrin	GABA transaminase inhibitor (irreversible)	Infantile spasms, refractory partial	Irreversible visual field defects
Lacosamide	Slow Na⁺ channel inactivation	Partial	PR prolongation

Seizure type → Drug of choice:

Absence: Ethosuximide (first-line), valproate
Juvenile myoclonic epilepsy (JME): Valproate (first-line); levetiracetam
Infantile spasms: ACTH, vigabatrin
Partial/focal: Carbamazepine, levetiracetam, lamotrigine
Status epilepticus: Lorazepam (IV) → fosphenytoin/valproate → phenobarbital → propofol/ketamine (refractory)

Pregnancy: Lamotrigine or levetiracetam preferred. Avoid valproate and phenytoin (teratogens). If must use, give folate supplementation.

CYP inducers (reduce other drugs): Phenytoin, carbamazepine, phenobarbital ("PCB" = destroys your drugs!)

CYP inhibitors: Valproate (inhibits epoxide hydrolase → ↑ phenytoin, carbamazepine)

PART 5: DRUGS FOR MOVEMENT DISORDERS

Parkinson's Disease

Pathophysiology: Loss of dopaminergic neurons in the substantia nigra pars compacta → ↓ DA in striatum → disinhibition of GABAergic output → excessive inhibition of thalamus → reduced motor cortex activation.

Classic triad: TRAP - Tremor (resting), Rigidity (cogwheel), Akinesia/Bradykinesia, Postural instability

Dopaminergic Drugs

Drug	Mechanism	Notes
Levodopa + Carbidopa	L-DOPA: DA precursor; crosses BBB → converted to DA. Carbidopa: peripheral DOPA decarboxylase inhibitor (prevents peripheral conversion)	Gold standard. Long-term: "wearing off", dyskinesias, on-off fluctuations. Take before meals
Pramipexole, Ropinirole	D2/D3 receptor agonists	Used early or as adjunct; compulsive behaviors (gambling, hypersexuality) as side effect
Rotigotine	D1/D2/D3 agonist	Transdermal patch
Bromocriptine	D2 agonist	Older; also used for hyperprolactinemia, acromegaly
Selegiline, Rasagiline	MAO-B inhibitors	Protect DA from breakdown; neuroprotective? Used early
Entacapone, Tolcapone	COMT inhibitors	Extend levodopa action; reduce "wearing off". Tolcapone: hepatotoxic (liver monitoring required)
Amantadine	Mechanism unclear (anti-NMDA, ↑ DA release)	Treats dyskinesias; mild antiparkinsonian effect; also antiviral

Anticholinergic Drugs (for tremor)

Drug	Notes
Benztropine	Block muscarinic receptors in striatum → reduce tremor and rigidity. Avoid in elderly (cognitive side effects)
Trihexyphenidyl	Similar to benztropine

Mnemonic for L-DOPA side effects: "DAWN" - Dyskinesias, Anxiety/agitation, Wearing off, Nausea.

Alzheimer's Disease (Cognitive Enhancers)

Pathophysiology: Loss of cholinergic neurons from basal nucleus of Meynert → ↓ ACh in hippocampus/cortex. Also amyloid plaques (Aβ) and neurofibrillary tangles (tau).

Drug	Mechanism	Stage	Notes
Donepezil	AChEI (reversible)	Mild-severe	Once daily; GI side effects; bradycardia
Rivastigmine	AChEI (pseudo-irreversible)	Mild-moderate	Also for Parkinson's dementia; patch form
Galantamine	AChEI + nicotinic receptor allosteric modulator	Mild-moderate
Memantine	NMDA receptor antagonist	Moderate-severe	Blocks excessive glutamate (excitotoxicity); can combine with AChEI
Lecanemab	Anti-Aβ monoclonal antibody	Early	2023 FDA-approved; slows progression; ARIA (amyloid-related imaging abnormalities) risk

PART 6: OPIOID ANALGESICS

Receptors: Three main types - μ (mu), κ (kappa), δ (delta). All are Gi-coupled (inhibitory) → ↓ cAMP, ↑ K⁺ efflux (hyperpolarization), ↓ Ca²⁺ influx → ↓ neuronal firing + ↓ neurotransmitter release.

Receptor	Location	Effect when activated
μ (MOR)	Brain, spinal cord, GI	Analgesia, euphoria, respiratory depression, constipation, miosis, physical dependence
κ (KOR)	Spinal cord, brain	Analgesia, sedation, dysphoria, miosis, diuresis
δ (DOR)	Brain	Analgesia, mood modulation

Mnemonic - "μ = Most effects" - all the major opioid effects are μ-mediated.

Opioid Drug Classes

Drug	Type	Notes
Morphine	Full μ agonist	Standard; active metabolite M6G accumulates in renal failure → avoid
Codeine	Prodrug → morphine (via CYP2D6)	Ultra-rapid metabolizers (African, Middle Eastern patients) = toxicity risk; can't use in nursing mothers
Oxycodone	Full μ agonist	Oral; OxyContin (extended-release) - epicenter of opioid epidemic
Hydromorphone	Full μ agonist	More potent than morphine; OK in renal failure
Fentanyl	Full μ agonist	Very lipid-soluble; transdermal, IV, intranasal; 100x more potent than morphine; illicit fentanyl in drug supply
Meperidine (Pethidine)	Full μ agonist	Metabolite normeperidine → seizures; avoid in renal failure, elderly; serotonin syndrome with MAOIs
Methadone	Full μ agonist + NMDA antagonist	Long T½ (24-36h); QT prolongation; used for addiction treatment, chronic pain
Tramadol	Weak μ agonist + SNRI	Lowers seizure threshold; serotonin syndrome risk; "mild" opioid
Buprenorphine	Partial μ agonist / κ antagonist	Ceiling effect on respiratory depression (safer); used for addiction; available as Suboxone (+ naloxone)
Nalbuphine, Butorphanol	κ agonist / μ antagonist	Mixed agonist-antagonist; can precipitate withdrawal
Tramadol	Weak μ + NE/5-HT reuptake inhibitor

Opioid Antagonists

Drug	Use
Naloxone	IV/IM/intranasal; reverses overdose; short T½ (re-dose for fentanyl!); can precipitate acute withdrawal
Naltrexone	Oral; alcohol use disorder + opioid use disorder (maintenance); no dependence
Methylnaltrexone	Peripheral μ antagonist; does NOT cross BBB; treats opioid-induced constipation without reversing analgesia

Opioid Overdose Triad: "Pinpoint pupils + Coma + Respiratory depression". Treatment: Naloxone (0.4mg IV; repeat every 2-3 min; infusion for long-acting opioids).

Constipation does NOT develop tolerance - always prescribe stool softeners/laxatives with opioids.

PART 7: CNS STIMULANTS

Drug	Mechanism	Use
Amphetamine	Reverses DAT/NET (efflux of DA, NE) + MAO inhibition	ADHD, narcolepsy
Methylphenidate	Blocks DAT/NET (reuptake inhibition)	ADHD, narcolepsy
Cocaine	Blocks DAT/NET/SERT	Drug of abuse; also topical anesthetic (vasoconstriction)
Modafinil	Unclear; promotes wakefulness via histamine, NE, DA	Narcolepsy, shift work disorder; low abuse potential
Caffeine	Adenosine receptor antagonist	Promotes wakefulness

PART 8: MOOD STABILIZERS

Lithium

Mechanism: Not fully understood. Inhibits inositol monophosphatase → depletes IP3/DAG second messengers; also affects glycogen synthase kinase-3 (GSK-3) → neuroprotective.

Uses: Acute mania (bipolar I), bipolar maintenance (best evidence), reduces suicide risk.

Pharmacokinetics: Renally eliminated. Narrow therapeutic index (0.6-1.2 mEq/L therapeutic; >1.5 = toxicity). Replaces Na⁺ ions in the body.

Drug interactions that RAISE lithium levels (→ toxicity):

Thiazide diuretics (Na⁺ depletion → kidney compensates by retaining Li⁺)
NSAIDs (reduce GFR)
ACE inhibitors

Mnemonic: "TAN makes you TOXIC" - Thiazides, ACE inhibitors, NSAIDs

Toxicity progression:

Mild (1.5-2): Fine tremor, GI, polyuria, polydipsia
Moderate (2-2.5): Coarse tremor, ataxia, confusion
Severe (>2.5): Coma, seizures, arrhythmias, cardiac arrest

Chronic toxicity: Nephrogenic diabetes insipidus (treat with amiloride, not thiazides), hypothyroidism, renal tubular acidosis.

PART 9: ANESTHETICS (CNS Overview)

General Anesthesia Stages (Guedel Classification)

Analgesia (awake, conscious)
Excitement (delirium, involuntary movement - dangerous stage)
Surgical anesthesia
Medullary depression (respiratory/CV arrest)

IV Anesthetics

Drug	Mechanism	Notes
Propofol	↑ GABA-A + ↓ NMDA	Rapid onset/offset; antiemetic; "milk of amnesia"; propofol infusion syndrome (acidosis, rhabdomyolysis)
Ketamine	NMDA antagonist	Dissociative anesthesia; bronchodilator; ↑ ICP; emergence reactions (hallucinations); preserves airway reflexes; analgesic
Thiopental	Barbiturate (GABA-A)	Ultra-short; ↓ ICP; "fixed dilated pupils" if extravasated
Etomidate	↑ GABA-A	Minimal CV/respiratory depression; adrenal suppression
Midazolam	BZD (GABA-A)	Anxiolysis, amnesia; no analgesia
Dexmedetomidine	α2 agonist	Sedation without respiratory depression; ICU sedation

MASTER COMPARISON TABLE: Drug Classes at a Glance

Drug Class	Core Target	Key Drugs	Major Toxicity
BZDs	GABA-A (↑ Cl⁻ frequency)	Diazepam, lorazepam, midazolam	Sedation, dependence, withdrawal seizures
Barbiturates	GABA-A (↑ Cl⁻ duration)	Phenobarbital, thiopental	Respiratory depression, narrow TI
SSRIs	SERT	Fluoxetine, sertraline	Serotonin syndrome, sexual dysfunction
SNRIs	SERT + NET	Venlafaxine, duloxetine	HTN (venlafaxine)
TCAs	SERT + NET + mACh + H1 + α1	Amitriptyline, nortriptyline	Anticholinergic, cardiotoxic
MAOIs	MAO-A/B	Phenelzine, tranylcypromine	Hypertensive crisis ("cheese reaction")
Typical APs	D2 blockade	Haloperidol, chlorpromazine	EPS, TD, NMS
Atypical APs	D2 + 5-HT2A blockade	Clozapine, olanzapine, aripiprazole	Metabolic syndrome; clozapine → agranulocytosis
Phenytoin	Na⁺ channel	Phenytoin	Zero-order kinetics, gingival hyperplasia
Valproate	Na⁺, GABA, T-Ca²⁺	Valproate	Teratogen, hepatotoxicity
Levetiracetam	SV2A	Levetiracetam	Behavioral effects
Opioids	μ, κ, δ receptors (Gi)	Morphine, fentanyl, oxycodone	Respiratory depression, constipation, addiction
Levodopa/Carbidopa	DA precursor	L-DOPA + Carbidopa	Dyskinesias, wearing-off
AChEIs	AChE inhibition	Donepezil, rivastigmine	GI, bradycardia
Lithium	IP3 depletion, GSK-3	Lithium	Narrow TI, DI, hypothyroidism

HIGH-YIELD MNEMONICS SUMMARY

Mnemonic	What it Recalls
"BZD = Frequency; Barb = Duration"	GABA-A opening pattern
"FINISH"	SSRI discontinuation syndrome
"Cheese Reaction"	MAOI + tyramine
"SHAM"	TCA receptor blockade
"TRAP"	Parkinson's features
"DAWN"	L-DOPA side effects
"Pinpoint pupils + Coma + Respiratory depression"	Opioid overdose triad
"TAN" (Thiazides, ACE-I, NSAIDs)	Lithium toxicity triggers
"FEVER"	NMS features
"4 A's of EPS"	EPS in order of onset
"PCB" (Phenytoin, Carbamazepine, Phenobarbital)	CYP inducers

HOW IT ALL CONNECTS - THE BIG PICTURE

INHIBITORY SIDE                           EXCITATORY SIDE
(GABA, Glycine, Opioids)                 (Glutamate, Catecholamines)
        ↑                                         ↑
BZDs, Barbiturates,                     Stimulants (amphetamine),
Ethanol, Propofol                       Ketamine (disrupts GABA 
                                         interneurons → net excitation)
        ↓                                         ↓
Too much inhibition                     Too much excitation
= Sedation, coma,                       = Seizures, psychosis,
  respiratory depression                  anxiety, mania

Every CNS drug tilts this balance in some direction. When you see an unknown drug, ask:

Does it increase or decrease inhibitory tone (GABA)?
Does it increase or decrease monoamine activity (DA/5-HT/NE)?
Which receptor subtypes, which brain circuits?
What happens when you remove it suddenly? (Withdrawal)

This guide covers the full breadth of CNS pharmacology. Each section can be expanded further. Good next steps would be practicing clinical vignettes for each drug class - let me know if you'd like practice questions, mechanism diagrams, or a deep dive into any specific area!

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