Neuropharmacology - Principles

What is pharmacology?

The study of drugs and their effects on biological systems

What is neuropharmacology?

The branch of pharmacology focused on how drugs affect the nervous system

what is a xenobiotic?

A substance foreign to the body that is introduced into the system

What is a pharmaceutical?

A chemical substance used to diagnose, treat, or prevent disease

what is a neuroactive xenobiotic?

A foreign substance that specifically affects the nervous system

What does pharmacokinetics study?

How the body handles and interacts with a drug

What does “ADME” stand for in pharmacokinetics?

Absorption

Distribution

Metabolism

Excretion/Elimination

What are the main methods of drug administration?

1. Oral

2. Intravenous

3. Topical/dermal

4. Intramuscular (under muscle)

5. Subcutaneous (under skin)

6. Sublingual (under tongue)

7. Intraperitoneal (abdominal cavity)

8. Inhalation

9. Intranasal

10. Rectal/suppository

11. epidural

12. intracranial

How is sublingual drug administration absorbed

It bypasses the GI tract and absorbs into blood vessels under the tongue

Which drug administration route delivers substances directly into the abdominal cavity?

Intraperitoneal

what is a key advantage of oral drug administration?

Ease of use an patient compliance

what is a disadvantage of oral drug administration?

Slower absorption and variable dose timing/amount into the bloodstream

Can oral drug administration be reversed?

Yes, it is somewhat reversible before full absorption

What is the main advantage of intravenous (IV) administration?

Fastest absorption and controlled dosing

what is a limitation of IV administration?

Requires a professional to administer and is non-reversible once delivered.

what are advantages of transdermal drug administration?

Ease of use and patient compliance

what are disadvantages of transdermal drug administration?

Slower absorption, somewhat reversible before full absorption, and variable dose timing/amount depending on the person

Which absorption method gives the fastest rise in plasma concentration?

Intravenous (IV)

Which absorption method maintains the most stable plasma concentration over time?

Transdermal

Which absorption method shows variable peaks in plasma concentration depending on dose timing?

Oral administration

What defines the “therapeutic range” in pharmacology graphs?

The concentration window where the drug is effective without being toxic

Why might oral administration require multiple doses in a day?

Because plasma concentration fluctuates with variable absorption and metabolism

What drug is commonly prescribed for ADHD and narcolepsy? 

Methylphenidate 

What clinical issue is associated with methylphenidate use?

Acute tolerance (reduced effectiveness after repeated doses in a short period)

What are examples of methylphenidate formulations?

• Ritalin (immediate-release)

• Ritalin LA (long-acting: 50% released immediately, 50% released later, effective for 6-8 hours)

• Concerta (extended release: 22% released immediately, 78% released gradually overtime, effective for 10-12 hours)

• Daytrana (transdermal patch).

Why are different formulations of methylphenidate developed? 

To control the rate of absorption, extend therapeutic effects, and reduce dosing frequency 

What is the benefit of transdermal methylphenidate (Daytrana)?

Provides steady drug delivery over hours, improving compliance and reducing fluctuations

What is the main limitation of immediate-release methylphenidate?

Short duration of action, requiring multiple doses per day 

How does concerta differ from other formulations of methylphenidate? 

It maintains plasma concentration within the therapeutic range for the longest duration 

Why are extended-release and long-acting formulations clinically useful? 

They improve patient compliance, reduce fluctuations in drug levels, and lower the risk of acute tolerance 

What is the therapeutic window in relation to methylphenidate formulations?

The plasma concentration range where the drug is effective but not toxic

What is Concerta’s brand name drug?

Methylphenidate 

What is unique about Concerta’s dosage form 

It provides a sustained and ascending drug release over a prolonged period 

how does concerta maintain therapeutic plasma levels?

By combining an initial immediate-release portion with a sustained-release mechanism

How does Concerta differ from immediate-release methylphenidate dosing schedules? 

Concerta maintains therapeutic effects with one dose per day, while immediate-release requires multiple doses every few hours 

What is the clinical benefit of Concerta’s ascending release profile?

It reduces fluctuations in drug levels, helps maintain consistent symptom control, and lowers the risk of side effects from peaks and troughs

In plasma concentration studies, how does Concerta compare tomultiple immediate-release doses?

Concerta produces a smoother, sustained curve while immediate-release causes repeated sharp peaks and drops

What is a product monograph? 

An official document that provides detailed prescribing and labeling information about a drug 

Who is the prescribing information in a product monograph intended for?

Physicians and other healthcare professionals

Who is the labeling information in a product monograph intended for?

Patients

Why are product monographs important?

They ensure safe and effective use of medications by providing standardized information for both prescribers and patients 

After ingestion, what organ processes xenobiotics before they enter systemic circulation? 

The liver, via portal blood 

What are the main elimination pathways for xenobiotics? 

• Feces (via GI tract)

• urine (via kidney)

• expired air (via lung)

Which compartments can xenobiotics distribute into once in the blood and lymph?

Extracellular fluid, fat, other organs, soft tissues, bone, and the brain

What is the step-by-step pathway for an oral xenobiotic to the brain?

1. Ingestion → GI tract

2. Transport via portal blood

3. Processed in the liver (first-pass metabolism)

4. Enters blood and lymph circulation 

5. Distributed to extracellular fluid, organs, fat, bone

6. Crosses into the brain/CNA if able 

What is the main function of the blood-brain barrier (BBB)?

To protect the brain by maintaining homeostasis in the neuronal/glial environment

How does the BBB maintain homeostasis for neurons and glia?

• Regulates ion balance and osmolarity via CSF 

• Facilitates uptake of nutrients (e.g., glucose) and hormones (e.g., insulin) 

• reduces fluctuations in blood (e.g., stress hormones, infection) 

What type of cells form the structural wall of the BBB? Where are they located?

Endothelial cells, which line the lumen of blood vessels

What connects endothelial cells in the BBB? What are they made of, and what do they contribute to? 

Tight junctions made of occludins and claudins, which create high electrical resistance across the BBB 

What is the BBB basement membrane made of, and role does it play?

Made of collagen, laminin, and fibronectin; it prevents the transport of macromolecules 

Why is the BBB significant in neuropharmacology?

It restricts which xenobiotics and drugs can reach the brain

What role do pericytes play in the BBB?

They surround endothelial cells, regulate blood flow, and help maintain BBB stability

How do astrocytes contribute to the BBB?

Their endfeet (glia limitans) provide structural support, regulate transport, and maintain the neuronal environment

What immune cells interact with the BBB and where are they located?

Antigen-presenting cells and leukocytes, found in perivascular and endothelial spaces 

What is the role of efflux enzymes like P-glycoprotein at the BBB?

They pump xenobiotics and drugs back into circulation, reducing CNS drug penetration

Which supporting structures around blood vessels contribute to BBB regulation?

Astrocytes, pericytes, and vascular smooth muscle cells (VSMCs)

Why can’t strictly hydrophilic drugs cross the BBB?

Because the BBB blocks water-soluble molecules that cannot diffuse through lipid membranes 

What type of drug property increases the chance of crossing the BBB? 

Hydrophobicity (e.g., nicotine crosses due to being hydrophobic) 

How does the octanol/water partition coefficient influence BBB penetration?

It measures lipophilicity; drugs with higher partition coefficients cross more easily

How does the partition coefficient explain the difference btween diphenhydramine (Benadryl) and loratadine (claritin) in crossing the BBB? 

Diphenhydramine is more lipophilic, allowing it to cross the BB easily, where it blocks central histamine receptors and causes sedation (drowsiness).. Loratadine, although also an antihistamine, is less lipophilic and designed to stay mostly peripheral, so it does not cross the BBB effectively and does not cause sedation 

What is the paracellular pathway across the BBB and how can it be used?

It involves temporarily disrupting tight junctions (e.g., with osmotic shock, electric fields, focused ultrasound) to allow xenobiotics to pass between endothelial cells 

What is transporter-mediated entry into the brain? 

Xenobiotics mimic endogenous molecules (e.g., glucose, insulin) and use transport proteins to cross the BBB

What type of xenobiotics typically cross by lipophilic diffusion?

Lipophilic molecules like ethanol, nicotine, benzodizaepines, and opiates

How does receptor-mediated transcytosis allow drugs to cross the BBB?

Xenobiotics attach to ligands that bind to specific receptors (e.g., insulin, LDL receptors), undergo endocytosis, travel across the endothelial cytoplasm, and are exocytosed into the brain

What is adsorptive-mediated transcytosis, and what makes it different from receptor-mediated transcytosis? 

Positively charged xenobiotics bind to negatively charged endothelial membranes, enter via endocytosis, cross the cytoplasm, and exit via exocytosis. Unlike receptor-mediated, it is non-specific to the BBB 

What are examples of xenobiotic carriers used in adsorptive-mediated transcytosis?

Positively charged cell-penetrating peptides like penetratin and transportan 

What is the intracerebroventricular delivery, and how does it bypass the BBB?

A drug is injected directly into the brain’s ventricles (e.g., via an Ommaya reservoir) using a pump or catheter, bypassing the BBB and entering the CSF 

What is convection-enhanced delivery, and how does it differ from diffusion alone? 

Drugs are infused into brain parenchyma using catheters and a positive pressure gradient pump, which drives both convection and diffusion into tissue 

What is intraparenchymal/intracerebral delivery?

Direct drug injection or implant into brain tissue after surgical exposure, bypassing the BBB completely 

How does intranasal delivery bypass the BBB?

Drugs sprayed into the nasal cavity reach the brain via olfactory and trigeminal nerve pathways, using extracellular diffusion and intraneuronal transport

What is the intratympanic method of BBB bypass? 

Drug is injected through the tympanic membrane into the middle ear, crosses the round window membrane, enters perilymph/CSF, and travels to the brain 

What is the main clinical advantage of physical BBB bypass methods?

They allow direct delivery of drugs to the brain, avoiding systemic metabolism and efflux transporters 

What are the main molecular targets of pharmaceutical xenobiotics in the brain?

Neurotransmitter receptors, transporters, metabolites, enzymes, and genetic mechanisms 

How can xenobtioics target neurotransmitter receptors? 

By acting as agonists, antagonists, or modulators to alter neuronal signalling 

How can xenobiotics affect transporters in the brain?

By blocking or enhancing reuptake/efflux of neurotransmitters or other molecules, changing synaptic concentrations 

How can xenobiotics influence brain metabolites and enzymes? 

They may alter metabolic pathways or inhibit enzymes to modify neurotransmitter levels 

What genetic tools can xenobiotics or drug-like agents target in neuropharmacology? 

• CRISPR/Cas9 for gene editing

• RNA interference for silencing genes

• Epigenetic modifications for regulating gene expression

What structural features define G-protein coupled receptors (GPCRs)?

They are single peptides with 7 transmembrane domains that span the cell membrane 

How do GPCRs activate intracellular signaling?

By binding GTP to a tetometic G protein composed of alpha, beta and gamma subunits

What determines the specific effector apthway of a GPCR?

They type of G-alpha subunit (Gs, Gi, G1, etc)

What does the G-alpha-s pathway do?

Activates adenylyl cyclase, increases cAMP, and activates PKA for phosphorylation events 

What does the G-alpha-i pathway do?

Inhibits adenylyl cyclase, decreases cAMP production, and activates GIRK (G-protein inwardly rectifying K+) channels via beta-gamma subunits

WHat is the functional effect of opening GIRK channels?

K+ ions leave the neuron, hyperpolarizing it and reducing excitability

What does the G-alpha-q pathway do?

Activates phospholipase C (PLC), which converts PIP2 → P3 and DAG

How does G-alpha-q signaling affect ion channels?

Depletion of PIP2 may close PIP2-supported K+ channels (e.g., KCNQ/Kv7), causing depolarization

How do IP3 and DAG affect neurons? 

IP3 increases intracellular Ca2+ release; DAG activates PKC, leading to phosphorylation events 

What are some targets of GPCR beta-gamma subunits?

GIRKs (open), N-type Ca2+ channels (inhibit), phospholipase C-beta-2 (activate), adenylyl cyclases (stimulate or inhibit depending on subtype), PI2-kinase (activate), protein tyrosine kinase (activate), MAPK pathways (activate)

Why are GPCRs major drug targets in neurpharmacology? 

They regulate neurotransmission broadly and control key pathways for excitability, synaptic signalling, and gene expression 

Which GPCR subtypes does glutamate act on, and what G-proteins do they couple to? 

• mGluR1, mGluR5 → Gq

• mGluR2-4, 6-8 → Gi 

Which GABA receptor is a GPCR, and what G-protein does it couple to?

GABA-_B  receptor; couples to Gi 

Which muscarinic acetylcholine receptors couple to Gq, and which to Gi? 

Gq: m1, m3, m5

Gi: m2, m4

Which serotonin (5-HT) receptors couple to Gs, Gq, and Gi?

• Gs: 5-HT4, 5-HT6, 5-HT7

• Gq: 5-HT2

• Gi: 5-HT1, 5-HT5 

Which dopamine receptors couple to Gs and which to Gi?

• Gs: D1, D5

• Gi: D2, D3, D4

Which opioid receptors couple to Gi?

μ (mu), δ (delta), κ (kappa).

What family do ligand-gated ion channels (LGICs) with 4 transmembrane domains belong to? 

The Cys-loop receptor family 

What is the general structure of Cys-loop ligand-gated ion channels?

They are composed of five subunits, each containing four transmembrane domains M1-M4

Can Cys-loop LGICs form homomeric and heteromeric receptors?

Yes, they can assemble as homomeric (identical subunits) or hetermomeric (different subunits) receptors. 

How is ion selectivity determined in LGICs?

By the amino acid composition within the ion pore:

• Negative residues → selective for cations (Na+, K+, Ca2+)

• Positive residues → Selective for anions (Cl-)

What is the main functional effect of LGIC activation?

Opening of the channel allows rapid ion flow, altering membrane potential (e.g., depolarization or hyperpolarization). 

Which neurotransmitter receptors are cation-selective LGICs?

Nicotinic acetylcholine receptors and 5-HT3 receptors (allow Na+, K+, Ca2+ to pass)