MedChem Exam #3

What is the primary function of pharmacodynamics?

The study of what the drug does to the body

What kind of drug would target intracellular receptors like nuclear hormone receptors?

Glucocorticoids such as Prednisone

How would glucocorticoids target a nuclear hormone receptor?

They diffuse into the cell and bind to gluticorticoid receptors, forming a complex that translocates to the nucleus

Is the serotonin transporter (SERT) an example of a cellular, extracellular or intracellular target?

Cellular - it’s a membrane transporter located on the cell surface of the neurons

Which class of drugs typically targets voltage-gated ion sodium channels?

Anticonvulsants or local anesthetics such as phenytoin or lidocaine.

Would glucocorticoids act on intracellular or extracellular receptors?

Intracellular - they bind nuclear hormone receptors inside the cell

What are the most common drug targets?

Proteins

What type of coupling mechanism is used by ligand-gated ion channels?

Direct ion channel coupling (ionotropic) - the receptor itself is an ion channel that opens upon ligand binding

What type of coupling occurs in G-protein coupled receptors?

G-protein signaling receptors activate intracellular G-proteins which then trigger 2nd messenger pathways like cAMP, IP3, DAG

How do transmembrane receptors linked to intracellular enzymes transmit signals?

Enzymatic coupling - ligand binding activates intrinsic or associated enzyme activity, for example kinase activity in receptor tyrosine kinases

What kind of coupling is involved with receptors that stimulate cGMP synthesis?

Guanylyl cyclase coupling - receptors catalyze conversion of GTP to cGMP upon ligand binding

What type of coupling is used by nuclear hormone receptors and transcription factors?

DNA coupling - these intracellular receptors bind ligand, translocate to the nucleus, and directly regulate gene transcription

If there are 4 subunits/domains, with 6 transmembrane helices each, how many TOTAL transmembrane helices are there?

24 transmembrane helices

What structural feature makes the S4 segment of voltage-gated ion channels sensitive to changes in membrane potential?

The S4 helix contains positively charges residues (arginine/lysine) every 3rd amino acid, allowing it to detect voltage changes across the membrane

Which transmembrane segments form the pore and selectivity filter of a voltage-gated ion channel?

The S5 and S6 segments, along with the P-loop between them, form the pore and determine ion selectivity

If a voltage-gated ion channel has 24 transmembrane helices, how many domains or subunits foes it likely have?

4 domains with 6 transmembrane helices (S1-S6)

What are 2 major types of voltage-gated sodium channels?

NaV1 and NaV2

What is the primary physiological role of voltage-gated Na channels?

They generate and propagate action potentials in excitable tissues like neurons and muscle cells

What can result from mutations in sodium channel genes?

Loss of function or gain of function mutations can lead to neurological and muscular disorders

Why are voltage gated Na channels considered drug targets?

Because they are critical for electrical signaling, they are targeted by toxins and drugs to modulate nerve and muscle activity

Name a drug and toxin that target voltage-gated Na channels

Drug: Lidocaine
Toxin: Tetrodotoxin

HVA

High voltage activated - big change needed, more regulatory subunits

LVA

Low voltage activated - small change needed

Depolarization of the neuron causes the VGCC to ______

open

What is it called when calcium enters the cell through the open VGCC?

Influx

Influx of calcium is essential for triggering _____ _______ _______ with the plasma membrane, leading to the exocytosis of neurotransmitters into the synaptic cleft

synaptic vesicle fusion

What will lead to increased NT exocytosis?

Calcium stabilizing and activating the release machinery at the synaptic terminal.

What is the concept of a receptor?

Macromolecules bind to endogenous substance and initiate a conformational change that activates a cell signaling pathway inside the cell

What type of membrane protein opens in response to ligand binding, is directly coupled to ion channels, mediates fast responses, and plays a key role in neurotransmission, cardiac conduction, and skeletal muscle contraction? Give examples of both excitatory and inhibitory types.

Ligand-gated ion channels (LGICs).

• Excitatory examples: nicotinic ACh receptors (nACh), NMDA (glutamate) receptors

• Inhibitory examples: GABA_A receptors, glycine receptors

• These receptors are less selective than voltage-gated ion channels and respond in milliseconds.

Oligomeric

5 subunits (2 alpha and others such as beta and gamma)

For the alpha-subunit of a ligand-binding site, both of the alpha sites need to be _____ to be open

bound

Depolarization

Excitation - leads to neurotransmission and muscle contraction

Hyperpolarization

inhibition - stops neurotransmission and muscle contraction

A 78 year old patient is prescribed diphenhydramine for allergies. A few days later, he reports confusion, dry mouth, and difficulty urinating. What is the likely cause of these symptoms, and what patient population is most vulnerable?

These are anticholinergic side effects (anti-SLUD) caused by 1st generation H1 blockers like diphenhydramine, which block muscarinic receptors. Elderly patients are especially vulnerable due to increased CNS sensitivity and risk for anticholinergic toxicity (delirium, urinary retention)

A patient is experiencing seasonal allergic rhinitis but wants a nn-drowsy option for daytime use. The pharmacist recommends loratadine. Why is this a better option than diphenhydramine?

Loratadine is a 2nd generation H1 blocker that does not cross the BBB effectively, causing minimal sedation. In contrast, diphenhydramine is a 1st gen antihistamine that is highly lipophilic and enters the CNS, causing drowsiness.

A patient asks why their antihistamine isn’t stoing their seasonal allerges completely. You explain the H1 blockers don’t prevent histamine release. What is their mechanism of action?

H1 receptor blockers (antihistamines) are inverse agonists that bind to H1 receptor and stabilize it in its inactive form, reducing receptor activity. They do not prevent histamine release, but they block its effects on smooth muscle vasculature and sensory nerves.

A college student is taking cetirizine for allergies but still feels slightly sleepy. They ask why its happening despite it being a 2nd gen antihistamine. What do you tell them?

While cetirizine is a 2nd gen anthistamine with limited CNS penetration, it stil has mild sedative potential in sensitive indivisuald. Other 2nd gen options like fexofenadine or loratadine may be even less sedating due to lower CNS activity and being P-glycoprotein substrates.

A patient on an ACE inhibits develops angioedema. What is the role of kinins in this ADE and which receptor is involved?

ACE breaks down bradykinins; when ACE is inhibited bradykinin accumulates, activating B2 receptors. This leads to vasodilation and increased vascular permeability, resulting in angioedema. This is a common non-allergic side effect of ACE inhibitors.