Pharmacology – Quiz Review, Receptor Regulation & Signal Transduction

Quiz #2 Review & Applied PK/PD Concepts

• Format of quiz questions mirrors real‐world package-insert reading and filtering of clinically relevant data.

Atenolol (Tenormin) – Steady-State Calculation

• Package-insert elimination half-life: $t<em>{1/2}\approx 6\text{–}7\,\text{h}$ (IV and PO identical once distribution complete). • Time to steady state $\approx 4\text{–}5\;t</em>{1/2}$ ⇒ $24\text{–}35\,\text{h}$.
• MCQ correct stem given: $32\,\text{h}$ (fits inside range; others impossible).
• Key reminder: rule only predicts time, not actual steady-state concentration.

Fluoxetine (Prozac) – CYP2D6 Inhibition

• Fluoxetine = strong CYP2D6 inhibitor → converts normal metabolizers → "phenotypic poor metabolizers".
• Concomitant 2D6 substrates with narrow TI (e.g.
• antidepressants, antipsychotics,
• anti-arrhythmics such as flecainide)
require low‐end dosing.
• Predicted outcome with flecainide + fluoxetine:
– Plasma flecainide ↑ significantly (correct answer).
– Half-life ↑ (not ↓).
– Dose lowered, not raised.
– Fluoxetine levels not markedly ↓.

Tamsulosin (Flomax) – Food Effect

• PK facts
– $T<em>{\max}$ fasting: $4\text{–}5\,\text{h}$; fed: $6\text{–}7\,\text{h}$. – Fasting ↑ bioavailability by $\approx 30\%$, ↑ $C</em>{\max}$ by $40\text{–}70\%$.
– Higher $C<em>{\max}$ ⇒ more α-blocker side-effects (dizziness, orthostasis). • Counseling: take 30 min after same meal each day (fed state) to blunt peak & limit AEs. • Food decreases, not increases, $F$ and $C</em>{\max}$.

Carvedilol – Hepatic Impairment

• Cirrhotic pts show $4\text{–}7\times$ higher AUC after single dose.
• Interpretation:
– Extensive hepatic metabolism.
– In liver disease → dose reduce; DO NOT increase.
– Requires adjustment; not renally excreted unchanged.

Symbicort (Budesonide + Formoterol)

• Budesonide (ICS): unionized, non-polar, ↑ lipid solubility ⇒ rapid membrane passage, tissue & fat distribution.
• Formoterol (LABA): more polar ⇒ slower diffusion; fewer distal systemic AEs vs steroid.
• Correct quiz statement: The steroid will pass membranes easily and may deposit in adipose tissue.

Nitroglycerin for Angina – Route Choice

• Potent vasodilator but high first-pass extraction.
• Need rapid relief: sublingual tablet/spray bypasses hepatic first pass.
• Oral & rectal routes insufficiently rapid.

Receptor Regulation & Plasticity

Fundamental Ideas

• Biological systems constantly modulate receptor number, location, conformation, or coupling to maintain homeostasis.
• Regulation timescale: seconds (phosphorylation) → hours/days (synthesis/degradation).

Mechanisms

• ↓/↑ gene transcription of receptor protein.
• Covalent modification (e.g., phosphorylation → inactivation).
• Association w/ regulatory proteins (β-arrestin).
• Receptor internalization (endocytosis).
• Uncoupling of downstream second‐messenger cascade.

Synaptic Transmission Refresher

Anatomy of a Chemical Synapse

• Presynaptic neuron synthesizes & stores neurotransmitter (NT) in vesicles.
• Action potential → $\mathrm{Ca^{2+}}$ influx → vesicle fusion & exocytosis.
• NT diffuses across cleft → binds postsynaptic receptors.

Termination of Signal

1. Reuptake transporter (dominant for monoamines).
2. Enzymatic degradation (e.g., acetylcholinesterase).
3. Autoreceptor‐mediated negative feedback (self or heterologous NT).

Norepinephrine (Adrenergic) Terminal – Drug Targets

• Precursor pathway: $\text{Tyrosine}\xrightarrow{\text{TH}}\text{DOPA}\xrightarrow{AADC}\text{Dopamine}\xrightarrow{DBH}\text{NE}$.
• Vesicular monoamine transporter (VMAT) loads NE.
• NET reuptake pump recovers NE (blocked by cocaine, TCA, SNRIs).
• Amphetamines: substrate for NET & VMAT → displace NE from vesicles → ↑ synaptic NE (indirect agonist).
• Presynaptic α2 autoreceptors: excess NE binds → ↓ further release (negative feedback).
• Enzymes (MAO, COMT) metabolize NE intra- & extra-neurally.

Acetylcholine (Cholinergic) Terminal – Drug Targets

• Choline uptake transporter brings precursor in; inhibited by hemicholinium.
• ChAT forms ACh from choline + acetyl-CoA.
• Vesicular ACh transporter (VAChT) blocked by vesamicol.
• Release blocked by botulinum toxin (fusion inhibitor).
• ACh degraded by acetylcholinesterase; inhibitors (e.g., physostigmine) ↑ ACh levels → indirect agonism.
• Muscarinic or nicotinic autoregulation plus heteroreceptors (e.g., 5-HT on cholinergic terminals).

Down-Regulation / Desensitization (Tachyphylaxis)

• Continuous/high agonist → progressive ↓ response despite constant [drug].
• Example: chronic albuterol overuse in asthma → β2-receptor desensitization → tolerance.
• Opioids: euphoria tolerance develops faster than respiratory-depression tolerance → OD risk.

Cellular Model (β-Arrestin Pathway)

1. Agonist binds GPCR → activates G protein & response.
2. GRK phosphorylates receptor.
3. β-Arrestin binds phospho-receptor.
4. Clathrin-coated pit internalizes receptor.
   – Short exposure → de-phosphorylation & recycling.
   – Prolonged exposure → lysosomal degradation; resensitization requires de novo synthesis.

Up-Regulation (Supersensitivity)

• Chronic antagonist or low agonist → cells ↑ receptor density/efficacy.
• Clinical example: chronic β-blockers → abrupt withdrawal can precipitate rebound tachycardia/HTN.

Homologous vs Heterologous Desensitization

Graph interpretation:
• Agonist A repeated → diminished response. Agonist B still works ⇒ homologous.
• If both A & B fail after A repeat → heterologous.

Four Major Receptor Superfamilies

1. Ligand-Gated Ion Channels (Ionotropic)

• Millisecond onset; direct ion flux.
• Examples & ions
– Nicotinic AChR: $Na^{+}$ in.
– GABA_A: $Cl^{-}$ in → hyperpolarize.
– 5-HT_3.
• Structure: pentameric subunits with central pore; ligand binds extracellular α-subunits.

2. G Protein-Coupled Receptors (GPCR)

• 7-TM α-helices, extracellular ligand pocket, cytosolic G-protein interface.
• G_s, G_i/o, G_q/11 dictate effector (AC ↑/↓, PLC).
• Examples: adrenergic (α,β), muscarinic (M1–M5), dopamine, histamine, many peptides.

3. Enzyme-Linked (Catalytic) Receptors

• Single-pass transmembrane proteins; ligand binding causes dimerization & intrinsic kinase or activates bound enzyme.
• Prototype: Insulin receptor (tyrosine kinase) → IRS phosphorylation → GLUT4 translocation.
• Others: EGFR, VEGFR, natriuretic peptide GC receptors.

4. Intracellular (Nuclear) Receptors

• Lipophilic ligands traverse membrane; complex binds specific DNA response elements.
• Timeframe: hours (gene transcription/protein synthesis).
• Ligands: steroid hormones (cortisol, estradiol), thyroid hormone, vitamin D, retinoic acid.

Major Second-Messenger Systems

Example pathway (α1-adrenergic): Epinephrine → GPCR (G_q) → PLC → $IP_3 + DAG$ ⇒ $\uparrow [Ca^{2+}]$ + PKC → vascular smooth-muscle contraction.

Clinical / Practical Nuggets

• Statins ↓ hepatic cholesterol synthesis → hepatocytes up-regulate LDL-R to pull LDL from plasma (receptor up-regulation concept).
• Nitrates: prescribe BID with nightly "nitrate-free interval" to prevent tolerance.
• Opioid addicts chase initial euphoria; genetic factors influence addiction vulnerability.
• Desensitization reversible; recovery depends on exposure duration & whether receptors recycled vs degraded.

Study Strategy for Upcoming Autonomic Pharmacology Block

• Before first lecture, review ANS physiology (sympathetic vs parasympathetic anatomy, transmitters, receptors).
– Use concise resources: Khan Academy, YouTube, etc.
• Build drug tables for each class:

1. Drug name
2. Mechanism/target
3. Therapeutic uses
4. Common adverse effects
5. Unique pearl/exception (leave blank, fill later).
   • Work individually, then compare with peers — active recall beats passive copying.
   • Leverage mnemonics but ground them in mechanism.