Pharmacology Exam 3

Which of the following is not controlled by the autonomic nervous system (ANS)?

a. Heartbeat

b. GI motility

c. Skeletal muscle contraction

d. Vascular tone

c. Skeletal muscle contraction

Which of the following correctly pairs the autonomic branch with its main neurotransmitter at the effector organ?

a. Sympathetic - Acetylcholine

b. Parasympathetic - Norepinephrine

c. Sympathetic - Norepinephrine

d. Parasympathetic - Epinephrine

c. Sympathetic - Norepinephrine

The “fight or flight” response is primarily mediated by:

a. Parasympathetic nervous system

b. Enteric nervous system

c. Sympathetic nervous system

d. Somatic nervous system

c. Sympathetic nervous system

The adrenal gland functions as a special endocrine organ for:

a. Parasympathetic nervous system

b. Sympathetic nervous system

c. Both systems

d. Neither system

b. Sympathetic nervous system

Which of the following best describes a ganglion?

a. The target organ for autonomic neurons

b. A relay station where pre- and post-ganglionic neurons synapse

c. The endocrine gland for PANS

d. The site where neurotransmitters are degraded

b. A relay station where pre- and post-ganglionic neurons synapse

During a “fight or flight” response, blood flow to skeletal muscles ______, while blood flow to the GI tract ______.

Increases; decreases

Which of the following correctly describes adrenergic receptors?

a. Used by parasympathetic neurons

b. Activated by acetylcholine

c. Activated by norepinephrine and epinephrine

d. Found only in skeletal muscles

c. Activated by norepinephrine and epinephrine

Activation of β-adrenergic receptor typically involves which G-protein and second messenger system?

a. Gi → ↓ cAMP

b. Gs → ↑ cAMP

c. Gq → ↑ IP₃/DAG

d. Gs → ↓ cAMP

b. Gs → ↑ cAMP

Which statement is true regarding α₂-adrenergic receptors?

a. Coupled to Gs protein

b. Increases adenylyl cyclase activity

c. Decreases intracellular cAMP levels

d. Causes smooth muscle contraction

c. Decreases intracellular cAMP levels

Which effect occurs during parasympathetic (rest and digest) activation?

a. Pupil dilation

b. Increased heart rate

c. Bladder wall relaxation

d. Sphincter relaxation

d. Sphincter relaxation

T/F: The enteric nervous system is a major focus of autonomic pharmacology.

False

T/F: Sympathetic and parasympathetic systems are never active at the same time.

False

T/F: The balance between sympathetic and parasympathetic tone determines physiological outcomes.

True

T/F: Epinephrine and norepinephrine bind to the same adrenergic receptor subtypes.

True

T/F: Smooth muscle contraction or relaxation depends on the type of G-protein coupled to the receptor.

True

T/F: All FDA-approved adrenergic drugs trigger the entire “fight or flight” response.

False

T/F: Vasoconstriction generally increases blood pressure.

True

T/F: During “fight or flight”, the bladder wall contracts and sphincter relaxes to promote urination.

False

How does the autonomic nervous system (ANS) control blood pressure by regulating vascular tone?

• Vasoconstriction (via SANS) decreases vessel diameter → increases resistance → raises BP.

• Vasorelaxation (via PANS or decreased SANS tone) widens vessels → decreases resistance → lowers BP.

Describe the sequence of neuronal communication in the ANS, starting from the spinal cord to the target organ.

• ANS pathway:

  • Spinal cord → preganglionic neuron → autonomic ganglion → postganglionic neuron → target organ.

• Where neurotransmitters differ → SANS uses NE, PANS uses ACh at the effector.

Compare the physiological effects of sympathetic and parasympathetic activation on the heart, GI tract, and bladder.

• Heart:

  • ↑ Heart rate, ↑ contractility (sympathetic)

  • ↓ Heart rate (parasympathetic)

• GI tract:

  • ↓ Motility, ↓ secretion (sympathetic)

  • ↑ Motility, ↑ secretion (parasympathetic)

• Bladder:

  • Wall relaxes, sphincter contracts; harder to urinate (sympathetic)

  • Wall contracts, sphincter relaxes; easier to urinate (parasympathetic)

Using the β and α₂ adrenergic receptor example, explain how the same neurotransmitter (epinephrine) can cause opposite effects in different tissues.

• β-receptors (Gs) activate adenylyl cyclase:

  • ↑ cAMP → contraction (e.g., heart or certain smooth muscles).

• α₂-receptors (Gi) inhibit adenylyl cyclase:

  • ↓ cAMP → relaxation.

Same first messenger, opposite cellular effects due to different G-proteins.

What are 2 examples of clinical conditions that can result from autonomic nervous system (ANS) dysfunction?

• Orthostatic hypotension (failure of SANS to constrict vessels upon standing).

• Bladder incontinence (loss of PANS control of bladder and sphincter muscles).

Drugs that activate adrenergic receptors elicit which type of physiological response?

a. Parasympatholytic

b. Sympathomimetic

c. Cholinergic

d. Muscarinic

b. Sympathomimetic

Which of the following drugs would most likely increase heart rate?

a. β-blocker

b. Muscarinic agonist

c. Muscarinic antagonist

d. α-blocker

c. Muscarinic antagonist

Which receptor subtype is primarily responsible for bronchodilation when activated?

a. α₁

b. β₁

c. β₂

d. α₂

c. β₂

Albuterol is classified as a:

a. Non-selective β agonist

b. β₁-selective agonist

c. β₂-selective agonist

d. α₁-selective agonist

c. β₂-selective agonist

Which statement correctly describes a “sympatholytic” drug?

a. Mimics the parasympathetic nervous system

b. Inhibits sympathetic activity

c. Stimulates adrenergic receptors

d. Activates muscarinic receptors

b. Inhibits sympathetic activity

Activation of which G-protein leads to stimulation of adenylyl cyclase and increased cAMP?
a. Gq

b. Gi

c. Gs

d. Gβγ

c. Gs

α₁-adrenergic receptors are coupled to which G-protein and second messenger pathway?

a. Gs → cAMP

b. Gq → IP₃/DAG

c. Gi → ↓cAMP

d. Gs → Ca²⁺ influx

b. Gq → IP₃/DAG

Which of the following effects would be expected during a “fight or flight” response?

a. Decreased heart rate and bronchodilation

b. Increased GI motility and vasodilation in skin

c. Pupil dilation and increased cardiac contractility

d. Bronchoconstriction and increased salivation

c. Pupil dilation and increased cardiac contractility

Which statement best explains the paradox between α₁ and β₂ receptor activation on vasculature?

a. Both cause vasodilation

b. Both cause vasoconstriction

c. α₁ causes vasoconstriction while β₂ causes vasodilation

d. β₂ causes vasoconstriction while α₁ causes vasodilation

c. α₁ causes vasoconstriction while β₂ causes vasodilation

Excessive activation of cardiac β₁ receptors can lead to:

a. Bradycardia and hypotension

b. Tachycardia and arrythmias

c. Miosis and bronchoconstriction

d. Increased GI motility

b. Tachycardia and arrythmias

T/F: Adrenergic agonists are also known as “sympatholytics”.

False

• Adrenergic agonists are sympathomimetics

T/F: Parasympathetic drugs inhibit the “rest and digest” system.

True

T/F: Both adrenergic agonists and muscarinic antagonists can increase heart rate.

True

T/F: Gq protein signaling involves generation of cAMP as a second messenger.

False

• Gq uses IP₃/DAG, not cAMP

T/F: β₂ receptor activation increases intracellular cAMP.

True

Why can both β₂ agonists and muscarinic antagonists be used in asthma treatment?

• β₂ agonists cause bronchodilations via Gs → cAMP

• Muscarinic antagonists block PANS bronchoconstriction

Describe the difference in signaling between β-adrenergic receptors and α₁-adrenergic receptors.

• β receptors → Gs → ↑cAMP

• α₁ receptors → Gq → IP₃/DAG → ↑Ca²⁺

A patient overdoses on a non-selective adrenergic agonist. Predict 2 possible adverse effects and explain their physiological basis.

1. Excessive β₁ stimulation that results in tachycardia and arrhythmias

2. β₂ stimulation, leading to tremors and hypokalemia

What determines whether a drug is “sympathomimetic” or “sympatholytic”, is it based on receptor type or physiological response?

Based on physiological response, not receptor type (or PD)

Explain how activation of α₁ and β₂ receptors in different vascular beds support redistribution of blood during “fight or flight”.

• α₁ receptors constricts non-essential vessels (e.g., skin, GI)

• β₂ receptors dilates skeletal muscle vasculature for oxygen delivery

What are different aspects of ligand-receptor pair that one can use to design drugs?

• Affinity — how strongly the ligand binds to the receptor

• Efficacy (intrinsic activity) — whether it activate (agonist) or blocks (antagonist) the receptor

• Selectivity — preference for one receptors subtype over another (e.g., α1 vs. β2)

• Receptor subtype localization — targeting receptors found in specific tissues/organs

• Signal transduction pathway — designing drugs that favor certain intracellular responses (e.g., Gs vs. Gq coupling)

What does “direct-acting” mean?

A direct-acting drug binds directly to a receptor and either activates it (agonist) or blocks it (antagonist)

• e.g., Phenylephrine is a direct-acting α1 agonist that binds and activated the α1 adrenergic receptor

What does “indirect-acting” mean?

Indirect-acting drugs (e.g., amphetamine) increase the amount of endogenous ligand (e.g., norepinephrine) that’s available to stimulate the receptor

What are catecholamines?

Endogenous adrenergic neurotransmitters derived from tyrosine that contain a catechol (benzene with two -OH groups) and an amine group

What are the 3 main catecholamines?

1. Epinephrine (adrenaline)

2. Norepinephrine (noradrenaline)

3. Dopamine

Phenylephrine — what receptor subtype is it selective for? agonist or antagonist?

α1-selective agonist

• Causes vasoconstriction; used for nasal decongestion and to reduce edema

Midodrine — what receptor subtype is it selective for? agonist or antagonist?

α1-selective agonist

• Used to raise blood pressure in patients with orthostatic hypotension

How is α1 adrenergic receptor different from G-protein coupled receptors (GPCRs)?

The α1 adrenergic receptor itself is a GPCR, but it couples specifically to Gq

How is Gq different from the other G proteins?

Gq activates phospholipase C (PLC), producing IP₃ and DAG.

IP₃ increases intracellular Ca²⁺ by releasing it from the sarcoplasmic reticulum.

• Gs, which is used by β receptors, activates adenylyl cyclase → increases cAMP

• Gi inhibits adenylyl cyclase → decreases cAMP

α1 receptors → Gq → PLC/IP3/DAG → Ca²⁺ increase → contraction

How does activation of α1 in vascular smooth muscle cells lead to muscle contraction?

1. Agonist (e.g., epinephrine or phenylephrine) binds to α1 receptor.

2. Gq protein activates phospholipase C (PLC).

3. PLC generates IP₃ and DAG.

4. IP₃ triggers Ca²⁺ release from the sarcoplasmic reticulum.

5. Ca²⁺ binds to calmodulin, forming a Ca²⁺- calmodulin complex.

6. This activates myosin light chain kinase (MLCK).

7. MLCK phosphorylates myosin light chain (MLC), allowing myosin-actin cross-bridge formation and smooth muscle contraction.

• High MLCK activity → contraction → vasoconstriction → ↑ blood pressure

• Low MLCK activity (e.g., via β2 activation) → relaxation → vasodilation → ↓ blood pressure

How does selective α1 receptor activation help with nasal congestion or edema?

α1 activation causes vasoconstriction of blood vessels in nasal and inflamed tissues. This reduces vascular permeability and tightens endothelial gaps, preventing fluid leakage into surrounding tissue.

• Results in decreased swelling (edema) and relief from nasal congestion.

• e.g., phenylephrine in Sudafed PE

What are α1-selective agonists used for, and why?

• Treats nasal congestion or edema (phenylephrine)

• Treats orthostatic hypotension (midodrine)

• Adjunct with local anesthetics (epinephrine, to reduce systemic absorption)

• Treats anaphylaxis (epinephrine helps via α1-mediated vasoconstriction)

What are potential undesirable side effects of α1-selective agonists?

• Hypertension (due to excessive vasoconstriction)

• Reflex bradycardia (baroreceptor response to increased BP)

• Ischemia in extremities (from decreased blood flow)

• Urinary retention (in prostate smooth muscle contraction)

Orthostatic (postural) Hypotension

When blood pressure drops abnormally upon standing from sitting or lying down, causing dizziness, lightheadedness, or fainting.

• Due to inadequate sympathetic α1-mediated vasoconstriction when standing.

• Midodrine, an α1 agonist, helps increase vascular tone and maintain BP

How does epinephrine help resolve anaphylaxis?

Acts on multiple adrenergic receptor subtypes:

• α1: Vasoconstriction → increases BP, reduces edema, decreases mucosal swelling.

• β₁: Increases heart rate and contractility → restores cardiac output.

• β₂: Relaxes bronchial smooth muscle → bronchodilation and improved airflow.

• Inhibits histamine release from mast cells.

Reverses hypotension, airway constriction, and tissue swelling rapidly

What are main organs/tissues of interest when it comes to β₁ and β₂ receptors?

• β₁ receptors: Primarily in the heart (and kidneys)

  • Increases heart rate, contractility, and renin release.

• β₂ receptors: Found in smooth muscle of the lungs, vasculature, and uterus

  • Causes bronchodilation, vasodilation, and smooth muscle relaxation.

Dobutamine — what is its main therapeutic use?

β₁-selective agonist

• Used for acute heart failure or cardiac stress testing; increases cardiac output.

Albuterol — what is its main therapeutic use?

β₂-selective agonist

• Used for asthma or COPD; causes bronchodilation

What would be the potential risk(s) of using dobutamine for long term, and why?

• Increased myocardial oxygen demand due to enhanced contractility and workload.

• If oxygen supply cannot keep up (especially in HF), ischemia occurs.

• Myocyte death and fibrosis follow, worsening cardiac function over time.

Hence, dobutamine is only used short-term in acute settings

Which of the following best describes the primary pathology in asthma?

a. Overproduction of surfactant in alveoli

b. Chronic inflammation and airway remodeling

c. Degeneration of smooth muscle in bronchioles

d. Bacterial infection of upper airways

b. Chronic inflammation and airway remodeling

Metaplasia refers to:

a. Increase in cell number

b. Replacement of one cell type by another

c. Accumulation of fibrotic tissue

d. Mutation in epithelial cells

b. Replacement of one cell type by another

What is the main histopathological change in asthmatic airways?

a. Increased smooth muscle apoptosis

b. Loss of ciliated cells only

c. Fibrosis and epithelial cell hyperplasia

d. Decrease in mucus production

c. Fibrosis and epithelial cell hyperplasia

In the 2008 Nguyen et al. study, β-blocker treatment of asthmatic mice led to:

a. Worsening of airway inflammation

b. No effect on inflammation

c. Complete loss of β2 receptor expression

d. Improvement of airway inflammation

d. Improvement of airway inflammation

β2 receptor activation in which cell type was associated with airway inflammation in the 2017 Nguyen et al. study?

a. Smooth muscle cells

b. Epithelial cells

c. Fibroblasts

d. Neutrophils

b. Epithelial cells

The phosphorylation of adrenergic receptor C-terminus after activation is catalyzed by which of the following?

a. G-protein receptor kinase (GRK)

b. Protein kinase A

c. Tyrosine kinase

d. Adenylate cyclase

a. G-protein receptor kinase (GRK)

Which of the following correctly describes “biased agonism”?

a. Activation of both G-protein and β-arrestin pathways equally

b. Preferential activation of one signaling pathway over another

c. Non-specific binding to multiple receptor subtypes

d. Complete blockade of receptor activity

b. Preferential activation of one signaling pathway over another

Which transport is blocked by cocaine?

a. VMAT

b. MAO

c. NET

d. COMT

c. NET

Amphetamines increase norepinephrine (NE) levels primarily by…

a. Blocking VMAT and increasing cytoplasmic NE release

b. Inhibiting MAO degradation

c. Stimulating β2 receptors directly

d. Increasing NE synthesis via tyrosine hydroxylase

a. Blocking VMAT and increasing cytoplasmic NE release

Which of the following is a mixed-acting adrenergic agonist?

a. Albuterol

b. Cocaine

c. Ephedrine

d. Methylphenidate

C. Ephedrine

T/F: β-arrestin binding promotes receptor internalization and desensitization.

True

T/F: Tachyphylaxis occurs because GPCRs permanently lose their ligand-binding ability.

False

• It’s usually reversible after receptor recycling

T/F: Ipratropium is an anti-muscarinic agent that complements β2 agonists in asthma therapy.

True

T/F: Corticosteroids reduce airway inflammation partly by decreasing β2 receptor expression.

False

• They upregulate β2 receptor expression and reduce inflammation

T/F: Amphetamines can cross the blood-brain barrier due to their high lipid solubility.

True

Why are β2 agonists like albuterol beneficial for asthma treatment.

Stimulates β2 receptors on airway smooth muscle → activates adenylate cyclase → ↑ cAMP → relaxation of bronchial smooth muscle → bronchodilation and symptom relief

Why are corticosteroids often co-administered with β2 agonists in asthma or COPD?

Corticosteroids suppress inflammation and enhance β2 receptor expression, improving efficacy and preventing tolerance to β2 agonists.

Two mechanisms that occur after β-arrestin binds to a GPCR

1. Receptor internalization via endocytosis

2. Activation of β-arrestin-mediated signaling pathways independent of G-proteins

How does methylphenidate (Ritalin) differ from amphetamine (Adderall) mechanism-wise?

Methylphenidate blocks DAT and NET reuptake transporters; amphetamine increases neurotransmitter release by reversing transporters and inhibiting VMAT.

Describe the function of NET

Uptake of NE from synaptic cleft back into presynaptic neuron

Describe the function of VMAT

Packages NE into vesicles for storage/release

Describe the function of MAO

Degrades cytoplasmic monoamines like NE, dopamine, and serotonin

What is wrong with asthmatic airways?

Etiology: Chronic inflammatory disorder of the airways, often triggered by allergens, infections, or irritants.

Symptoms: Wheezing, coughing, shortness of breath, chest tightness.

Pathophysiology: Airway hyperresponsiveness and bronchoconstriction due to smooth muscle contraction, mucus overproduction, and inflammation.

Histopathology: 

• Goblet cell hyperplasia → excess mucus

• Epithelial cell damage and metaplasia

• Fibrosis of basement membrane

• Smooth muscle hypertrophy and infiltration of eosinophils and mast cells

What is metaplasia?

Reversible replacement of one differentiated cell type with another (e.g., ciliated epithelium → squamous epithelium)

How is metaplasia different from hyperplasia?

Metaplasia is the replacement of one cell type with another

Hyperplasia is the increase in number of cells due to proliferation

What is fibrosis?

Excessive deposition of extracellular matrix (mainly collagen) → thickening and stiffening of tissue

What is ‘epithelium’ or ‘epithelial cells’?

Epithelium is a layer of cells covering body surfaces and lining airways

Epithelial cells form a barrier and secrete mucus

What are knockout (KO) mice and transgenic mice?

Knockout (KO): Animals where a specific gene (e.g., β₂ adrenergic receptor) is deleted or inactivated to study its function.

Transgenic: Mice that carry an inserted foreign gene to study gene overexpression or functional effects.

Nguyen et al. (2008): What was the outcome of β-blocker treatment in asthmatic mice?

Chronic β-blocker treatment (e.g., propranolol) improved airway function and reduced inflammation in the mice.

• Suggests that prolonged blockade of β₂ receptors may desensitize inflammatory signaling and restore normal receptor balance.

Nguyen et al. (2017): What are the main take-home messages?

β₂ receptor activation in airway epithelial cells, not smooth muscle, promoted inflammation via pro-inflammatory gene expression.

• Chronic β₂ agonist use (like albuterol) can worsen inflammation if not paired with anti-inflammatory drugs (e.g., corticosteroids).

What would happen if β₂ receptor gene was deleted in smooth muscle cells while using albuterol?

Albuterol would not produce pro-inflammatory effects, because those depend on β₂ activation in epithelial cells, not smooth muscle.

Why use an anti-muscarinic agent, such as ipratropium, with β₂ agonists in treatment of asthma and COPD?

β₂ agonists relax smooth muscle via sympathetic stimulation; Ipratropium blocks parasympathetic M₃ receptors, preventing bronchoconstriction and mucus secretion.

• Together, they provide additive bronchodilation and reduce airway resistance.

Why use corticosteroids with β₂ agonists in the treatment of asthma and COPD?

Corticosteroids suppress airway inflammation and upregulate β₂ receptor expression; β₂ agonists prevent tolerance and enhance bronchodilator response.

• Combination therapy is standard for long-term asthma and COPD control (e.g., fluticasone + salmeterol).

What enzyme phosphorylates the C-terminus of adrenergic receptors?

G-protein receptor kinase (GRK)

• Consequences:

  • Receptor desensitization (reduced G-protein coupling)

  • β-arrestin recruitment → internalization

• Effect on receptor activity:

  • Decreased receptor responsiveness (tachyphylaxis)

What two things can happen following the binding of β-arrestin to the C-terminus?

1. Receptor internalization (endocytosis for recycling or degradation)

2. Activation of β-arrestin-mediated signaling independent of G-protein pathways

What are the mechanisms of tachyphylaxis following GPCR (e.g., adrenergic receptor) activation?

• GRK-mediated phosphorylation → β-arrestin binding → receptor internalization

• Receptor downregulation from chronic stimulation

• Depletion of second messengers (e.g., cAMP)

What is biased agonism?

• Biased agonism: When a ligand preferentially activates one signaling pathway (e.g., G-protein) over another (e.g., β-arrestin).

• Biased agonist: Ligand with pathway selectivity — can reduce side effects by avoiding unwanted signaling.

• How it’s different from conventional agonists or natural ligands: Traditional agonists activate all receptor pathways equally.

Differences between direct, indirect, and mixed-acting adrenergic agonists

• Direct-acting:

  • Directly bind and activate adrenergic receptors 

  • e.g., albuterol, phenylephrine

  • Mimic natural ligands

• Indirect-acting:

  • Increase NE or dopamine availability

  • e.g., amphetamine, cocaine

  • Promote release or inhibit reuptakes

• Mixed-acting:

  • Both direct activation and NE release

  • e.g., ephedrine

  • Dual mechanism