Pharmacology Ch 2 Pharmacodynamics

Questions and Answers

What primarily determines the relative efficiency of occupancy-response coupling at the receptor level?

The binding affinity of the agonist

The type of agonist involved (correct)

The number of available receptors

The resting membrane potential of the cell

How do full agonists differ from partial agonists in their effect on receptor conformational equilibrium?

They do not affect the equilibrium.

They produce no cellular response.

They have lower binding affinities.

They shift the equilibrium more strongly. (correct)

What is true about the relationship between drug occupancy and response for ligand-gated ion channels?

Response is not affected by receptor occupancy.

Response occurs only at high agonist concentrations.

It is complex and highly variable.

Response can be directly proportional to receptor occupancy. (correct)

What role do downstream biochemical events play in occupancy-response coupling?

They transduce receptor occupancy into cellular response. Signup and view all the answers

Which of the following statements is incorrect regarding full and partial agonists?

Partial agonists always induce a stronger receptor response than full agonists. Signup and view all the answers

Which type of proteins are specifically identified as drug receptors according to the content?

Enzymes Signup and view all the answers

What is the role of dihydrofolate reductase in drug receptor systems?

It acts as a receptor for the antineoplastic drug methotrexate. Signup and view all the answers

What does Bmax indicate in the equation related to drug-receptor binding?

Total concentration of receptor sites Signup and view all the answers

Which of the following represents the concentration of free drug at which half-maximal binding is observed?

Kd Signup and view all the answers

What type of receptors do norepinephrine and serotonin transporter proteins represent?

Transport receptor proteins Signup and view all the answers

How does a drug act as an agonist in receptor binding?

By occupying a distinct class of biologic molecules Signup and view all the answers

What is an example of a drug that targets Na+/K+-ATPase?

Digitalis glycosides Signup and view all the answers

What type of binding do drug-receptor systems often confirm using radioactive receptor ligands?

Occupancy assumption Signup and view all the answers

What is the initial state of the epidermal growth factor receptor before activation?

Inactive monomeric state Signup and view all the answers

What occurs to the cytoplasmic domains of the EGF receptor upon activation?

They are phosphorylated on specific tyrosine residues Signup and view all the answers

What role does EGF play in the activation of its receptor?

It promotes conversion to an active dimeric state Signup and view all the answers

What is the primary function of the activated EGF receptor?

To phosphorylate substrate proteins Signup and view all the answers

How does the mechanism of the EGF receptor compare to that of insulin?

Both lead to increased glucose uptake in cells Signup and view all the answers

What happens to the EGF receptor after it has been internalized?

It recycles back to the plasma membrane Signup and view all the answers

What substance is involved in the energy transfer during receptor activation?

ATP Signup and view all the answers

What is an unclear aspect regarding higher-order complexes of ligands and receptors?

Their pharmacologic significance Signup and view all the answers

Which G protein is primarily associated with increasing cAMP levels?

Gs Signup and view all the answers

What is the signaling effect of Gi proteins?

Open potassium channels Signup and view all the answers

Which of the following is NOT a receptor that interacts with Gq proteins?

Glucagon Signup and view all the answers

What is the common effect of activating Golf proteins?

Increase cAMP levels Signup and view all the answers

Which G protein is associated with the phototransduction process?

Gt1 Signup and view all the answers

The main effect of activating Gq proteins involves which of the following pathways?

Increased phospholipase C activity Signup and view all the answers

Which neurotransmitter is associated with both Gq and Gi proteins?

Serotonin Signup and view all the answers

In which signaling pathway does cGMP play a crucial role?

Phototransduction path Signup and view all the answers

What effect does β-arrestin have on β adrenoceptors?

It promotes endocytosis from the plasma membrane. Signup and view all the answers

What happens to cAMP when the hormonal stimulus stops?

It is degraded to 5′-AMP. Signup and view all the answers

How does Milrinone work in treating acute heart failure?

By inhibiting type 3 phosphodiesterases. Signup and view all the answers

What is a consequence of the endocytosis of β adrenoceptors?

It can lead to down-regulation of the receptors. Signup and view all the answers

What role can β-arrestin play in GPCR signaling?

It can act as a positive signal transducer. Signup and view all the answers

Which mechanism is used by caffeine and theophylline to produce their effects?

They inhibit the degradation of cAMP. Signup and view all the answers

Which second messenger system involves hormonal stimulation of phosphoinositide hydrolysis?

Phosphatidylinositol pathway. Signup and view all the answers

What is one way phosphatases help in receptor regulation?

They reverse the desensitized state of receptors. Signup and view all the answers

What occurs to the response when a full agonist is used concurrently with increasing concentrations of a partial agonist?

The total response gradually decreases. Signup and view all the answers

How does the maximal response of a receptor change when occupied by a partial agonist compared to a full agonist?

The partial agonist produces a lower maximal response. Signup and view all the answers

What role does receptor occupancy play in the interaction between full and partial agonists?

Increased occupancy by partial agonists reduces full agonist binding. Signup and view all the answers

What happens to the fractional response from a single high concentration of a full agonist when a partial agonist is introduced?

It decreases progressively. Signup and view all the answers

What is a potential target for developing new drugs based on receptor occupancy mechanisms?

Exploiting the dynamics of receptor occupancy. Signup and view all the answers

What effect does using a physiologic antagonist have compared to a receptor-specific antagonist?

Physiologic antagonists offer less control over effects. Signup and view all the answers

What could be a consequence of increased binding by a partial agonist in a therapeutic setting?

Reduced efficacy of the full agonist treatment. Signup and view all the answers

In the context of receptor interactions, what defines a partial agonist?

It competes with other agonists but produces a limited response. Signup and view all the answers

What happens to the total response when both a full agonist and a partial agonist are administered together?

The total response declines toward the response of the partial agonist alone. Signup and view all the answers

What general characteristic distinguishes full agonists from partial agonists in response amplitude?

Full agonists produce a higher maximal response than partial agonists. Signup and view all the answers

What is the mechanism of action of sildenafil in producing vasodilation?

It inhibits the breakdown of cGMP. Signup and view all the answers

Which substances are involved in the calcium-phosphoinositide signaling pathway?

PIP2 and IP3. Signup and view all the answers

In which context do the calcium-phosphoinositide and cAMP signaling pathways interact?

They may oppose each other in some cells and be complementary in others. Signup and view all the answers

Which of the following is a substrate of the calcium-phosphoinositide signaling pathway?

Calmodulin. Signup and view all the answers

What role do phosphodiesterases play in signaling pathways?

They inhibit metabolic breakdown of cyclic nucleotides. Signup and view all the answers

Why is it correct for the physician to discontinue propranolol in this case?

Propranolol can cause bronchoconstriction. Signup and view all the answers

What is the primary mechanism by which epinephrine improves the patient's breathing?

By stimulating beta-2 adrenergic receptors. Signup and view all the answers

Why is verapamil a better choice for managing hypertension in this patient?

Verapamil is a calcium channel blocker, reducing vascular resistance. Signup and view all the answers

What alternative treatment might the physician consider for managing the patient's condition?

Prescribing a corticosteroid for inflammation. Signup and view all the answers

Which of the following statements about drug-receptor interactions is true?

Drugs exhibit effects by altering receptor activity. Signup and view all the answers

How does receptor affinity influence pharmacologic effects?

Lower affinity results in increased dose requirements. Signup and view all the answers

Which physiological change is most likely to occur with beta-blocker discontinuation in an asthmatic patient?

Increased heart rate. Signup and view all the answers

What is a common therapeutic goal of managing bronchial asthma?

Reducing airway inflammation and resistance. Signup and view all the answers

What is the effect of hormone binding on the glucocorticoid receptor?

It initiates transcription of target genes after a lag period. Signup and view all the answers

What is the role of the heat-shock protein hsp90 in relation to hormone receptors?

It prevents the receptor from achieving its active conformation. Signup and view all the answers

What persistently occurs after the agonist concentration of a hormone decreases to zero?

The effects of the hormone can last for hours or days. Signup and view all the answers

What does the activation of the glucocorticoid receptor require?

Binding of a hormone ligand. Signup and view all the answers

Which statement reflects a misconception regarding glucocorticoid effects?

Glucocorticoids provide immediate relief for conditions like asthma. Signup and view all the answers

What is a primary characteristic of the effects of hormones acting through gene regulation?

They initiate protein synthesis after a delay. Signup and view all the answers

What type of domain does the glucocorticoid receptor have?

A heat-shock protein binding domain. Signup and view all the answers

What is an important therapeutic implication of hormone action via gene expression?

Treatment may take hours to show significant effects. Signup and view all the answers

What happens to the glucocorticoid receptor after hormone binding?

It dissociates from hsp90 and becomes active. Signup and view all the answers

What is the effect of a competitive antagonist on the agonist concentration-effect curve?

It requires higher concentrations of agonist for the same effect. Signup and view all the answers

What occurs to the maximal effect of an agonist in the presence of a noncompetitive antagonist?

It may be reduced but EC50 stays the same. Signup and view all the answers

How does the agonist concentration required for a specific effect change in the presence of an irreversible antagonist?

It does not change regardless of concentration. Signup and view all the answers

In the presence of a competitive antagonist, what happens to the agonist concentration (C') required for a specific effect?

It shifts to the right. Signup and view all the answers

What is the primary difference in the effect of a competitive antagonist compared to a noncompetitive antagonist?

Competitive antagonists have no effect on the maximal effect of the agonist. Signup and view all the answers

What formula represents the agonist concentration (C') in the presence of a competitive antagonist?

C' = C(1 + [I]/K) Signup and view all the answers

Which of the following effects is characteristic of a competitive antagonist?

It shifts the concentration-effect curve to the right. Signup and view all the answers

Which statement regarding EC50 is true in the context of competitive and noncompetitive antagonists?

EC50 remains unchanged with competitive antagonists. Signup and view all the answers

What principle underlies the ability of a competitive antagonist to be overcome by high concentrations of agonist?

The competitive nature of binding. Signup and view all the answers

Which of the following best describes the interaction of a noncompetitive antagonist with an agonist?

It does not affect the agonist's binding. Signup and view all the answers

Study Notes

Drug Receptors and Their Mechanisms

Regulatory receptors interact with drugs through a specific affinity, reflecting a distinct class of biologic molecules.
Drug agonists bind to these receptors, often confirmed using radioactive receptor ligands to establish the occupancy assumption.
Enzymatic targets include dihydrofolate reductase (methotrexate) and HMG-CoA reductase (statins), which can be inhibited or activated by drugs.
Transport proteins are significant drug targets: Na+/K+-ATPase for digitalis glycosides, norepinephrine and serotonin transporters for antidepressants, and dopamine transporters for cocaine.
Structural proteins like tubulin, the receptor for colchicine, also represent important drug targets.

Drug-Receptor Dynamics

Receptor function involves three key aspects: binding affinity, biological response, and receptor occupancy.
Bmax indicates total receptor site concentration, while Kd is the equilibrium dissociation constant, reflecting drug concentration where half-maximal binding occurs.
Coupling efficiency between occupancy and response is influenced by receptor characteristics: full agonists significantly shift the conformational equilibrium compared to partial agonists.
Ligand-gated ion channels exemplify simple relationships, as ion current directly correlates with receptor occupancy.

Epidermal Growth Factor Receptor Activation

The EGF receptor, a receptor tyrosine kinase, transitions from an inactive monomeric state to an active dimeric state upon EGF binding, triggering phosphorylation on tyrosine residues.
This activation catalyzes substrate protein phosphorylation, impacting glucose and amino acid uptake, as well as glycogen and triglyceride metabolism.

G Protein-Coupled Receptors (GPCRs)

Diverse ligands (e.g., β-adrenergic amines, acetylcholine) interact with different G proteins, leading to varied signaling pathways, such as increased cyclic adenosine monophosphate (cAMP) or phospholipase C activation.
Responses are generated based on ligand binding, where one ligand can elicit different effects in various cell types due to G protein promiscuity.

cAMP Regulation and Desensitization

cAMP actions are reversed by phosphatases, while degradation occurs through cyclic nucleotide phosphodiesterases (PDEs).
β-arrestin modulates receptor endocytosis, impacting receptor sensitivity and helping restore previously desensitized states.
Milrinone, a selective PDE type 3 inhibitor used in heart failure treatment, highlights therapeutic applications of cAMP signaling modulation.

Phosphoinositides and Calcium Signaling

Stimulation of phosphoinositide hydrolysis represents another critical second messenger system, facilitating various hormonal responses and downstream signaling cascades.

Case Study Overview

A 51-year-old male with acute difficulty breathing, mild hypertension managed with propranolol.
Symptoms include tachycardia, tachypnea, and diffuse wheezes; afebrile and normotensive.
Physician diagnoses bronchial asthma, discontinues propranolol, and prescribes verapamil.
Epinephrine given intramuscularly improves breathing after several minutes.

Discontinuation of Propranolol

Propranolol, a beta-blocker, can exacerbate bronchial asthma symptoms.
Beta-adrenergic antagonists may cause bronchospasm, worsening airway constriction.
Verapamil is a calcium channel blocker, safer for asthmatic patients to manage hypertension without affecting airway function.

Drug Interactions and Receptor Dynamics

Drug effects are determined by interactions with specific macromolecules, particularly receptors.
High-affinity binding influences the pharmacologic effect and dose-response relationship.
Competitive antagonists shift agonist concentration-effect curves to the right, requiring higher agonist concentrations for effect.
Noncompetitive antagonists can reduce the maximum effect attainable by the agonist.

Agonists and Partial Agonists

Full agonists produce a maximal response by fully activating receptors, while partial agonists activate but not to full potential, creating a lower maximal response.
Co-administration of a full agonist and a partial agonist can lead to a decrease in the total pharmacologic response as they compete for receptor binding.

Cellular Mechanisms of Drug Action

Hormones, including glucocorticoids, regulate gene expression by activating transcription processes.
The activation mechanism involves a heat-shock protein (hsp90) that dissociates upon ligand binding, allowing receptor folding into an active conformation.
The time lag for effects due to the need for protein synthesis ranges from 30 minutes to several hours.

Therapeutic Implications

Administering physiologic antagonists yields less specific and controllable effects compared to receptor-specific antagonists.
Hormones' effects can persist long after ligand concentration decreases, enhancing therapeutic efficacy.

Signaling Pathways

Primary signaling routes include the calcium-phosphoinositide pathway and cyclic AMP (cAMP) signaling.
These pathways can have opposing effects in some contexts while being complementary in others.
Agents like sildenafil enhance vasodilation by inhibiting phosphodiesterases to prevent breakdown of cGMP, utilized in erectile dysfunction and pulmonary hypertension management.

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Description

This quiz explores the molecular structures and biochemical mechanisms involved in drug action and receptor signaling. It delves into how drug agonists function by binding to specific biological molecules and the importance of receptor affinity in pharmacology.