Foundations 2 Week 1

Question 1

You just prescribed a drug that works as a non-competitive antagonist.

What does this mean regarding how the drug binds to its receptor and its effect on receptor activation?

How is this similar/different to a drug that works as an uncompetitive antagonist?

Answer 1

It either binds irreversibly to the agonist binding site OR binds to another distinct site (allosteric site) other than the agonist binding site and prevents receptor activation (this CANNOT be overcome by increasing agonist concentration)

Uncompetitive antagonists can’t bind to inactive receptors, however once the receptor is activated an uncompetitive antagonist can bind and inhibit, producing a reduced response

• Lecture 35a: Pharmacodynamics: General Principles of Receptors and Dose-Response Relationships*
• Objective 1: List the differences between the three forms of receptor antagonism, competitive, noncompetitive and uncompetitive*

Question 2

Correctly order the following steps of a neuronal action potential

• Voltage gated K channels are activated and K leaves the cell
• Membrane is hyperpolarized
• Membrane depolarizes towards its highest voltage of the action potential
• Na channels inactivate
• Membrane is depolarized to its threshold magnitude
• Voltage gated Na channels open and Na rushes into cell
• Membrane is repolarized to its resting membrane potential
• Voltage gated K channels close

Answer 2

1. Membrane is depolarized to its threshold magnitude – this occurs due to syntaptic signal summing
2. Voltage gated Na channels open and Na rushes into cell
3. Membrane depolarizes towards its highest voltage of the action potential – it nears the Na equilibrium potential
4. Na channels inactivate – these channels will remain inactive until the mebrane is repolarized, the physiological reason for the presence of a refractory period
5. Voltage gated K channels are activated and K leaves the cell
6. Membrane is hyperpolarized
7. Voltage gated K channels close
8. Membrane is repolarized to its resting membrane potential

Lecture33a: Pharmacodynamics: Membrane PotentialO
Objective 4:Explain the physiology of initiation, generation and propagation of neuronal action potential

Question 3

What ion is responsible for the long plateau that is characteristic of phase 2 of a cardiac action potential (especially in the early part of phase 2)?

a. Ca²⁺
b. Na⁺
c. K⁺
d. Cl^-

Answer 3

a. Ca

Following the upstroke of phase 0 depolarization (caused by Na influx), voltage-gated (L-type) calcium channels will activate and Ca will flow into the cell (with a small amount of residual Na). This Ca influx will be balanced by an efflux of K that will ultimately allow for repolarization in phase 3.

Lecture 33a: Pharmacodynamics: Membrane Potential
Objective 5: Recognize differences in neuronal, muscle, and cardiac action potentials

Question 4

What type of transport process (active, passive, facilitated diffusion) are the following membrane proteins involved with?

GLUT 1 (a uniporter)
Voltage gated Na⁺ channel
Na⁺/K⁺ ATPase
Na⁺/Cl^- co-transporter

Answer 4

GLUT1 (a uniporter): Facilitated diffusion – allows for transport of glucose across a concentration gradient

Voltage gated Na channel: Passive – allows for transport of Na across an electrochemical gradient

Na⁺/K⁺ ATPase: Active transport – requires ATP to transport Na and K against their concentration gradients

Na⁺/Cl^- co-transporter: Facilitated diffusion – electroneutral transporter that allows for movement of Na and Cl in the same direction

Lecture 34a: Pharmacodynamis: Ion Channels and Transport Proteins
Objective 1: Describe basic mechanisms involved in transporting ions across cell membranes
Objective 2: Distinguish the various types of ion transporting proteins

Question 5

Your patient comes into clinic and reports having difficulty sleeping. You decided to prescribe Zolpidem (Ambien) which works at benzodiazepine binding sites.

When Zolpidem binds to its predominant receptor (which is?) what happens and why does that help the patient?

Answer 5

Zolpidem binds to Gamma Amino Butryic Acid (GABA) receptors in the CNS. GABA is the main inhibitory receptor in the CNS and binding by Zolpidem increases the frequency of opening of the inhibitory GABA gated Cl^- channels, hyperpolarizing the membrane away from firing.

Lecture 36a: Pharmacodynamics: Receptor Families and Signaling I
Objective 2: List the 6 types of receptors that are ligand-gated channels and any clinically-important agents that target these receptors

Question 6

Growth factor receptors function as receptor tyrosine kinases (RTKs). Describe what happens when a ligand (epidermal growth factor, EGF) binds to its RTK receptor?

1.

2.

3.

4.

5.

Answer 6

1. The receptor dimerizes and the kinases will phosphorylate the tyrosine residues on the other subunit
2. Phosphorylated tyr residues recruit cytoplasmic proteins that act as scaffolds (Scaffold = Growth Receptor Bound Protein 2)
3. The scaffold protein (GRB2) will bind to the receptor and the scaffold tyr residues will be phosphorylated
4. Scaffold protein will then pass through multiple protein kinases (RAS/MAP Kinase Pathway) to travel to the nucleus
5. Within the nucleus it can alter gene signaling leading to a biological response
   * Lecture 37a: Pharmacodynamics: Receptor Families and Signaling II*
   * Objective5: Describe the transmembrane enzyme signaling processes employed by growth factors and by insulin*

Question 7

ABC transporters and SLC transports are responsible for what specific type of active transport?

How are these active transport mechanisms similar/different?

Answer 7

ABC transporter: ATP Binding Cassette transporters – primary active transport

SLC transporter: SoLute Carrier transporters – secondary active transport, facilitated diffusion

Primary active transporters (ABC) relies directly on the coupling of energy from ATP hydrolysis to the translocation of solute across a membrane against its concentration gradient. However in secondary active transport, the movement of ions against their concentration gradient is coupled with a favorable chemical gradient (that may have been created by a primary active transport mechanisms) and doesn’t utilize cellular energy directly.

Lecture 39a: Pharmacokinetics: Drug Transport
Objective 2: Differentiate types of active transport mechanisms that are mediated by ABC transporter and SLC transporters and their importance in drug actions

Question 8

Define the following terms…

• Bioavailability
• Bioequivalence
• Pharmaceutical equivalence

Answer 8

Bioavailability: Fraction of an administered dose of unchanged drug that reaches the systemic circulation

Bioequivalence: Drug preparations that exhibit the same bioavailability and pharmacokinetics

Pharmaceutical equivalence: Drug preparations with same active ingredient, concentration, dose, and route of administration

Note pharmaceutical equivalence does NOT necessarily equal bioequivalence

Lecture 40a: Pharmacokinetics: Drug Absorption and Distribution
Objective 2: Explain bioavailability, bioequivalence and pharmaceutical equivalence