PHA 340: Pharmacodynamics (part I)
Antacids are bases that neutralize stomach acid. These include drugs such as aluminum hydroxide and magnesium hydroxide. This is an example of what type of non-specific interaction?
Docusate salts reduce surface tension of stool to allow mixing of fatty and aqueous substances. This is an example of what type of non-specific interaction?
Astringents, such as witch hazel or calamine lotion, shrink or constrict (mucus) membranes. This is an example of what type of non-specific interaction?
Mannitol causes changes in the distribution of water to promote diuresis. This is an example of what type of non-specific interaction?
Selective toxicity (i.e. chemotherapeutic agents) is a non-specific interaction that can target what things?
- Nucleic Acids
What is an example of lipids being targeted?
Amphotericin B creates pores in lipids of fungi
What are examples of drugs that target DNA
What are examples of drugs that target RNA?
- Macrolides (antibiotic)
- Aminoglycosides (antibiotic)
- Fomivirsen (antiviral)
- Amantidine (antiviral)
What is an example of a drug that effects enzymes as its target?
Cholinesterase inhibitor (i.e. Aricept (donepezil))
What is an example of a drug that effects Structural proteins as its target?
Colchcine -- used for Gout to decrease inflammation (binds to tubulin)
What is an example of a drug that effects tansporters/carriers as its target?
What can receptor proteins / physiological receptors be activated by?
A drug acting at the molecular level would have an effect where?
At the immediate target (i.e. receptor)
A drug acting at the cellular level would have an effect where?
Signal transduction and intracellular processes
A drug acting at the tissue level would have what effect?
Organ function altered
A drug acting at the system level would have what effect?
Organ system function altered
Each receptor on the cell membrane has what 3 regions?
- Extracellular region
- Transmembrane region
- Intracellular region (may have cytoplasmic loops)
How can a molecule pass through a cell membrane?
Must be small and lipophilic OR have a carrier
What are ways to classify receptors?
- Pharmacological subtyping
- Mechanism of Action (MOA)
____________ is a way of classifying receptors by naming them for the selective ligands that bind them.
What are the 4 main types of MOA classified receptors?
- Ion channels (ligand gated and voltage gated)
- G-protein Coupled Receptors (GPCR)
- Enzyme-linked receptors
- Regulators of Gene expression
Which type of receptors interact with the highest percentage of drugs currently on the market?
Ion channels are important for the function of __________
Ligand-gated receptors are also known as
Ionotropic receptors / Ion channel receptors
What are some examples of endogenous ligands?
True/False: Na+ ligand channel usually allows for the influx of Na and K+.
What is an example of a ligand gated ion channel?
Nicotinic Acetylcholine Receptor
Nicotine is an ______________ ligand (endogenous/exogenous)
How many subunits does the Nicotinic Acetylcholine receptor have and in what combinations?
5; α, β, γ, δ
Where are α3β4 nicotinic receptor subtypes located?
Peripheral nervous system
Where are α4β2 nicotinic receptor subtypes located?
Where are α7 nicotinic receptor subtypes located?
In nicotinic ACh receptors, how many binding site does a receptor with 2 α subunits have?
2 -- will need 2 ACh molecules to bind and activate
Which region of the polypeptide chain in one subunit of a nicotinic ACh receptor forms the gate of the ion channel?
How many times does the polypeptide chain in one subunit of a nicotinic ACh receptor span the membrane?
The nicotinic ACh receptor is considered _______ (fast/slow) acting
What are examples of neuromuscular blockers that may act on the nicotinic ACh receptor?
What is the MOA of neuromuscular blockers?
Inhibit nAChRs and relax the skeletal muscle (i.e. used during surgery)
What do voltage gated channels respond to?
Change in voltage across the cell membrane (i.e. passage of Na+, K+, Ca2+, Cl- ions)
True/False: Voltage gated ion channels are highly selective.
Voltage gated Na+ channels have how many subunits?
3: 1α and 2β
The α subunit of the voltage-gated Na+ channel has how may homologous domains?
Which transmembrane segement in each α domain are voltage sensors in voltage gated Na+ channels?
______________ causes conformational change of S4 transmembrane segment that opens the pore of voltage-gated ion channels.
What forms the walls of the channel pore in voltage-gated ion channels?
S5, S6, and P loop
The inactivation site in voltage-gated ion channels are formed by the intracellular loop connecting which domains?
III and IV
If the intracellular loop between domains I and II are phosphorylated, how is activation affected (voltage gated ion channel)
If the intracellular loop between domains III and IV are phosphorylated, how is activation affected (voltage gated ion channel)
Slows Inactivation (stays activated longer)
What is the sequence of events that takes place when a voltage gated Na+ channel is activated?
- Depolarization: each domain becomes activated (S4 senses change)
- Channel opens and is in the active site
- Inactivation gate between domains III and IV closes, channel becomes inactivated
What are examples of drugs that use voltage-gated Na+ channels?
Local anesthetics (i.e. Lidocaine and benzocaine)
Inhibiting glucocorticoid receptors would most likely cause what?
- Inhibition of adenylyl cyclase
- Influx of sodium ions
- Increased formation of DAG
- Decreased formation of red blood cells
- Decreased gene transcription of inflammatory mediators
- Protein denaturation of mucus membranes
Why is the following statement false: Give a brief rationale, your answer must be 10 words or less.
The voltage-gated Na channel requires binding of a ligand in order to be activated
Voltage gated channels respond to change in voltage, not ligands.
Which of the following statements is INCORRECT?
- Heat shock proteins serve to activate and dimerize nuclear receptors in the absence of a ligand
- Cytokine receptors dimerize and use intracellular enzymes such as JAK, which phosphorylates STAT to regulate gene transcription
- Zinc fingers in the central domain of nuclear receptor bind to DNA
- Binding of epidermal growth factor (EGF) to its receptor causes receptor dimerization and stimulated the kinase activity of the receptors.
- The voltage gated Na+ channel has an inactivation gate located between domains III and IV of the alpha subunit.