Unit 1.Lec 4&5-Pharmacodynamics Flashcards
Define Pharmacodynamics
Is the study of biochemical and physiological effect of drugs and their mechanism of action
What are the mechanisms of action of pharmacodynamics?
Include
- the initial interactions btw drug and cellular marcomolecules (receptors) &
- the consequent biochemical and physiological responses that lead to the ultimate effects of the drugs on the body
Where is the site of drug action?
At a specific protein macromolecules, termed receptors sitting on the cell mebrane
What do most drug receptors include and what is their function?
- Most drug receptors have an endogenous ligand
- Drugs modulate activity (by either stabilizing inactive state or active state, stopping secondary effects)
Agonist=Endogenous ligand (ex: GABA for GABA-a receptor)
What is action of drug an interplay of?
The drug concentration and the endogenous ligand concentration
List non-membrane embedded protein drug receptors (4)
- Enzymes (HMG-COA reductase, acteylcholinestrase)
- Na+, K+ -ATPase pump
- Structural proteins (tubulin)
- Nucleic Acids (for cancer chemotherapeutic agents)
List examples of non-receptor mediated drug action (2)
- Gastric acid (Tums)
- Mannitol (used as osmotic diuretic)
List the binding forces that contribute to the three dimesional structure of proteins (receptors) and the ineractions of the drugs with its receptor
- Covalent
- Ionic
- Hydrogen
- Hydrophobic
- Van der Waals
What is the strongest but rarely used bond? and why?
- Covalent, its not reversable
What is the weakest bond?
Van der Waals
Which types of binding play an important role in drug/receptor interactions? and why?
- Hydrogen binding, ionic and hydrophobic interactions
- These bindings are reversable
How are receptors dynamic molecules?
- Receptors are always “dancing” or shifting from active to inactive state checking for ligands
- No ligands=Mostly inactive
Explain the two state model
Receptors are mainly in the inactived form. When ligand is added that binds to the active site (dependent on concentration) it will switch the receptor to active state
The concentration of drugs will change more receptors to active site
What occurs when a receptor has basal activity?
Basal activity means more receptors at the active site
Explain the two state model in the presence of an agonist
If you increase the concentration of an agonist ligand the more chance it will interact with the receptor and stabilize it in its active form
Agonist ligand: used to activate a receptors active site
List the general mechanisms for signal transduction (Receptor activation)
- Ion Channels (a. Ligand-gated, b.voltage-gated)
- Receptors coupled to G-proteins (to regulate generation of intracellular second messengers: cAMP and Ca2+)
- Receptors with intrinsic enzyme activity (tyrosine kinases)
- Receptors that are interalized to deliver receptor-complexes to intracellular targets (Steroids)
Describe the ligand-gated mechanism of drug receptors
Ligand agonist will bind to receptor in active configuration, stabilize, and allow for ions (Na+, Ca2+, K+, Cl-) to flow down their concentration gradient
Examples of Excitatory Ligand-gated Ion Channel
- Nicotinic Acteylcholine Receptors
- Glutamate (MAIN excitatory)
Examples of Inhibitory Ligand-gated Ion Channel
- GABAa Receptors (MAIN inhibitory)
- Glycine
Nicotinic Acetylcholine Receptors (excitatory)
- Found?
- Subunits?
- Drug?
- Agonist?
- Mechanism?
- Found on the the muscle cells in neuromuscular junction + also in the CNS/PNS
- Five subunits (2⍺, 1β, 1𝜎 and 1ϒ)
- Drug: Nicotine
- Agonist: Acetylcholine
- Mechanism: Binding of the agonist ACh will result in the opening of the pore allowing Na+ + K+ ions to go across the membrane (causes depolarization + firing AP)
GABAa Receptors (Inhibitory)
- Found?
- Subunits?
- Drug?
- Agonist?
- Mechanism?
- Found in CNS
- Subunits: ⍺1 to ⍺6, β1 to β3, ϒ1 to ϒ3, 𝜎, ε, ⍴ and π
- Drug: Barbiturates & Benzodiazepines
- Agonist: GABA
- Mechanism: Binding if agonist: GABA will result in the opening of the pore allowing the Cl- ions to flow across the membrane (Hyperpolarization)
GABA is made from glutamate
Examples of voltage-gated channels
- Voltage-gated Na+ channels
- Voltage gated Ca2+ channels
- Voltage-gated K+ channels
Where are voltage- gated sodium channels present?
In the mebrane of excitable cells, cardiac and skeletal muscles
What does transient change in the voltage membrane potential cause?
Opening of the gate allowing the passage of Na+ ions across the membrane
Local anesthetics bind to the _______________ of the voltage-gated sodium channel
Intracellular domain
How mamy members does G-protein-coupled receptors have? What do they include?
- Excess of 500 members
Including recptors for:
- Light
- Odorants
- Hormones
- Neurotransmitters
- Other Endogenous ligands
Receptors coupled with heterotrineric G-proteins can influence the activity of?
- Enzymes (adenylyl cyclase, phospholipase C)
- Channels (Ca2+, K+)
What is the outcome of receptor-coupled to G-proteins influencing enzyme and channel activity?
- It increase or decreases the level of intercellular second messengers such as cAMP, Ca2+
- cAMP and Ca2+ can then regulate the activites of other enzymes
What is contained in receptors coupled to G-protein?
- Seven membrane-spanning domains
- Ex: Angiotensin, glucagon, histamine, opiod, serotonin, β-adrenergic and ⍺2-adrenergic receptors
What are tyrosine kinase receptors? Function? Examples
- Ligand-regulated transmembrane enzymes that have their own kinase activity
- FXN: Phosphorylates a protein
- Ex: Insulin and epidermal growth factor receptors
What are Intracellular receptors? Examples? Function?
- Receptors in the cell: Have a high lipid: H2O parition coefficent, very lipid soluble, can cross the cell membrane
- Examples: Steroids (estrogen, androgen) receptors
- FXN: Modulates gene expression. Can increase expression and make many copies of mRNA
Explain the Drug-Receptor Interaction
A drug binds to receptor has intrinsic activity that causes amplication
What is the amplification of:
- GABAa receptors
- G-protein coupled receptor
- Steroid receptor
- GABAa receptor: Opening of Cl- ion channel, amplifies Cl-
- GPCR: w/ adenylyl cyclase amplifies cAMP
- Steroid receptor: d/t transcription amplifes mRNA
Explain the black, blue and pink lines on the graph below
*= EC50
- Three different drugs binding to the same receptor
- Muscarine (Pink): Has full efficacy (full agonist), and more potent (less [drug] for same effect)
- GABA (black): Has full efficacy (full agonist), less potent then muscarine
- Phenobarbital (blue): Has low efficacy (partial agonist)
Where is efficacy shown on the graph? Where is potency?
- Efficacy: Y-axis
- Potency:X-axis
Explain the black, pink, blue and green lines on the graph below
*=EC50
- Black line: Antagonist
- Pink Line: GABA conc. of 1 added
- Blue: GABA conc. of 10 added
- Green: GABA conc. of 1000 added
- This graphs demonstrates the Antagonist of GABA. Its actions can be reversed b/c it’s competing for the same site as GABA. If you increase the concentration of GABA high enough, you can overcome the antagonist ans get full effect
Explain the two types of Antagonist. Competitive and Non-competitive
- Competitive: Increase drug concentration will overcome antagonist (shift in x-axis)
- Non- competitive: Binds somewhere else (allosteric site), decreases efficiency. (e.g 100 GABA receptor, 10 blocked non-competively, Efficacy down 10%)
GABAa receptors correspond best with what type?
a. GPCR
b. Voltage gated sodium channels
c. Tyrosine Kinase Receptors
d. Ligand gated ion channels
d. Ligand gated ion channels
Which of the following does not correctly match the receptor with the method of signal transduction:
a. GABAa–>CL- influx
b. NMDA (Glutamate receptor)–>Na+ influx
c. GPCR–>cAMP/CA influx
d. Nicotinic Acetylcholine Receptors–>NA/K+ influx
e. Tyrosine Kinase–>Dephosphorylation of protein
e. Tyrosine Kinase–>Dephosphorylation of protein
Tyrosine kinase phosphorylates a protein as the method of signal transduction
True or False: The graph below demonstrates a drug which effects can be overcome by increasing the concentration of the endogenous ligand?
False (graph shows non-competitve)
The arrow in the graph below is demonstrating?
a. ED50
b.EC50
c. KD
d. TD50
b. EC50
True or False: ED50 values are used to compare potency between drugs?
False (It’s EC50)
