Pharmacodynamics Flashcards
What is pharmacodynamics?
How a drug affects the body. There are two types: physiological PD and molecular PD.
What does physiological pharmacodynamics entail?
Includes agonists, antagonists, partial agonist, efficacy, potency, and side effects.
What does molecular pharmacodynamics entail?
Includes receptor types, affinity, competitive and non-competitive antagonists, inverse agonists, and allosteric inhibitors.
The following graph represents what?
The pharmacodynamic effect of insulin on glucose after eating high carb meal.
What is the ED50?
The halfway point of dose-response curves. It is also the effective dose that gives 50% of the response.
What does the curved line on a dose-response curve mean?
The bottom line near the x-axis is the lowest dose of the drug that exerts a tiny bit of effect. The top part of the line that has flattened out again is where there is no longer a stronger effect even when more drug is added.
What is efficacy?
Efficacy describes the maximal level of response a drug can produce.
Which drug has the least efficacy, and which drug has the most?
The blue line is the least efficacious, and the red line is the most efficacious.
What is potency?
The potency of a drug reflects its affinity for its receptor.
Which drug is more potent? And which one has the lower ED 50?
Drug A is more potent than drug B. Drug A has a lower ED50 than drug B.
What are partial agonists?
These drugs bind and activate a receptor but only have partial efficacy at the receptor.
This dose-response curve shows a curve of a ______ agonist and a _______ agonist.
Full; partial
How is the therapeutic index found in graphs and mathematically?
In a graph, the therapeutic index is the range between the ED50 and LD50 (lethal dose). Mathematically, TI can be calculated by dividing the LD50 log conc by the ED50 log conc.
What is the maximum tolerated dose (MTD)?
How much drug can be given before intolerable side effects take place.
What is an agonist?
A drug that binds and produces a signal.
What are the dose-response curves for a full agonist, partial agonist, antagonist, and inverse agonist?
Full agonist is the full curve
Partial agonist is partial curve
Antagonist is a straight line
inverse agonist is negative curve
How does typical agonist binding work?
Agonist binds to a receptor which causes downstream signalling which can eventually target proteins inside the cell called effectors. Ultimate targets of receptors tend to be transcription factors which instill long-term change.
A drug HB increases heartrate by 20% over baseline when the dose is 200 mg. But a new drug called HBX increases heart rate by 20% in a 50 mg dose. Which of the following is changed in HBX? (ED50, efficacy, or side effects)
ED50
A drug HB increases heartrate by 20% over baseline when the dose is 200 mg. But a new drug called HBX increases heart rate by 20% in a 50 mg dose. Which of the following is HBX? (agonist, effector, partial agonist, or receptor).
Agonist
A drug HB increases heart rate by 20% over baseline when the dose is 200 mg. But a new drug called HBY increases the heart rate by 8% in a 50 mg dose- its ED50. Which of the following is HBY? (agonist, effector, partial agonist, receptor).
Partial agonist
A drug HB increases heartrate by 20% over baseline when the dose is 200 mg. But a new drug called HBY increases the heart rate by 8% in a 50 mg dose- its ED50. What is the relationship between HBY relative to HB? (higher, lower, or the same affinity).
?
What is Kd?
Kd is the equilibrium dissociation constant. It is that unique concentration of a drug that will occupy 50% of the total receptor population. Affinity and Kd are often used interchangeably.
How are affinity and Kd related?
If affinity decreases than Kd increases. The bigger the Kd, the less likely the drug-receptor dimer complex forms.
If affinity increases, than Kd decreases. The lower the Kd, the more likely the drug-receptor dimer complex forms.
What does K1 and K-1 mean in the affinity equation?
K1 is the rate at which the drug binds/associates with the receptor.
K-1 is the ease at which the drug dissociates from its receptor.
What are the drivers of drug affinity?
Different bonding types (ionic bonds, hydrogen bonds, van der waals forces, etc)
In classic occupation theory, the _______ equals the _________.
ED50; Kd
Erbitux/cetuximab is an antibdoy that binds and inhibits epidermal growth factor receptor (EGFR). Erbitux has a Kd of 0.2 nM. it has few cross-reactions with other kinases. Erlotinib is a small molecule that inhibits EGR. It has a Kd of 0.4 microM. It has a Kd for other kinases in 0.09-0.4 microM range. Which drugs binds EGFR with greater affinity?
Erbitux binds EGFR with higher affinity because its Kd value is smaller than that of Erlotinib.
What are antagonists?
Antagonist binds to receptors and deactivates it. It also blocks the agonist from working.
What are competitive antagonists?
Antagonists that bind in a reversbile manner to the receptor and prevent agonist action.
What happens graphically when an antagonist is introduced to ligand A and its receptor?
Adding antagonist will shift the curve to the right. Adding antagonist requires a greater concentration of ligand to achieve an effect.
What is IC50?
IC50 is the inhibitor concentration decreasing the activity of the agonist by half.
According to the graph, which ligand is the full agonist? The partial agonist? and the antagonist?
Isoproterenol is the full agonist.
Clenbuterol is the partial agonist.
Propronolol is the antagonist.
What does ibuprofen target?
Ibuprofen targets the activity of cyclooxygenase I and II (COX I and II). These enzymes cleave arachidonic acid to prostaglandins.
What is Ki?
Ki is the affinity of the inhibitor for the receptor. Low Ki means a more potent inhibitor while high Ki means less potent inhibitor.
How do you calculate the concentration of an agonist required to produce an effect in the presence of a competitive antagonist?
C’/C= 1 + ([I]/Ki)
What are two important features of a curve to describe enzymatic reactions?
Vmax and Km
What is Vmax?
Maximum velocity of an enzymatic reaction.
What is Km?
Substrate concentration when the Vmax is at half.
Tofacitinib (Xeljanz) inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM. Does that mean tofacitinib is more or less active against 1/3 or 2/2?
The lower the IC50, the more potent the drug. This means that tofacitinib is more active against JAK1/JAK3.
What happens to Vmax and Km if a non-competitive inhibitor is added?
Vmax is decreased while Km stays the same. Vmax decreases because the binding of non-competitive inhibitors lowers the concentration of binding sites. Km stays the same because the binding site for the substrate is still available for binding.
What happens to Vmax and Km if an uncompetitive inhibitor is added?
Km stays the same, but Vmax is lower.
What happens to Vmax and Km if a competitive inhibitor is added?
Vmax stays the same while Km is increased. Km is increased because more substrate will be needed to achieve 1/2 vmax. Eventually we can reach the same Vmax.
What are irreversible receptor antagonists?
These bind to receptors, and when they do in the presence of an agonist, a blockade cannot be overcome due to the loss of active receptors.
What are the neurons called that produce acetylcholine (Ach)?
Cholinergic neurons
What is acetylcholine synthesized from?
Acetyl CoA and Coline
What is the function of the bacteria Clostridium Botulinum?
Blocks release of Ach by blocking the pre-synaptic release into the synaptic cleft. This bacteria is used in botox, which typically stays localized.
What is the interaction between tetanus and Ach?
Tetanus toxin is produced by Clostridium Tetani, and it blocks the release of Ach from a pre-synaptic area like botox.
What is Acetylcholine broken down into?
Acetate and Choline
What enzyme breaks down Acetylcholine?
Acetylcholinesterase
What are the main functions of Acetylcholine?
Salivation, tears, urination, defecation, and decreased heartbeat
What is the function of a drug like Donepezil (Aracept)?
Selectively and reversibly inhibits the acetylcholinesterase enzyme that typically breaks down Ach. Used to treat Parkinson’s and Alziehmers.
What is the shorthand for acetylcholine/ cholinergic receptors?
AchR
What were the symptoms of Alexei Navalny, who was poisoned with a drug called Novichok?
Novichok blocks the breakdown of Ach, so it accumulates in the body. This causes extreme GIT cramping, diarrhea, salivation, and tears.
What is one receptor type that acetylcholine can bind to?
Acetylcholine/ cholenergic receptors
What are the two types of acetylcholine/cholinergic receptors?
- Metabotropic muscarinic receptors
- Ionotropic nicotinic receptors
How does the ionotropic nicotinic receptors work?
The nAchR is also an ion channel for the flow of K+ and Na+. In the closed state, there is a higher concentration of Na+ extracellularly and, therefore, lower inside the cell. There is higher K+ intracellularly and less outside the cell. When the agonist (Ach) binds, the receptor opens, and Na+ flows into the cell while K+ flows out of the cell.
Na+ flow creates a membrane potential that is the basis of sense, learning, and memory.
Are different acetylcholine receptors fast or slow?
These receptors are fast! Milliseconds type fast
What is the effect of black widow toxin on Ach release?
Black widow spider toxin induces the release of Ach increasing overall body concentrations.
Can the ionotropic nicotinic receptor only accept Ach as a ligand?
No, the nAchR has several other binding sites for other types of ligands.
Which of the inhibitors, A or B, is a competitive inhibitor?
B is the competitive inhibitor.
Imagine that someone develops a new version of ibuprofen called X-1000 and has a Ki 1000 times lowers than the current ibuprofen. Does that mean the new drug is more active or less active than the old one?
A lower Ki means a potent inhibitor so the new drug, X-1000, is more active than the old one.
Imagine that someone develops a new version of ibuprofen called X-1000 and has a Ki 1000 times lowers than the current ibuprofen. If someone mistook X-1000 for the original, could they reverse the effect by taking the same dose of the original ibuprofen?
No, because X-1000 is still more potent than the original ibuprofen and would beat out the original in its ability to be more potent.
Imagine someone was given a drug that inhibited Ach breakdown. What would be the effect?
They would have excess Ach hanging out in the synaptic cleft that would continue to bind and cause an increase in crying, urination, hypersalivation, defecation, and decrease heart rate.
What is the main medication used as an inhibitor of the Ach receptor?
Atropine
What can bind and inhibit the Ach receptor?
Glucocorticoids
Nicotine can affect nAchR’s everywhere including post-synaptically (__________) and pre-synaptically (_________).
altering signalling; increasing Ach release
Why does smoking make people happy?
Both nicotine and ethanol stimulate dopamine release which sets of the dopamine reward pathway.
What is desensitization?
This is when receptors often stop responding to ligands over time. It can be due to conformational change, receptors being internalized, or degraded.
What are G-protein coupled receptors?
These receptors span the cell membrane. It has an outside part that ligands bind to that converts it to the ‘on’ state, where the alpha subunit releases GDP and GTP replaces it.
What is a tyrosine kinase receptor?
Span the plasma membrane. Has two distinct domains; extracellular domain for ligand binding and intracellular kinase domain for enzymatic reaction.
For an agonist and receptor system, the formation of a complex is reflected by their concentration like this: Which of the following represents the Kd?
K-1/K1
Referring figure 1 shows a graph of a dose-response curve of agonist A1. Draw a curve for a related drug that has 50% of the efficacy of A1 with 2 x greater affinity of A1 for the same receptor.
Refer to figure 3. The blue line shows an increase in the rate of an enzymatic reaction when increasing doses of a substrate are added. The dashed red line shows the 50% point of the blue curve. Plot a line analogous to the solid line indicating the same reaction if a non-competitive inhibitor was added.
Non-competitive inhibitors will decrease Vmax while not affecting the Km
Based on the picture, which of these inhibitors is more active at inhibiting dopamine reuptake?
Sertraline. This is because it has the lowest Ki value meaning it has the highest affinity to inhibit the receptor.
