Pharmacodynamics Flashcards
What is pharmacokinetic tolerance?
Response is decreased due to drug being broken down before it gets to the target sites - Drug levels change
What is pharmacodynamic tolerance?
Response is decreased due to changes in receptor number or function
- Drug levels do NOT change
What is physiological tolerance? Provide an example.
When two agents with opposing physiological effects are administered together
- Histamines cause vasodilation while epinephrine causes vasoconstriction
What are the four factors that influence the variability in drug response?
- Differences in drug absorption
- Differences in ligand concentrations
- Differences in number/function of receptors
- Differences in post receptor effects
What is summation?
Two drugs elicit a similar response through different mechanisms; effect equals the sum of the two individual effects
What is synergism?
Two drugs elicit a similar response through different mechanisms; effect is greater than the sum of the two individual effects
Compare additive effect to summation effect
- Summation: two drugs work through different mechanisms
- Additive: two drugs work through the same mechanism
What is organ-directed toxicity? Provide two examples.
Drugs are toxic to organs/tissue that have no involvement in therapeutic effect
- Tylenol and liver issues
- Tetracyclines and teeth discoloration, less bone growth
What is tachyphylaxis? Provide an example.
Rapid development of tolerance following repeated doses over a short period of time
- Meth (aka stimulants)
What does the administration of antagonists do?
Causes up-regulation (more receptors due to prolonged presence of antagonist)
What is an example of metabolic enzyme deficiency?
Succinylcholine in patient’s with low serum cholinesterase
- Cholinesterase degrades succinylcholine but if it is deficient, the succinylcholine will remain in the plasma longer - 4 minutes of sedation turns into 4 hours
What is an example of competition for plasma binding sites?
Warfarin and Phenytoin
- When both are present, they compete for the same binding sites so Phenytoin can displace Warfarin and it will remain free (active) for longer → Warfarin dose must be reduced to avoid toxicity
What are six examples of “acceptable” adverse effects?
- Headache
- Fatigue
- Dizziness
- Upset GI
- Nausea
- Vomiting
What is overextension-type toxicity? Provide an example
Basically overdosing…
- Example is Warfarin causing hemorrhage
Provide three examples of organ-directed toxicity.
- Aminoglycoside antibiotics and ototoxicity
- Acetaminophen and hepatotoxicity
- Metabolite toxicity: Acetaminophen and Isoniazid hepatotoxicity
What is often the cause of an idiosyncratic drug response?
Mutation (polymorphism)
With drug allergies, what type of response is activated?
Immunologic response
What type of a response is Type I? How is this mediated? Provide an example.
Anaphylactic
- IgE antibody-mediated
- Ex. Penicillin-induced anaphylaxis
What type of a response is Type II? How is this mediated? What does this result in?
Cytotoxic
- IgM or IgG antibody-mediated
- Results in RBC lysis
What type of a response is Type III? How is this mediated? Provide an example.
Immune Complex (Arthus)
- Antigen antibody-mediated
- Ex. serum sickness
What type of a response is Type IV? How is this mediated? Provide an example.
Delayed Hypersensitivity
- Cell-mediated
- Ex. SJS or Erythema Multiforme
Differentiate between up regulation and down regulation.
Up-regulation: increase in number of receptors in order to increase response
Down-regulation: decrease in number of receptors in order to decrease response
What is covalent binding? Provide an example.
Strong, IRREVERSIBLE bonding
- Ex. Aspirin
Differentiate between the efficacy of full agonists, partial agonists and antagonists.
Also consider affinity…
- Full agonists have affinity and efficacy (a = 1)
- Partial agonists have affinity but lower efficacy (0 < a < 1)
- Antagonists have affinity but no efficacy (a = 0)
What does a low therapeutic ratio indicate about a drug? What if the TR is high? Provide an example of each.
- Lower the TR, riskier the drug (Warfarin)
- Higher the TR, the safer the drug (Penicillin)
What does a narrow margin of safety indicate about a drug? What if the margin of safety is wide?
- Narrower the margin of safety, the riskier the drug
- Wider the margin of safety, the safer the drug
Under what condition to spare receptors exist? How does this effect ED50, and Kd?
Spare receptors exist when it’s possible to elicit Emax without occupying all of the available receptors
- ED50 will decrease
- Kd will remain the same
Aka if ED50 does not equal Kd, spare receptors are present
What do partial agonists act like in the presence of full agonists?
Competitive antagonists
How will Emax be affected if competitive antagonists are present?
Emax will not change
How will Emax be affected if non-competitive antagonists are present?
Emax will decrease
- Even if more agonist is added, the receptor’s shape has been changed so there are fewer available receptors
How will ED50 be affected if competitive antagonists are present?
ED50 will increase (takes more medication to achieve 50% maximal effect)
How will ED50 be affected if non-competitive antagonists are present?
ED50 may change, but may not
How is agonist affinity affected if competitive antagonists are present?
Agonist affinity for its receptors will decrease
- Kd increases because more drug is needed to get effect
How can the affects of a competitive antagonist be overcome?
Competitive antagonists bind reversibly so if more agonist is added, the agonists will eventually “win the competition”
What is an example of physiological antagonism?
Histamines cause a fall in BP, which can be reversed with epinephrine
What is an example of chemical antagonism?
Neutralizing stomach acid with antacids
What is the role of intracellular receptors? How do these effects present?
Modify gene transcription and protein synthesis
- Effects are not immediate and tend to be long-lasting
What specific receptor type is associated with Transmembrane Receptors? What are two examples of ligands that act on this receptor type?
Transmembrane Receptors = Tyrosine kinase receptors
- Insulin
- Growth factor
What specific protein class is associated with Cytokine Receptors? What are three examples of ligands that act on this receptor type?
Cytokine Receptors = JAK
- Growth hormone
- Erythropoetin
- Interferons/Interleukins
What are two examples of ion channels?
- Ligand-gated
- Voltage-gated
What are two examples of ligand-gated channels?
- ACh: depolarize cell
2. GABA: hyperpolarize cell
What is an example of synergism related to GABA receptors?
Benzos and alcohol both act on GABA receptors so when both are present, the effect of each is much greater than the two added alone
Give three examples of compounds that use B1 and B2 receptors. Are these stimulating or inhibiting?
Stimulate Gs and activate cAMP
- Epinephrine
- Norepinephrine
- Isoproterenol
Give three examples of compounds that use a2 receptors. Are these stimulating or inhibiting?
Stimulate Gi and inhibit cAMP
- Epinephrine
- Norepinephrine
- Clonidine
What are two examples of receptors that involve a secondary signaling mechanism? What signaling pathway does each activate?
- Tyrosine kinase receptors activate the Ras/Raf signaling pathway
- Cytokine receptors activate the JAK/STAT signaling pathway
How do Gs proteins affect cAMP production?
Gs proteins increase cAMP production
How do Gi proteins affect cAMP production?
Gi proteins decrease cAMP production
What type of protein are beta receptors associated with?
Gs
What type of protein are alpha 1 receptors associated with?
Gq
What type of protein are alpha 2 receptors associated with?
Gi
What information does a quantal DR curve provide?
TR and margin of safety
What information does a graded DR curve provide?
Potency and Emax
