Lecture 29: Pharmacodynamics Flashcards
Describe mechanisms of drugs
-Drug molecules bind to particular constituents of cells and tissues (Drug receptor or drug target) in order to produce an effect
- Most drug targets are proteins
- Usually form weak bonds which are reversible
- Drugs are highly selective for a certain receptor (so it can bind and be useful)
Types of drug targets:
-Ion channels
Types of drugs that do this
-Some drug alter conductance of ion channels
Ex:
1) Local anesthetic
2) Sedative-hypnotics
3) Antipileptics
Types of drug targets:
-G-protein-linked receptors
Types of drugs that do this
-Majority of drugs bind to G protein linked receptors
Ex:
1) Albuterol (B2-Agnist, for asthma)
2) Propranolol (B-antagonist, for hypertension)
Types of drug targets:
Enzyme-linked receptors
Types of receptors
-Largest group = receptor tyrosine kinase family
Tyrosine Kinas Receptors:
-Contain extracellular hormone-binding domain and cytoplasmic enzyme domain (tyrosine kinase)
-Important for cellular growth and differentiation
-gain of function in receptors = cancer
-Inhibitors of tyrosine kinase receptors = anti cancer agent
Ex: Imatinib (Anti cancer drug against leukemia)
Ex:
1) Insulin receptor
2) Epidermal growth factor receptor (EGFR)
Nuclear Receptors
What does this
- Intracellular
- Regulate gene expression of genes controlling metabolism and development
Ex:
1) Steroid hormones
2) Thyroid hormones
3) Vitamin D
Enzymes
Types of drugs that do this
-Most drugs inhibit enzyme activity
Ex:
1) Aspirin
2) Ibuprofen
3) Omeprazole
Types of Transporters
Ex:
1) Neurotransmitter transporters
2) Antidepressants - act by blocking serotonin re-uptake
Effects of drugs binding to tubulin
- Some anti cancers drugs bind to tubulin = prevention of polymerization of this molecule into microtubules
- Arrests cells in metaphase
How is Antacid mediated?
- not mediated by binding to receptors
- Antacids neutralize gastric acid (doesn’t underact w/ macromolecular components)
Dose response curves
Equations and graphs
-Hyperbolic curve
E= Emax X C/ C + EC50
- E= effect of drug
- Emax = maximal response produced by drug
- EC50 = Drug [ ] that gives 50% maximal effect (Inverse w affinty)
Receptor Binding of drugs
Equations and graphs
-Describes relationship between drug bound to receptor and [ ] of free drug:
B= Bmax X C/ C + KD
B = Drugs bound
- Bmax= total [ ] of receptor site
- KD = equilibrium dissociation constant ( [ ] of drug required to occupy half of the receptors) and receptors AFFINITY for drug (inverse relationship KD and affinity)
Spare receptors and Signal Amplification
EC50 < KD
All receptors not occupied, still evoke full response = spare receptors present = signal amplification
Efficacy vs Potency
Efficacy = magnitude of the response the drug produces -(Emax= greatest effect) (similar to Vmax and same spot on graph)
Potency = [ ] or amount of drug needed to give effect
- (EC50 = potency)
- Shifted to left on graph = more potent
Agonists vs Antagonists
Agonists:
- Binds and activates receptor = stimulates effects
- Has receptor affinity
- Has receptor efficacy
Antagonist
- Inhibits agonist, no effect without agonist
- Has receptor affinity
- No receptor efficacy
Receptor Antagonism
A receptor antagonist binds to the same receptor to which the agonist binds (reversible or irreversible)
Competitive Antagonism
-Antagonist binds to agonist binding site on receptor = prevents agonist from binding to receptor
Kinds:
1) Reversible
2) Irreversible
3) Non competitive
Reversible Competitive Antagonism
- Need larger [ ] of agonist to overcome competitive antagonist and create response
- Curve shifts to the right (Change in potency, not Emax)
Irreversible Competitive Antagonism
- Cant bind or respond to agonist bc irreversibly bond to antagonist
- Emax = reduced
- Insurmountable = cannot overcome effect
Noncompetitive Antagonism
- Allosteric antagonism/binding site
- Binds to the receptor at a different site from the agonist binding site
- Reduces agonist action
- Insurmountable = cannot overcome effect
- Emax = reduced
Nonreceptor Anatagonism
- Nonreceptor antagonist does not bind to the same receptor the agonist would
- Can oppose drug through another receptor
Nonreceptor Anatagonism:
1) Physiologial Antagonism
2) Chemical Antagnonism
1) Physiologial Antagonism
Ex:
-Epinephrine = increases blood pressure and bronchodilation
-Histamine = decreases blood pressure and bronchoconstriction
2) Chemical Antagnonism
-Chemical antagonist reacts with agonist = inactive product
Ex:
-Protamine = + charged, counteracts heparin = - charged
Full vs partial agonists
Full agonists:
-Produce a maximal response
Partial agonists:
- Produce a submaximal response (lower)
- Can act as a competitive antagonist in the presence of a full agonist
Inverse Agonists
-Reverse constitutive activity of the receptor (activity in absence of agonist)
Quantal Dose-effect Curves
- Plots the fraction of the population that responds to a given dose of drug as a function of the drug dose (who it actually works on)
- Median effective dose (ED50) = 50% individuals exhibit the specified quantal effect
Therapuetic Index
TI = safety of drug
-Varies
TI= TD50/ED50
TI=LD50/ED50
