Lecture 29: Pharmacodynamics

Question 1

Describe mechanisms of drugs

Answer 1

-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)

Question 2

Types of drug targets:

-Ion channels

Types of drugs that do this

Answer 2

-Some drug alter conductance of ion channels

Ex:

1) Local anesthetic
2) Sedative-hypnotics
3) Antipileptics

Question 3

Types of drug targets:

-G-protein-linked receptors

Types of drugs that do this

Answer 3

-Majority of drugs bind to G protein linked receptors

Ex:

1) Albuterol (B2-Agnist, for asthma)
2) Propranolol (B-antagonist, for hypertension)

Question 4

Types of drug targets:

Enzyme-linked receptors

Types of receptors

Answer 4

-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)

Question 5

Nuclear Receptors

What does this

Answer 5

• Intracellular
• Regulate gene expression of genes controlling metabolism and development

Ex:

1) Steroid hormones
2) Thyroid hormones
3) Vitamin D

Question 6

Enzymes

Types of drugs that do this

Answer 6

-Most drugs inhibit enzyme activity

Ex:

1) Aspirin
2) Ibuprofen
3) Omeprazole

Question 7

Types of Transporters

Answer 7

Ex:

1) Neurotransmitter transporters
2) Antidepressants - act by blocking serotonin re-uptake

Question 8

Effects of drugs binding to tubulin

Answer 8

• Some anti cancers drugs bind to tubulin = prevention of polymerization of this molecule into microtubules
• Arrests cells in metaphase

Question 9

How is Antacid mediated?

Answer 9

• not mediated by binding to receptors

- Antacids neutralize gastric acid (doesn’t underact w/ macromolecular components)

Question 10

Dose response curves

Equations and graphs

Answer 10

-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)

Question 11

Receptor Binding of drugs

Equations and graphs

Answer 11

-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)

Question 12

Spare receptors and Signal Amplification

Answer 12

EC50 < KD

All receptors not occupied, still evoke full response = spare receptors present = signal amplification

Question 13

Efficacy vs Potency

Answer 13

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

Question 14

Agonists vs Antagonists

Answer 14

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

Question 15

Receptor Antagonism

Answer 15

A receptor antagonist binds to the same receptor to which the agonist binds (reversible or irreversible)

Question 16

Competitive Antagonism

Answer 16

-Antagonist binds to agonist binding site on receptor = prevents agonist from binding to receptor

Kinds:

1) Reversible
2) Irreversible
3) Non competitive

Question 17

Reversible Competitive Antagonism

Answer 17

• Need larger [ ] of agonist to overcome competitive antagonist and create response
• Curve shifts to the right (Change in potency, not Emax)

Question 18

Irreversible Competitive Antagonism

Answer 18

• Cant bind or respond to agonist bc irreversibly bond to antagonist
• Emax = reduced
• Insurmountable = cannot overcome effect

Question 19

Noncompetitive Antagonism

Answer 19

• 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

Question 20

Nonreceptor Anatagonism

Answer 20

• Nonreceptor antagonist does not bind to the same receptor the agonist would
• Can oppose drug through another receptor

Question 21

Nonreceptor Anatagonism:

1) Physiologial Antagonism
2) Chemical Antagnonism

Answer 21

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

Question 22

Full vs partial agonists

Answer 22

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

Question 23

Inverse Agonists

Answer 23

-Reverse constitutive activity of the receptor (activity in absence of agonist)

Question 24

Quantal Dose-effect Curves

Answer 24

• 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

Question 25

Therapuetic Index

Answer 25

TI = safety of drug
-Varies

TI= TD50/ED50

TI=LD50/ED50