Pharmacodynamics

Question 1

Pharmacodynamics definition

Answer 1

What the DRUG does to the BODY

Question 2

4 major targets for drug action

Answer 2

1. Receptors (acting on them)
2. Ion channels (modulating or inhibiting)
3. Carrier molecules (inhibiting)
4. Enzymes (inhibiting)

-Regulatory proteins are commonly involved as primary targets for drug action

Question 3

Non-protein target for drug action

Answer 3

1. DNA (antimicrobial, anti tumor drugs)
2. RNA (antivirus drugs)
3. Osmosis (osmotic diuretics)
4. Neutralizing (antiacids)

Question 4

Ways that the drug can get into the cell

Answer 4

1. Neural control
2. Hormonal control
3. Direct action on metabolism
4. Transport molecules

Question 5

Agonist vs. Antagonist

Answer 5

Agonist - a drug that mimics the response of the receptor to the endogeneous ligand. But when it binds, it produces an active response

Antagonist - a drugs that binds, but does not produce a response. It can prevent the receptor from being activated by the endogeneous ligand.

Question 6

1. Partial agonist

2. What happens when you have a partial and a full agonist?

Answer 6

1. a drug that binds an activate the receptor, but it has only a partial efficacy.
2. the concentration needed is higher, but the response will be the same as for the full agonist

Question 7

Competitive vs. Non-competitive antagonist

Answer 7

Competitive –> competes with the endogenous ligand for the binding site on the receptors (Reversible or Irreversible)

Non- competitive –> may bind to another site other than the receptor and affect the ability of the agonist to activate it (Reversible or Irreversible)

Question 8

1. Agonist + competitive reversible antagonist

2. Agonist + competitive irreversible antagonist

Answer 8

1. a higher dose is needed to have a desired effect –> 100%
2. the dose remains the same and the effect will be only 50%

Question 9

Drug antagonism types (5)

Answer 9

1. Competitive: both drugs binding to the same receptor
2. Non- competitive
3. Pharmacokinetic: one drug affecting the metabolism, absorption and excretion of the other
4. Chemical: interaction in solution
5. Physiological: 2 agents producing opposing physiological effects

Question 10

The two-state receptor model (5)

Answer 10

• the receptor contains two conformational states: active and resting which remain in equilibrium
• agonists have a higher affinity for the activated state, so it will shift the equilibrium towards the active side
• inverse agonist have a higher affinity for the resting state, so it will shift the equilibrium towards the resting side
• antagonists, are neutral. They do not affect the equilibrium, but reduces by competition for the binding of other ligands.
• all know H1 antihistamines function as inverse agonists

Question 11

Desensitization (tachyphylaxis)

Answer 11

• when the biological response to a drug diminishes when giving it continuously or repeatedly
• Changes that happen:
  1. Change in receptors: phosphorylation of intracellular regions of the receptors protein by which ion channels become desensitized
  2. Loss of receptors: internalization of the receptors
  3. Exhaustion of mediators: depletion of an essential intermediate substance
  4. increase metabolic degradation of the drug
  5. physiological adaptation
  6. active extrusion of drug from cells

Question 12

Signalling mechanisms for drug effect (5)

Answer 12

1. Steroid: transmembrane diffusion of the drug
2. Tyrosine kinase: transmembrane enzyme receptors, outer domain has receptor function and inner domain has effector functions
3. JAK- STAT: transmembrane receptors, activation of appropriate ligand activates cytoplasmic tyrosine kinase (JAKs) which phosphorylate STAT (regulate transcription)
4. Ion channels: transmembrane channels that are either open or closed by binding of a drug to the receptor site
5. G- protein coupled receptors: use a coupling protein to activate a separate effector molecule

Question 13

Transmembrane protein receptors (3)

Answer 13

1. Ligand- gated
2. G- protein coupled receptors
3. Tyrosine kinase receptors

Question 14

Ligand- gated ion channel (5)

Answer 14

• response in milliseconds
• fast synaptic transmission
• ionotropic receptors (Na+, K+, Ca2+, Cl-)
• Nicotinic acethycholine (excitatory Na+), GABA type A (inhibitory Cl-)

1. Agonist binds to extracellular receptor site
2. Conformational changes happens and opening of the ion channel
3. Allows ions to flow across the membrane

Question 15

G- protein coupled receptor (3)

Answer 15

• response in seconds
• 7-pass transmembrane proteins that are coupled with G-proteins
• Targets for G-protein:

1. Adenylyl cyclase –> cAMP formation
2. Phospholipase C –> IP3 and DAG formation
3. Ion channels –> calcium and potassium channels
4. Rho A and Rho kinase –> many intracellular pathways

***look at the summary

Question 16

Kinase-linked receptors (5)

Answer 16

• response in min/ hours
  1. Receptors tyrosine kinases: incorporate tyrosine kinase in the intracellular domain (insulin, epidermal growth factor, nerve growth factor receptors)
  2. Serine/ threonine kinases: incorporate serine/ threonine kinases in the intracellular domain (transforming growth factor receptors)
  3. Cytokine receptors: lack intracellular domain and activate cytosolic tyrosine kinases like JAK
  4. Guanylyl cyclase linked receptors: incorporate guanylyl cyclase in the intracellular domain and stimulate cGMP formation (atrial natriueretic peptide receptor)

Question 17

Nuclear receptors (3)

Answer 17

• response in min/ hours/ days
• family of 48 soluble receptors that sense lipid and hormonal signals and modulate gene transcription
• two categories: present in cytoplasm and present in nucleus

Present in cytoplasm: form homodimers, migrate to nucleus. Mainly endocrine ligands, ex: glucocorticoid, estrogen, prolactin receptors…

Present in nucleus: forms heterodimers with retinoid X receptors (fatty acids –> peroxisome proliferator receptor)