Pharmacodynamics

Question 1

1. Define Drug.

Answer 1

Any substance that when administered to a living organism, produces a biological effect – it does not add function but rather stimulates or inhibits normal cellular functions to alter the basic processes in body cells

Question 2

2. Define pharmacology.

Answer 2

Study of how the function of living systems is affected by chemical agents

Question 3

3. Define pharmacokinetics and pharmacodynamics.

Answer 3

Pharmacokinetics → study of absorption, distribution, metabolism and excretion of drugs (what we do to the drug)
Pharmacodynamics → study of effects of drugs and their mechanisms of action (what the drug does to us)

Question 4

4. Define toxicology.

Answer 4

Study of the adverse side effects of drugs

Question 5

5. What are the different major types of drug receptors?

Answer 5

1. ion channels
2. G protein-linked receptors
3. Enzyme linked receptors
4. Intracellular receptors
5. Extracellular receptors
6. transporters

Question 6

6. What are the two types of ion channels?

Answer 6

1. voltage-gated – conductance (opening and closing) of channels is regulated by changes in the membrane potential
2. ligand-gated – conductance is controlled by ligand binding

Question 7

7. How do local anesthetics act as ion channels?

Answer 7

Local anesthetics block the voltage-gated sodium channels in neurons that transmit pain information from the periphery to the CNS therefore preventing the action potential propagation and pain perception

Question 8

8. How do benzodiazepines act as ion channels?

Answer 8

Benzodiazepines bind to the GABAa receptor in neuronal membranes in the CNS. GABAa channels usually function as a chloride ion channel which is activated by the GABA neurotransmitter. When benzodiazepines are added to the equation, it enhances the ability of GABA to open the chloride channel for longer causing hyperpolarization and more inhibition.

Question 9

9. What are G protein linked receptors?

Answer 9

A majority of prescription drugs function with G protein linked receptors. Signaling through these mechanisms uses 3 membrane-bound components: cell surface receptor, G protein and an effector (enzyme or ion channel). The G protein has 3 polypeptide subunits: alpha, beta, gamma. Once the drug binds the receptor, the alpha subunit is hydrolyzed from GDP → GTP, is released and activates the effector (ex. adenylate cyclase).
Ex. Albuterol (B2 agonist) for asthma
Propranolol (B antagonist) for HTN
Bethanechol (muscarinic agonist) for atonic bladder
Ipratropium (muscarinic antagonist) for asthma

Question 10

10. What are examples of G protein effects?

Answer 10

1. ion channels
2. membrane-bound enzymes that interact with the G proteins with enzymes leading to the production of second messengers (ex. adenylyl cyclase catalyzes formation of cAMP and phospholipase C catalyzes the formation of IP3 and DAG)

Question 11

11. What are the different G protein signalling pathways?

Answer 11

1. Gs increases adenylyl cyclase
2. Gi decreases adenylyl cyclase and opens potassium channels
3. Gq increases phospholipase C

Question 12

12. What are different examples of cAMP mediated hormonal responses?

Answer 12

B-adrenoreceptor activation causes breakdown of glycogen in liver (with glucagon receptors as well), TG in adipose tissue, increased HR and contraction force and relaxation of smooth muscle.

Question 13

13. What is the pathway of IP3 once activated?

Answer 13

IP3 = inositol-1,4,5-triphosphate
PLC → PIP2 moves to DAG and IP3
IP3 activates Ca2+ release from ER
Ca2+ activates several enzymes leading to smooth muscle contraction, increased force of contraction of cardiac muscle, secretion from exocrine glands, neurotransmitter release from neurons, hormone release.

Question 14

14. What are the different enzyme linked receptors?

Answer 14

1. ligand-regulated transmembrane enzymes
2. cytokine receptors – mediate actions of peptide ligands such as growth hormone, prolactin, EPO, and interferons they have no intrinsic enzymatic activity and bind to the intracellular tyrosine kinase in the JAK family

Question 15

15. What are ligand-regulated transmembrane enzymes?

Answer 15

These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain. The enzyme domain can be a tyrosine kinase (largest group), serine/threonine kinase or guanylyl cyclase.

Question 16

16. What is the signaling pathway of tyrosine kinase receptors?

Answer 16

1. inactive receptors of tyrosine kinase sit on the cell membrane
2. signaling molecules bind to the receptor activating them causing them to dimerize leading to the phosphorylation of each other
3. The phosphorylation of the receptors cause intracellular signaling proteins to bind leading to activation of signaling cascade and regulation of transcription (gene expression)
   **tyrosine kinase receptors play an important role in cellular growth and differentiation. Gain or function mutations in these receptors can lead to cancer (proto-oncogenes → oncogenes)
   Ex. insulin receptors, EGFR, PDGFR, NGFR
   **These are examples of ligand-regulated transmembrane enzymes

Question 17

17. What type of receptor is imatinib effective towards?

Answer 17

Imatinib is an FDA approved tyrosine kinase inhibitor effective for leukemia.

Question 18

18. What is the signaling pathway of the cytokine receptor?

Answer 18

1. inactive cytokine receptor
2. binding of ligand to the JAK receptor causes it to dimerize and JAKs phosphorylates each other and the receptors
3. STATs bind to the receptors and JAKs phosphorylate them
4. STATs dimerize and migrate to nucleus to regulate transcription

Question 19

19. What are the different types of intracellular receptors?

Answer 19

1. nuclear receptors
2. enzymes – common cytosolic target that most commonly binds drugs to inhibit the enzyme activity
3. structural proteins

Question 20

20. What are nuclear receptors?

Answer 20

These are ligand-activated transcription factors that contain binding sites for ligands and DNA. The ligand diffuses from the plasma membrane of the target cell and binds to the receptor inside. These receptors regulate the expression of genes that control physiological processes such as metabolism and development. Some receptors are in the cytoplasm and others reside in the nucleus.
Ex. steroid hormones, thyroid hormones, vitamin D

Question 21

21. What is the role of statins?

Answer 21

These are competitive inhibitors of HMG-CoA reductase which is the enzyme that catalyzes the first committed step of cholesterol biosynthesis. In this case the HMG-CoA reductase is the enzyme that gets bound by the drug. By inhibiting cholesterol synthesis states it decreases intracellular supply of cholesterol. The liver is sensitive though and monitors the cholesterol levels carefully so as soon as the cholesterol is depleted, the liver increases the production of LDL receptors to uptake more LDL (containing cholesterol) that needs to be used for cell membrane construction and other physiological processes. This results in an increased clearance of LDL from the blood.

Question 22

22. What is the role of structural proteins as intracellular receptors?

Answer 22

The vinca alkaloids bind to tubulin preventing its polymerization into microtubules. This results in the cells arresting in metaphase preventing the cells to divide. This is a function of anti-cancer drugs.

Question 23

23. What is the action of the ACE enzyme?

Answer 23

ACE is an angiotensin converting enzyme that acts as an extracellular enzyme. ACE converts angiotensin I to angiotensin II a potent vasoconstrictor. ACE inhibitors are used for heart failure and HTN.
Angiotensinogen → angiotensin I via renin→ angiotensin II via ACE in the lungs→ vasoconstriction and sodium and water retention

Question 24

24. Give an example of a transporter target of drugs?

Answer 24

Selective serotonin-reuptake inhibitors (SSRIs) act by blocking serotonin reuptake

Question 25

25. What is the action of antacids, Mesna and Mannitol?

Answer 25

Antacids → neutralized gastric acid Mesna → reacts in the bladder with acroleine (metabolite of anticancer drug cyclophosphamide) preventing hemorrhagic cystitis