GP 05 - Pharmacodynamics 1

Question 1

What is the technical definition of a drug?

Answer 1

Any substance that when administered to a living organism produces a biological effect

Question 2

Define and differentiate pharmacodynamics and pharmacokinetics

Answer 2

• Pharmacodynamics - the study of biochemical and physiological effects of drugs and their mechanisms of action
• Pharmacokinetics - the study of the absorption, distribution, metabolism, and excretion of drugs

Question 3

Define and differentiate toxicology, pharmacotherapeutics, pharmacotherapy, and clinical pharmacology.

Answer 3

• Clinical Pharmacology (aka - pharmacotherapeutics) - the study of the use of drugs in the prevention and treatment of disease
• Pharmacotherapy - the use of drugs to treat disease
• Toxicology - the study of the adverse effects of drugs

Question 4

List the major types of drug targets

Answer 4

• Ion Channels
• G-protein linked receptors
• Enzyme linked receptors
• Nuclear receptors
• Enzymes
• Transporters
• Structural proteins

Question 5

What is a local anesthetic’s mechanism of action?

Answer 5

They bind to the intracellular domain of v-gated Na channels in nuerons and prevent them from opening

Question 6

What is the mechanism of action of benzodiazepines?

Answer 6

The GABA_A receptor is present in neuronal membranes in the CNS and functions as a Cl- channel. It is activated by the inhibitory neurotransmitter, GABA.

Benzodiazepines bind to the receptor and enhance its ability to open the Cl- channel, thereby hyperpolarizing the cell

Question 7

Describe the basics of how a G protein receptor works.

Answer 7

A trimeric G-protein consisting of an α, β, and γ subunit has GDP bound to the α subunit (when off) and is also bound to a receptor. When that receptor binds its ligand, a conformational change converts the GDP to GTP and the α subunit separtes from the rest of the G-protein to go have its effect on something.

Question 8

What are the most common G-protein effectors?

Answer 8

Ion channels

Membrane-bound enzymes (e.g. - adenylyl cyclase)

Question 9

What is the mnemonic for rembering which type of GPCR utilizes which type of G protein?

Answer 9

α₁α₂β₁β₂

qiss

Question 10

Describe the PIP2 pathway

Answer 10

1. GPCR binds ligand
2. G_αq activates PLC
3. PLC cleaves PIP₂ IP3 and DAG
4. IP3 opens up Ca++ channels on the ER membrane
5. Ca++ and DAG bind to and activate PKC

Question 11

List the types of enzyme-linked receptors

Answer 11

• Ligand-regulated transmembrane enzymes
• Cytokine receptors

Question 12

Describe the basic structure of ligand regulated TM enzymes. What is the largest family of this receptor type? What are the most physiologically important receptors from this family?

Answer 12

These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain which is either a tyrosine kinase (largest family), serine/threonine kinase, or a guanylyl cyclase.

The most physiologically important tyrosine kinase receptors are:

• Insulin Receptor
• Epidermal Growth Factor Receptor (EGFR)
• Platelet-derived growth factor (PDGFR)
• Nerve growth factor receptor (NGFR)

Question 13

Describe how a tyrosine kinase receptor (TKR) works?

Answer 13

1. Two TKRs bind their ligand and then dimerize
2. They phosphorylate each other’s tyrosines
3. Intracellular signalling proteins bind to phosphorylated tyrosines and become activated
4. The signalling proteins activate a cascade which eventually leads to regulation of transcription

Question 14

What is the drug Imatinib used for and why?

Answer 14

Imatinib is used to treat leukemias

This drug is a tyrosine kinase receptor (TKR) inhibitor. Most TKRs play a role in cellular growth and differentiation. Many leukemias are caused by TKR gain of function mutation

Question 15

Describe how cytokine receptors work

Answer 15

1. Inactive cytokine receptors have janus kinases (a type of tyrosine kinase) associated with their intracellular domain. These receptors dimerize when they bind a ligand and the JAKs phosphorylate each other and the receptors
2. STATs bind to receptors at the phosphorylated sites
3. JAKs phosphorylate the STATs
4. STATs dissociate from the receptor, dimerize, and then migrate to the nucleus to regulate transcription.

Question 16

What are most cytokine receptors responsible for?

Answer 16

Mediating the actions of many peptide ligands, such as:

• Growth Hormone (GH)
• Prolactin
• Erythropoietin
• Interferons

Question 17

Describe how nuclear receptors work and the ligands we need to know that bind them.

Answer 17

Nuclear receptors are ligand-activated txn factors that contain a binding site for the ligand and one for the DNA.

• Steroid Hormones
• Thyroid Hormones
• Vitamin D

Question 18

What do statins do and how?

Answer 18

Statins are competitive inhibitors of HMG-CoA reductase, the enzyme that catalyzes the first committed step of cholesterol synthesis. By inhibiting that reaction, intracellular cholesterol is depleted which leads to the the up-regulation of LDL receptors in hepatocytes, resulting in increased clearance of LDL from the blood.

Question 19

What are vinca alkaloids and what do they do? What are they used for?

Answer 19

Vinca alkaloids are structural protein binding drugs that bind tubulin and prevent the formation of microtubules. As a consequence, cells are arrested in metaphase.

Used as an anticancer drug

Question 20

List the drugs we need to know that don’t bind to receptors. What do they do?

Answer 20

• Mesna - reacts in the bladder with acroleine, a metabolite of the anticancer drug cyclophosphamide, preventing hemorrhagic cystitis
• Mannitol increases the osmolarity of various body fluids, promoting diuresis or reducing cerebral edema
• Cholestyramin, colestipol, and colevelam bind bile acids in the intestines and prevent their reabsorption, treating hyperlipidemia
• Pyrimidine and Purine analogs can be incorporated into nucleic acids and alter their function. Used for cancer and antiviral chemotherapy