59-291 Section 1, Lecture 7 Pharmacodynamics Detailed mechanism of action by which drugs produce drug produce their biochemical and physiological effect Dose response relationship; relationship between drug concentration and magnitude of drug effect Provides scientific basis for the selection and use of drugs to counteract specific pathophysiologic mechanisms in particular disease

Nature of drug receptors Drugs produce their effects by interacting of receptors Most ligands bind to protein receptors, which are embedded in the membrane Some agents act directly to on DNA or membrane lipids

Table 3-1 Drug Receptors Types of Drug Receptors Examples of Drugs that Bind Receptor Hormone and Neurotransmitter Receptors Adrenergic receptors Epinephrine and propranolol Histamine receptors Cimetidine and diphenhydramine 5-Hydroxytryptamine (serotonin) receptors Insulin receptors Tegaserod, ondansetron, and sumatriptan Insulin Muscarinic receptors Atropine and bethanechol Nicotinic receptors Tubocurarine Opioid receptors Morphine and codeine Steroid receptors Cortisol, estradiol, and tamoxifen Enzymes Carbonic anhydrase Acetazolamide Cholinesterase Donepezil and physostigmine Cyclooxygenase Aspirin and celecoxib DNA polymerase Acyclovir and zidovudine DNA topoisomerase Ciprofloxacin Human immunodeficiency virus (HIV) protease Indinavir Monoamine oxidase Phenelzine Na+,K+-adenosine triphosphatase Digoxin Xanthine oxidase Allopurinol Membrane transport proteins Ion channels Lidocaine, quinidine, and verapamil Ion transporters Furosemide and hydrochlorothiazide Neurotransmitter transporters Amitriptyline, cocaine, and fluoxetine Other macromolecules Membrane lipids Alcohol and amphotericin B Nucleic acids Cyclophosphamide and doxorubicin

Types of drug receptors G-protein coupled receptors (GPCR) Guanine nucleotide binding protein (G protein) Extracellular/transmembrane domain binds to ligand Intracellular domain binds to effector molecules (G protein)

Types of drug receptors G-protein coupled receptors (GPCR) Guanine nucleotide binding protein (G protein) Enzymes Competitive and noncompetitive inhibitors Membrane transport proteins Ligand and voltage-gated ion channels Neurotransmitter transporters Membrane lipids and phospholipids Anesthetics and alcohol Steroid hormone receptors Intracellular proteins, translocate to nucleus

A small # of drugs produce their physiological effect without interacting with receptors. Examples: Drugs that bind to enzymes interfere with the normal activity of the enzyme in one of 2 ways Competitive- Non-competitive- Drugs can also bind to membrane transport proteins (competitively and non-competitively) and inhibit their function. Some drugs can also bind to membrane lipids and DNA in order to produce their action.

Drug receptor interactions are very specific Drug receptor interactions are very specific. They form ionic, hydrophobic and H-bonds with their receptor. The receptor binding site recognizes the 3-D shape of their ligands. L-isoproterenol binds to a -adrenergic receptor with higher affinity than its mirror image D-isoproterenol.

The non-covalent interactions are reversible as a result drugs dissociate from their receptors as their concentration in the plasma decreases. Affinity- is the tendency of a drug to combine with its receptor [D] + [R] [D-R] Effect Law of mass action: the # of R occupied by D depends on the [D] And the K D - the ratio of drug receptor dissociation k2 and association k1 rate K D= k2/ k1 The lower the K D higher the affinity. This occurs if the association rate constant k1 >> (much greater than) k2 . k1 k2

KD= the concentration of drug required to saturate 50% of the receptors Most effective drugs have KDs in the micromolar (10-6) to nanomolar (10-9) range. Signal transduction: the process where the binding of a drug to its receptor initiates a cascade of biochemical events that result in the physiological effect. Membrane receptors are coupled to with a G-protein, an ion channel or an enzyme For example G proteins:

Gas = Stimulatory; increase adenylate cyclase (AC) activity Gai = Inhibitory ; decrease AC activity Gaq= activate phospholipase C >> formation of Inositol triphosphate (IP3) and diacylglycerol from (DAG) from membrane phospholipids

Efficacy or Intrinsic activity- the ability of a drug to initiate a cellular effect Agonist- drug has both receptor affinity and intrinsic activity Antagonist- drug has receptor affinity only.

3 Types of Agonists Full- max physiological response Partial- sub maximal physiological response In the presence of a full agonist a partial agonist behaves like an antagonist. Inverse agonist- decreases the rate of signal transduction Antagonists bind to receptor binding-site and prevent the action of agonists and inverse agonists.

Practice Questions Which of the following drug is more effective if they are administered with the same dose? Why? Drug A with KD = 3x10-10 Drug B with KD = 2x10-5 Drug A, because it has a lower KD

How does a Gaq increase IP3? How does IP3 function in the cells Activates phospholipase C IP3 releases calcium from intracellular storage sites and augment calcium-induced processes such as muscle contraction