BASIC PHARMACOLOGY 2 SAMUEL AGUAZIM(MD)

PHARMACODYNAMICS Pharmacodynamics describes the actions of a drug on the body and includes the principles of receptor interactions, mechanisms of therapeutic and toxic action and dose- response relationships

How is Pharmacodynamics related to pharmacokinetics? the pharmacokinetics processes of absorption, distribution and biotransformation and excretion determine how quickly and to what extent a drug will appear at a target site. Pharmacodynamics concept explain the pharmacological effects of drug and mechanism of action

Receptor Interactions What is a receptor? A macromolecule typically made up of proteins that interacts with either an endogenous Ligand or a drug to mediate a pharmacologic or physiologic effect

What are two main functions of receptors? 1. Ligand binding 2. Activation of an effectors system ( message propagation)

What is an effectors? Effectors transduce drug receptor interactions into cellular effects. There are four types of well- know effectors mechanisms

1.Transmembrane- some ligands such as insulin bind to receptors that have both extracellular and intracellular component. Binding of the extracellular component stimulates the intracellular component, which is coupled to an enzyme, for example tyrosine kinase

2. Ligand-gated ion channels- drugs bind to these receptors, which then alter the conductance of ion through the cell membrane Example of ligand-gated ion channel drugs are benzodiazepines and acetylcholine

3.Intracellular- thyroid and steroid hormones bind to nuclear receptors to form complexes that interact with DNA which causes changes in gene expression

4.Second messenger system- Drugs bind to receptors that activate second messenger systems involving G protein Second messenger system allows signals form cell surface receptors to be converted and amplified into a cellular response

3 types of second messenger 1. Cyclic adenosine monophosphate (cAMP) – produced by adenylate cyclase 2. Cyclic guanosine monophosphate( cGMP) produced by guanylate cyclase 3. Inositol triphosphate (IP3)- produced by phospholipase C

Mechanism of Therapeutic and Toxic Action What is an agonist: a drug that binds to and activate receptors. What is a full agonist? A drug that when bound to a receptor, produces 100% of the maximum possible biologic response What are partial agonists? Produces the biological response but cannot produce 100% of the biological response even at very high dose

What are antagonists? Drugs that bind to receptors or other drugs and inhibit a biologic response What does a competitive antagonist do? It binds reversibly to the same active site of an enzyme as an agonist

How can a competitive antagonist be overcome? By increasing the concentration of the drug(agonist). The maximum efficacy of the drug will not change in the presence of a competitive antagonist

What does a noncompetitive antagonist do? It binds irreversibly to a different site on the enzyme than the antagonist. Noncompetitive agonists cannot be overcome by increasing concentrations of the drug. Note: maximum efficacy will be reduced in the presence of a noncompetitive antagonist

Dose-Response Relationships What is the difference between efficacy and potency Efficacy is the ability to produce a biologic effect. Potency is related to the amount of drug necessary to cause a biologic effect E.g. Two Drugs A and Drug B are both claimed to reduce a patient’s heart rate by 25%, then they both have the same efficacy.

Give an example of potency. Only 1 mg of drug A needs to be given to achieve a reduction in heart rate. Whereas 10mg of drug B are needed. Therefore , it can be inferred that drug A is more potent.

What is Kd? The concentration of drug yielding 50% occupancy of the receptor( dissociation constant) What is EC50? The drug concentration that produces 50% of the maximum possible response in a graded dose- response curve

Drug Dosing and Prescription Writing What three factors are involved in determining an appropriate drug dose for a patient? 1. type of infection or disease 2. patient variables( e.g. weight, liver or kidney disease) 3. Plasma concentration needed to achieve efficacy

What is volume of distribution(Vd)? The apparent volume into which a drug is able to distribute How is Vd calculated? Vd= total drug in the body divide by plasma concentration of the drug What is the significance of a large Vd? Based on the equation presented above, a large Vd signifies that most of the drug is being sequestered in some organ or compartment

What is a maintenance dose? A dose of a drug given to achieve a therapeutic plasma concentration over an extended period of time

What is the equation for calculating a maintenance dose? Maintenance does= clearance multiply by desired plasma concentration What is important to remember in performing this calculation? You must be absolutely certain that the units are correct.

What is a loading dose? It is a single large dose of a drug that is used to raise the plasma concentration to a therapeutic level more quickly than would occur through repeated smaller doses.

What is the equation for calculating a loading dose? Loading dose= Vd x desired plasma concentration

Define peak and trough concentrations? These are maximum and minimum plasma concentrations, respectively, which are observed during dosing intervals. these variable will fluctuate around the steady state plasma concentration

What is the steady state plasma concentration? The point at which the rate of drug availability is equal to the rate of drug elimination Frequency of dosing does not affect steady state of concentration

What is clearance? Is a term that indicates the rate at which a drug is cleared from the body. Clearance is defined as the volume of plasma cleared of drug per unit of time. What is an excretion rate? The rate at which a drug is eliminated from the body, which is measured by clearance x plasma concentration

What is therapeutic index? It is a measure of drug safety. The ratio of a drug’s toxic to its therapeutic dose. A safe drug will have high therapeutic index. How to calculate therapeutic index? Therapeutic index= LD 50/ED50 LD: Lethal dose ED: Effective dose