Basic Principles of Pharmacology I

Question 0

Drug effect

Answer 0

Pharmacologic effect= visible response

Question 1

Drug action

Answer 1

Molecular action= invisible

Question 2

Drug selectivity

Answer 2

• property of drug to cause a specific effect-few drugs produce a single effect
• primary effect= desired
• secondary effect- side effects- may or may not be desired

Question 3

Interactions of Drug Actions and Effects

Answer 3

• some drugs have a single major mechanism of action and this action produces multiple effects
• another drug may have several different actions either or both of which are responsible for a single effect and then have an additional action which causes a single effect

Question 4

Pharmacokinetics

Answer 4

• time course of drug absorption, actions and elimination
• has to deal with the systemic circulation what is bound and what is free and what is tissue bound
• and elimination

Question 5

Pharmacodynamics

Answer 5

• types of drug actions
• physiochemical actions- simple chemical interactions- ie antacids, antiseptics- not very specific
• receptor interactions- internation of drug with physiologic receptors-macromolecular most drugs

Question 6

Basic Sciences and Clinical Medicine of Pharm

Answer 6

• define the physiology of the target tissue: identify the receptors and the endogenous agonists that stimulate the tissue
• create drugs that mimic the endogenous agonists
• tests the drugs in the target tissues- laboratory and clinical trials

Question 7

Doses and weights

Answer 7

• doses are quantities measured by weight (mg, mcg)
• pharmacodynamic interactions and the pharmcokinetic events occur at the molecular level
• mg and molecules- mole 6.022 x 10^23

Question 8

Receptors

Answer 8

• Macromolecules, particularly proteins. May be on or in a cell or free in the plasma or extracellular fluid
• these are present as part of the normal biochemical and physiologic mechanisms and usually interact with endogenous compounds. They are specific
• they function both as ligand binder and as an effector
• the natural ligand (agnoist) or a drug which resembles it can bind a receptor and modulate its usual activity
• each receptor occupied might be stimulated (agonist) or inhibited (antagonist)
• each cell in a tissue contains a large population of receptors that are easily accessible to drugs
• each drug receptor interaction produces a small change in the biochemical or electrochemical homeostasis of the cell. The cumulative effects of many drug receptor interactions will lead to a change in the function of the cell
• when enough cells in a tissue are affected then the function of the tissue is altered and an observalbe pharmacologic response can be noted
• a maximal response is eventually achieved which is related to the number of drug receptor interactions and the physiologic capacity of the tissue (normal vs. diseased)

Question 9

Types of Receptors

Answer 9

• Membrane bound- eg. in neural synapse, ion channels
• enzymes- intracellular or extracellular
• structural macromolcules- eg microtubules
• intracellular macromolecules- eg steroid receptors, RNA
• cell membrane itself- change electrical potential fluidity

Question 10

Regulated by alpha subunits

Answer 10

• alpha s- increase adenylyl cyclase, increase Ca2+
• alpha i- decrease adenylyl cyclase, increase K+ currents
• alpha o- decrease Ca2+
• alpha q- increase phospholipase CB
• alpha 13- increase Na+/H+ exchange
• alpha t-increase cGMP-phosphodiesterase (vision)
• alphaolf- increase adenylyl cyclase (olfaction)

Question 11

Beta subunit regulation

Answer 11

• receptor-operated K+currents
• adenylyl cyclase
• phospholipase CB

Question 12

Reversible Bonds

Answer 12

• Ionic
• Van der Waals
• Hydrogen

Question 13

G proteins

Answer 13

• drug- receptor interations- fractions of seconds activate G protein activity that lasts for seconds
• G proteins (GTP binding proteins)- regulate the activity of
• distinct effector proteins in the cell- enzymes, channels, transport proteins
• there can be multiple G proteins in a single cell
• act as switches that are turned on by the receptor and turn themselves off in a few seconds
• several drugs can stimulate different receptors but ultimately influence the same effector protein through the mediation of a G protein that is shared by the different receptors. Thus stimulus averaging or modulation can be achieved

Question 14

Second Messenger

Answer 14

• also produce amplification of the drug receptor interaction
• converts an event that happens outside the cell (ie receptor binding) into a change that happens inside the cell-some second messengers can cause different effects in different tissues

Question 15

Changing biochemical balance

Answer 15

• changing the biochemical balance of substrates in metabolic pathways and activating or deactivation enzyme systems can have profound effects on the function of the cells in a tissue
• eg cAMP, Ca2+ may be stimulated or inhibited by G proteins

Question 16

Structure-Activity Relationships

Answer 16

• the structure of the drug determines how it will fit into the receptor
• the better the fit, the better the stimulation
• subtle changes in structure amongst a class of drugs can greatly influence the drugs’ effects
• stereoisomers

Question 17

Quantitative Descriptions of Drug Action

Answer 17

• these are attempts to take experimental data, combine it with certain assumptions and make a model that works for most systems
• interaction at equilibrium: Drug (D)+ Receptor (R) -> Effect

Question 18

Dose response relationship

Answer 18

• how to measure and compare drug effects
• you have have dose response curve but also can change it to log dose relationship
• thresold- the beginning of the curve- dose of agonist at which a response begins. May related to the affinity of the agonist for the receptor
• slope-rate of rise of the response on the steep portion of the curve, Log of EC50 also relates to affinity
• maximal asymptote- the top of the curve represents E Max for that particular agonist

Question 19

Receptor Occupancy

Answer 19

• intensity of response is proportional to the fraction of the receptors occupied
• Effect = Emax [D] / Kd + [D] where Kd= EC 50
• like enzyme Michaelis-Menton- like enzyme but drug is not consumed as a substrate the macromolecule is one of the reactants and not simply a catalyst

Question 20

Intrinsic Activity

Answer 20

• ability to stimulate the receptor once bound
• relates to structure and influences efficacy and potency
• greater intrinsic activity= greater efficacy

Question 21

Spare Receptors

Answer 21

• not all receptors need to be occupied to achieve Emax

- less efficacious agonists may need to occupy more receptors than highly efficacious agonists

Question 22

Secondary Receptors

Answer 22

-outside of the target tissues, may mediate other effects of the drug side effects

Question 23

Receptor Regulation

Answer 23

• a cell can up or down regulate a population of receptors by changing the total number of receptors or their sensitivity
• homeostasis
• eg denervation hypersensitivity
• eg desensitization- can occur with down regulation of the receptor or with fatigue or depletion of the intracellular or tissue mechanisms

Question 24

Agonist Drugs

Answer 24

• these bind to the receptor and produce a pharmacologic effect
• two important events: bind to the receptor and activate receptor after binding
• better fit to the receptor from more specific structure of the molecule results in more DR and an effect at lower doses
• in classes of drugs there will be variation in intrinsic activity, based on differences in structure, that will influence the therapeutic effect and use of particular agents
• 3 different agonists- all able to achieve Emax but with different doses- they differ by binding but not in activating the receptor, all have the same intrinsic activity
• there can be agonists with different intrinsic activity but the same affinity- these agonists bind to receptor in the same way but differ in activating the receptor
• two agonists with different intrinsic activity and different affinity

Question 25

Efficacy

Answer 25

• the ability of the drug to activate the effector portion of the receptor once the drug is bound to the receptor
• depends on the structure of the drug

Question 26

Potency

Answer 26

• relates to the amount of drug that is needed for an effect
• depends upon: the biologic system: receptor density, efficiency of the stimulus-response mechanisms of the tissue
• interaction of the drug with the receptor- affinity and efficacy

Question 27

Antagonist Drugs

Answer 27

• many things are learned about the structure and function of receptors from the use of antagonists
• antagonists can block the binding of agonists and prevent the pharmacologic response
• therapeutic agents to slow the system down ie paralytic agents

Question 28

Competitive Antagonists

Answer 28

• antagonist effect can be overcome by increasing the dose of the agonist
• simple competitive antagonist- a simultaneous equilibrium exists for both the agonist and antagonist
• binding of antagonist to the receptor is a weak bond and easily reversed

Question 29

Noncompetitive Antagonists

Answer 29

• can’t be overcome by increasing doses of agonist
• receptor remain occupied by antagonist and not enough DR interactions occur to achieve Emax
• simple explanation of noncompetitive inhibition: binding of antagonist to receptor is a strong bond- such as covalent- and not easily reversed (proton pump inhibitors)
• the inhibitor can either change the effector or the binding site

Question 30

Noncompetitive Antagonist

Answer 30

• change the effector, does not change binding of drug to the ligand site
• antagonist alters the effector site
• even if the ligand binds to the receptor it cannot initiate the effect
• inhibitor inactivates the effector

-also changes the binding site for the agonist by directly binding to it or by attaching to a different portion of the receptor and altering the agonist binding site