Basic Principles I Flashcards
pharmacology
-bio, biochem, phys, path, micro, psych, medicinal chem all go into pharmacology, which lead to pharmacodynamics, therapeutics and chemo, and tox (treatment of patients)
pharmacodynamics
-given meds, leading to a response
drug action
- molecular action
- invisible
drug effect
- pharmacologic effect
- visible response
selectivity
- property of drug to cause a specific effect
- few drugs produce a single effect
- primary effect is desired and second may or may not be
- can be one molecular action leading to multiple effects or two molecular action leading to combined effects
pharmacokinetic
-drug and elimination
pharmacodynamic
-how it works
-types of drug actions”
physiochemical and receptor interactions
physiochemical actions
- simple chemical interactions
- antacids
- antiseptics
- not very specific
receptor interactions
- interaction of drug with physiologic receptors-macromolecules
- most drugs
drug receptors
- drug receptor interactions cause molecular events to occur in each cell
- enough of these events cause a change in cell function
- ultimately results in change in tissue function
receptors
- macromolecules, particularly proteins
- may be on or in a cell or free in the plasma or extracellular fluid
- present as part of the normal biochemical and physiologic mechanisms and usually interact with endogenous compound
- function both as ligand binder and as an effector
- the natural ligand or a drug which resembles it can bind and modulate usual activity
- each receptor occupied might be stimulated or inhibited
- each cell in a tissue contains a large population of receptors that are easily accessible to drugs
receptors 2
- each drug receptor interaction produces a small change in the biochemical or electrochemical homeostasis of the cell
- cumulative effects of many drug receptor interactions will lead to a change in the function of the cell and then the tissue
- when enough cells in a tissue are affected then the function of the tissue is altered and an observable pharmacologic response can be noted
- maximal response is eventually reached which is related to the number of drug receptor interactions and the physiologic capacity of the tissue
types of receptors
- membrane bound-neural synapse, ion channels
- enzymes-intracellular or extra
- structural macromolecules- MT
- intracellular macro- steroid receptors, RNA
- cell membrane itself- change electrical potential, fluidity
as subunit
-increases adenylyl cyclase and Ca currents
ai subunit
-decreases adenylyl cyclase and increases K currents
ao subinit
-decrease Ca currents
aq subunits
-increases phospholipase CB
a13 subunit
-increase Na/H exchange
at subunit
-increases cCMP-phosphodiesterase (vision)
aolf subunit
-increase adenylyl cyclase (olfaction)
drug receptor bonds
- reversible are ionic, van der waals, hydrogen
- irreversible is covalent
receptor amp and transduction
- aB together
- GDP off, interaction with receptor and ligand, GTP binds
- subunits split
- action
- GTPase on A gets rid of GTP
- back together
G proteins
- regulate the activity of:
- distinct effector proteins in the cell- enzymes, channels, transport proteins
- 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 different receptors
- stimulus averaging or modulation can be achieved
second messenger
- also produce amplification of the drug receptor interaction
- converts an even that happens outside the cell into a change that happens inside the cell
- some second messengers can cause different effects in different tissues
- changing the biochemical balance of substrates in metabolic pathways and activating or deactivating enzyme systems can have a profound effects on the function of the cells in a tissue
structure-activity relationships
- 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 effects
quantitative descriptions of drug action
-attempts to take experimental data, combine it with certain assumptions and make a model that works for most systems
interaction at eq
-drug + receptor equil with DR and leads to an effect
dose response relationships
- dose to % max response
- log dose to % makes it easier to make comparisons to other drugs and find effective doses
threshold
- beginning of the curve
- dose of agonist at which a response begins
- may relate to affinity of the agonist for the receptor
slope
- rate of rise of response on the steep portion of the curve
- log of EC50 also relates to affinity
maximal asymptote
-intensity of response is proportional to the fraction of receptors occupied
-effect = Emax x D / Kd + D
Kd is EC 50
intrinsic activity
- ability to stimulate the receptor once bound
- relates to structure and influences efficacy and potency
- greater intrinsic activity=greater efficacy
spare receptors
- not all receptors need to be occupied to achieve emax
- less efficacious agonists may need to occupy more receptors than highly efficacious agonists
secondary receptors
- outside of the target tissues
- may mediate other effects of the drug side effects
receptor regulation
- a cell can up or down regulate a population of receptors by changing the total number of receptors or their sensitivity
- homeostasis
- denervation hypersensitivity
- desensitization
agonists
- bind to receptor and produce pharmacologic effect
- bind to receptor and activate
- can cause desensitization
- better fit results in better results at lower doses
- variations in intrinsic activity based on structure
- better agonists need lower doses
- can have same intrinsic activity- ability to achieve emax
- can have different intrinsic activity and same affinity- bind the same but dont reach emax the same
- can have different affinity and different intrinsic ability (different emax)
antagonists 1
-can cause hypersensitivity if stopped suddenly
efficacy
- stimulation after its bound
- ability of a drug to activate the effector protein of the receptor once the drug is bound to the receptor
- depends upon structure of drug
potency
- relate to the amount of drug needed for an effect
- depends upon
1. biologic system- receptor density, efficiency of stimulus response mechanisms of the tissue
2. interaction of the drug with the receptor - affinity, efficacy
relative potency
- has horizontal relationship between two drugs
- increases EC 50 with different drug
relative efficacy
- vertical relationships
- reach higher emax
antagonists 2
- many things are learned about the structure and function of receptors from the use of antagonists
- block binding of agonists and prevent the pharmacologic repsonse
competitive antagonists
- bind to same spot
- can be overcome by enough agonists
- just need more agonist
- antagonist has weak bond and is easily reversed
- two equilibriums-one to RL and one to RI
- increases L shifts eq that way and same for increasing I
noncompetitive antagonists
- can’t be overcome by increasing doses of agonist
- receptors remain occupied by antagonist and not enough DR interactions occur to achieve emax
- strong bond and not easily reversed
- proton pumps
- inhibitor can either change effector or binding site
- if changes effector- ligand can bind but nothing happens- quad eq- bottom two inactive even after ligand binds (ligand plus inhibitor is inactive) - irreversible
- can also change binding site- bind to it or attaching to a different portion and altering site
- back to competitive eq- either ligand binds or inhibitor binds, but not both- reversible
