Week 1 - General Principles, pharmacodynamics, drug receptors Flashcards
GABA
gamma aminobutyric acid
mechanism of action of anesthesia
not precisely known, primary site- membrane receptors, NOT lipid bilayer
primary mechanism of action for injected and inhaled anesthetics
GABA receptors
pharmacology
the processes by which a drug produces one or more measured physiologic responses
biosphere - protein receptor site
2 functions
1- site of drug binding
2- regulator of pharmacologic response
Bind, regulate
four additional influences of pharmacologic responses
1- absorption
2- distribution
3- metabolism (biotransformation)
4- excretion
Abs distinctly metabolize excrement.
drug receptors are typically a __ that binds to a __ or endogenous substance
protein
drug
three receptor properties
1- sensitivity (how much drug to elicit effect)
2- selectivity (response to structurally similar drugs)
3- specificity (receptor response is always the same)
drug receptor subunits - 2 points
1- primary regulator of onset/offset response
2- individual genetic variation in receptor proteins may account for variations in response to different drugs among different populations
bonds between drugs and receptors from weakest to strongest
1- Van der Waals 2- Hydrogen 3- Ionic 4- Covalent "Vandy hides iconic co-valet parking spots and forces us take the shuttle"
four regulatory protein types
1- cell surface proteins 2- enzymes 3- carrier proteins (transporters) 4- ion channels "cell phones enzymatically carry ion channels"
three drug receptor protein locations
1- within luminal membranes
2- ion channel surfaces
3- intracellular
“INSIDE the lumen membrane or ON the ion channel has the best cellular reception”
prototypical Mu receptor agonist first used 5,000 years ago in ancient Samaria
morphine
the most frequent receptor site for IV anesthetics, may play significant role in inhalation anesthetic activity (as inhalation agents bind to this receptor)
GABA receptor
anesthetics bind to receptors at at least __ points causing a conformational change
three
anesthetics DO NOT bind by ___
covalent, otherwise your patient would never wake up
drugs also bind to ACCEPTORS like plasma proteins which… (2 points)
1- DO NOT elicit a pharmacologic response
2- reduce the amount of drug available to bind to RECEPTORS
describe a GABA receptor
5 peptide subunits arranged in a ring
“lady GAGA has a 5 carat diamond ring that she got for shooting the new Pepsi/Tide (peptide) commercial”
the two opioid receptors that McCarver emphasized
Mu and Kappa receptors
four types of opioid receptors
delta, kappa, mu, sigma
McCarver stated “sigma” as a receptor, but that has been disproven. It is actually “nociceptin”. Contact me if you want the evidence.
two adrenergic receptors
alpha, beta
two acetylcholine receptors
nicotinic, muscarinic
two OTHER types of receptors
histamine, capsaicin
signal transduction
conversion of one signal to a new signal, a sequence of biochemical reactions
anesthetic signal transduction
drug ->
G protein coupled receptor (cell surface receptor) ->
cyclic AMP ->
cyclic GMP ->
protein kinases, phosphatases, intracellular actions
“Yo G! You’re cyclic a/gmp has two aces!”
drug response equation
drug + receptor -> drug receptor complex -> tissue response
the drug receptor complex is a __ process
selective, only a few drugs may bind to a receptor type to create a response
three variables in tissue response
1- receptor
2- genetics
3- physiology
occupancy theory states that…
but what about population variability…
…the magnitude of a drug’s response is proportional to the number of receptors occupied, the more drug = greater tissue response
…the tissue response to a drug can be disproportionate to the number of occupied receptors
mean dose
average of the range of doses to produce a given response
median dose
the dose on either side of which half of the drug responses occur
mode dose
the dose representing the greatest percent of responses
the mean, median, and mode doses are typically close to each other but …
are not the same
two types of drug response curves
1- graded dose response
2- quantal dose response
graded drug response
change in response as dose in increased, has a hyperbolic shape
Similar to how your “grade” will change as your “dose” of studying increases
quantal drug response
provides information on the FREQUENCY which a drug produces a therapeutic response, all or nothing, helps determine ED, TD, LD using dose response curves
toxic dose
TD50
lethal dose
LD50
therapeutic index
LD50/ED50
safety margin
(LD1 - ED99) / (ED99 x 100)
(the lethal dose for 1% minus the effective dose for 99%) divided by (the effective dose for 99% times 100)
-the greater the therapeutic margin = safer drug
therapeutic index
the median therapeutic safety margin for a specific effect
LD50 / ED50
volatile inhalation agents have a narrow therapeutic effect
iso at 1.5% end tidal provides anesthesia, 4% causes circulatory collapse
median effective dose
ED50, the dose where 50% of patients respond as desired, helps to compare drug potency within a drug class
when the drug + the receptor combine and form a drug/receptor complex it causes a…
fractional tissue response
fractional tissue response
the desired drug effect, occurs when enough receptors are activated by a drug
intrinsic activity
the DEGREE of drug/receptor interaction for a given drug and receptor population
Think of Degree antiperspirant, it has “intrinsic activity” that varies for all of its different formulas and for different people.
two variables to describe intrinsic activity
1- affinity
2- efficacy
affinity
1- potency
2- used to differentiate between different agonists that activate the same receptor
3- the agonist (drug) that produces a maximal response at the lowest concentration has the greatest affinity or “potency”
efficacy
- the ability to produce a desired response by stimulation of a specific receptor
- the maximum effect that a drug may produce
four factors of fractional tissue response time
1- delay in delivery of drug to receptors effected by pharmacokinetics or drug elimination
2- time for conformational change of drug receptor
3- receptor up regulation (increased sensitivity to a drug)
4- receptor down regulation (decreased sensitivity to a drug)
agonist
- any substance that binds to a specific receptor and triggers a response
- mimics the action of an endogenous ligand that binds to the same receptor
- in sufficient concentrations may elicit maximal receptor activation
ligand
- molecules that bind to receptors and form a complex to produce a biological response
- can be endogenous chemicals or exogenously administered
- example: endogenous insulin vs. lantus
pure antagonist
- structurally similar to agonists but bind to the receptor without causing a conformational change and have no efficacy
- BUT, by occupying the receptor they MAY block an endogenous chemical and produce a physiological response (ie. beta BLOCKERS)
competitive antagonists
- possess weak affinity (atropine, esmolol)
- may be displaced by an agonist
antagonists have __ affinity for receptors than agonists
higher
NONcompetitive antagonists
- STRONG affinity for receptors
- form STRONG covalent bonds
- NOT displaced by agonists (it was NO competition for the NONcompetitive antagonist to win over the agonist)
- ex. ASA, phenoxybenzamine
partial agonists
-activates receptor but cannot produce maximal response (it only PARTIALLY produces a response), thus it has lower efficacy than a full agonist
partial agonists may __ block the effect of full agonists
partially
partial agonists have __ efficacy than full agonists
lower
inverse agonist
drug or endogenous chemical that binds to a receptor and produces the OPPOSITE action of an agonist
inverse agonists bind preferentially to __ receptors
inactivated
for an inverse agonist to work, the receptor must have some base level activity in the __ of any ligand
absence
an inverse agonist __ the activity __ the basal level
decreases, below
the efficacy of a full agonist is __
100%
an inverse agonist has less than __% efficacy
0
examples of inverse agonists
cimetidine, ranitidine, haldol, prazosin, timolol, clozapine, yohimbe
physiologic antagonism involves __ agonists binding to __ receptors to create opposing responses and cancel each others effects
two, different
example- beta blocker and levophed
chemical antagonism is when a drug’s action is __ but no receptor is involved
example__
blocked
heparin/protamine, sugammadex/roc
receptors are controlled by __ and __ mechanisms
regulatory, homeostatic
four factors that influence receptor regulation and adaptation
1- synthesis and degradation 2- covalent modification 3- association with regulatory proteins 4- relocation in the cell "new and old (synthesis and degradation) friends make the strongest bonds (covalent) during the "teens rule" years (regulatory proteins) even after we moved to a new neighborhood (relocation)
receptor DOWN regulation is when the __ stimulation of cells by agonists results in __ and is commonly called __
continuous, DEsensitization, tolerance
receptor UP regulation is when continuous __ administration results in increased number and __ of receptors. Tolerance to __ requires __ doses to counteract the increased number of receptors
ANTAgonist, sensitivity, ANTAgonist, larger
tolerance is when an __ concentration of drug is required to produce a response and usually results from __ exposure to an agonist
increased, chronic
five causes of tolerance
1- up and down regulation 2- enzyme induction 3- depleted neurotransmitters 4- protein conformational changes 5- changes in gene expression
“Tolerance is when my up and down enzymes deplete the conforming genes”
tachyphylaxis is the __ __ __ __ due to acute drug exposure
rapid development of tolerance
the “spare receptor concept” states that a __ response can be produced by the activation of only a __ of receptors
maximal, fraction
THAT’S __ FOLKS
ALL
