Chapter 3: How Drugs Act Flashcards
It is a basic principle of pharmacology that…
the pharmacological, physiological, or behavioral effects induced by a drug follow from their interaction with receptors.
how is pharmacokinetics different from pharmacodynamics?
pharmacokinetics (the study of what the body does to drugs), pharmacodynamics is the study of what a drug does to the body (AKA “drug action”)
three different types of receptors?
1.ionotropic
2.metotropic
3. transporter carrier proteins
as a rule, receptors are usually…
large molecules (usually protein)
-involves hundreds of known receptor types
where are receptors located?
Located in site(s) where naturally occurring compounds (transmitters or modulators) produce biological effect
how many receptors can a neurotransmitter have?
more than one and sometimes many different types
why is a drug more specific than an neurotransmitter?
so they can act on the correct receptor type in order to produce the correct effects
what metaphor aligns with drugs and receptors?
lock and key
a general rule of psychopharmacology is that drugs do not create any unique effects.. how is this?
they merely modulate normal neuronal functioning, mimicking or antagonizing the actions of a specific neurotransmitter.
Drug binding may mimic or facilitate neurotransmitter action Or drug occupation of a receptor might block access of the neurotransmitter to that receptor and so prevent endogenous molecules from attaching, activating, and producing an effect at these sites.
what are ionotropic receptors?
function as ion channels
-activation opens channel (or pore) in membrane of cell, allowing flow of ions to trigger or inhibit neural firing
-it is typically closed until a drug sits on the activation site where the channel then opens
what is an excitatory signal and an inhibitory signal to the cells?
chloride flowing in is an excitatory signal
potassium flowing out is inhibitory
how do Benzodiazepines work on GABA receptors?
Bind to nearby sites and facilitate GABA, flooding neurons with chloride ions, inhibiting neural actions
Used as sedative, antianxiety, amnestic, antiepileptic
considered allosteric agonists
how does Flumazenil a a benzodiazepine antagonist?
binds to benzodiazepine site and prevents the benzo from occupying this site, but does not have an effect on GABA
what are G-Protein-Coupled Receptors (metabotropic receptors)?
Induce the release of intracellular protein which triggers second messengers (mediate the synaptic effects of many neurotransmitters that are involved in the action of psychoactive drugs)
Constitute a large and diverse family of proteins whose primary function is to change extracellular stimuli (transmitters and drugs) into intracellular signals
how is metatropic different than ionotropic?
produce effects much more slowly, and long-lasting
they look very different (they still have transmembrane; however, they have seven membranes and there is no ion channel in the middle)
what are first and second messengers?
first: drug or neurotransmitter
second: refers to something occuring within the cell, cellular processes such as ion channel function, energy metabolism, cell division/differentiation, neuron excitability
they mediate the synaptic effects of many neurotransmitters that are involved in the action of psychoactive drugs
describe the activation of metotropic receptors?
Process starts when hormone, neurotransmitter, or drug attaches to receptor
Receptor shapes changes and three-chain G protein on inside of cell membrane
Component of G protein is released and directly or indirectly activates ion channel
Ion channels opened, alteration of enzyme activities, or changes in gene activation may be produced
Communication between neurotransmitter-receptor complex and intracellular enzyme produce ultimate biological response
What is this a picture of?
of a G-protein-coupled (metabotropic) receptor
why are G-protein-coupled receptors considered the “middlemen,”
they are able to effect communication between the neurotransmitter-receptor complex and intracellular enzymes , the second messengers, to produce the ultimate biological response
explain the illustration of the G-protein activating an enzyme, which then produces a second messenger that opens the channel or causes other biochemical reactions
what are the Carrier Protein/Transporter Protein receptors?
Bind to neurotransmitters to transport them back to presynaptic neuron
They bind across cell membranes against concentration gradients.
Most important in psychopharmacology are the presynaptic transporters that bind dopamine, norepinephrine, or serotonin (and other neurotransmitters) in the synaptic cleft and transport them back into the presynaptic nerve terminal, terminating their synaptic action
probability of binding of transporter protein to neurotransmitter?
depends on two things
- how much neurotransmitter there is in the synapse
- how many receptors there are for the neurotransmitter
The fourth protein category relevant to the action of drugs is that of
enzymes
how do enzymes regulate neurotransmitters?
Function to break down neurotransmitters in synaptic cleft and presynaptic terminal
Monoamine oxidase inhibitors inhibit breakdown of NE and DA (used as antidepressants)
drugs that inhibit the action of enzymes do what?
increases transmitter availability and neurotransmission
Irreversible acetylcholine esterase inhibitors are used as
pesticides and nerve gases
explain what is occuring in this photo
Left: Transporter open to the synaptic cleft. Center: Transmitter “trapped” inside the transporter. Right: Inward-facing state with transmitter “released” into the cytoplasm of the neuron.
CLIP 5
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Receptors exhibit high specificity for…
- neurotransmitters
- certain drug molecules
*the shape and configuration of these molecules matter such that they are able to lock into the receptor and produce an effect
what are Isomers?
Molecules formed around a carbon atom that have the same molecular formula but have a different atomic arrangement
what are Enantiomers ?
molecules which have the same shape but are rather like mirrors of each other
-one of them will typically produce the biological effect and the other will produce little to none
-therefore, the FIT matters more than the shape
ESSAY QUESTION**
Describe the ways that drugs affect neurotransmission.
- Drug serves as a precursor to the neurotransmitter
-most often this will be an amino acid
-example: tryptophan for serotonin, tyrosine for dopamine - Drug inhibits or enhances neurotransmitter synthesis
-if its a precursor it will enhance it
-it will inhibit synthesis by blocking an enzyme - Drug prevents storage of neurotransmitter in vesicles
-normally neurotransmitters are stored as vesicles in presynaptic terminal because there are enzymes that would break it down
-by preventing the storage of the neurotransmitter, you deplete it - Drug stimulates the release of the neurotransmitter
-causes an enhanced release of neurotransmitter - Drug inhibits the release of the neurotransmitter
-any drug that interferes with calcium entering into the cell when it depolarizes will inhibit the release because neurotransmitter release is calcium dependent - Drug stimulates post-synaptic receptors
-it would produce the biological effect consistent with the neurotransmitter in the postsynaptic cell
-called direct agonism - Drug blocks post synaptic receptors
-direct antagonist - Drug stimulates auto-receptors, inhibits release of neurotransmitter
-SLOWS release of neurotransmitter
-causes a reductio n in neurotransmitter release which produces antagonist effects but acts as an agonist at the auto-receptor - Drug blocks auto-receptors, increases release of neurotransmitter
- Drug inhibits neurotransmitter degredation
-there are enzymes in the synaptic cleft (such as MAOI) which block activity of the enzyme and therefore enhance neurotransmitter levels - Drug blocks reuptake
-SSRI, cocaine
-block transporter proteins that transport these neurotransmitters back itno presynaptic terminal
-produce effects consistent with being indirect agonist (increase neurotransmitter levels)
what is the definition of a drug agonist?
what would it mean if it does this indirectly?
increases the effect of the neurotransmitter
-enhances release of neurotransmitters in the synaptic cleft without actually effecting the post synaptic receptors itself
what is the definition of a drug antagonist?
stimulate or block the dopamine receptors
discuss the steps of neurotransmission using the example of creating norepinephrine.
Site 1: Enzymatic synthesis:
Site 2: Storage:
Site 3: Release:
Site 4: Receptor interaction:
Site 5: Re-uptake:
Site 6: Monoamine Oxidase (MAO):
Site 7: Catechol-O-methyl transferase (COMT):
When a psychoactive drug binds to a receptor it produces which response?
immediate
what happens to the receptors when a drug is given over a LONG period of time?
what does it lead to?
When the drug is given over a longer period of time-it produces CHRONIC long -term changes in the properties and structure of the receptors
it leads to tolerance
tolerance produces changes at which 3 levels?
- nervous system
-long term changes reflect changes in the properties of the receptors (such as density, amount, or sensitivity) - liver
-enhanced capacity to regulate the drugs - capacity to manage behaviourally the effects of the drug
-moderate intake by watching behaviour cues
downregulation vs. upregulation?
- Downregulation (desensitization)
-less numerous or less sensitive
-example: anabolic steroids where body responds to all the new testosterone by downregulating testosterone
-diminishing return - Upregulation (supersensitivity)
-example: antipsychotic drugs where body responds to blocked dopamine receptors by enhancing the number and sensitivity of dopamine receptors, it’s not a problem because no number of upregulation will diminish the effects of the drug
what is a way to think about the drug and its effects is called
Dose-Response Relationships
To determine the effect of a drug, we have to …
study several doses and measure the change in some response
what is the dose-response curve (DRC)?
refers to relationship between dose and response
what does a dose-response curve look like?
x-axis: dose of drug
y-axis: any type of effect you expect the drug might have
you are looking for the shape and nature of corresponding response
this is a very common dose curve
Potency refers to…
how well drug molecules attach to their sites of action (receptors).
in the dose-response curve, potency is usually reflected by..
the more LEFTward a slope rises
what do more potent drugs usually do better than less potent drugs?
bind more tightly and usually attach better than less potent drugs (binding)
If two drugs produce an equal degree of stimulation, but one exerts this action at half the dose level of the other, the first drug is considered to be
twice as potent as the second drug.
The Slope (in the dose-response curve) refers to:
-The mostly linear central part of the curve
-How sharply the effect changes with each change in dose
If a small change in dose produces a large change in effect, the slope is
steep
If a large change in dose produces small changes in effect, the slope is
shallow
typically the drugs that have steep slopes have to be…
precisely dosed, and extremely careful with the therapeutic dose because they can produce dangerous reactions
Efficacy refers to …
maximum effect obtainable, with additional doses producing no effect.
A drug that is more efficacious (effective) can produce more of what compared to a drug that is less efficacious?
produce a greater peak, or maximum, effect
do all drugs that are potent produce a MAXIMUM effect?
Some drugs may be potent, but they might never be able to produce a peak response no matter how much is given.
efficacy vs. potency?
efficacy refers to the maximum effect, potency refers to the dosage which produces the maximum effect
discuss efficacy and potency in response to this graph.
shows theoretical dose-response curves for three psychostimulants
-equal efficacy of methamphetamine and dextroamphetamine
-increased potency of methamphetamine (because curve is more to the left)
-reduced potency and efficacy of caffeine.
Binding Refers to…
Affinity
which drug has greater affinity for its receptor?
a more potent drug because it binds more tightly to the receptor
Different drugs may bind to the same receptor, but may also have different…
affinities
Binding Results in One of Three Actions.
- Binding to site of normal endogenous neurotransmitter initiates similar cellular response by having affinity to the receptor (agonistic action)
- Binding to nearby site to facilitate transmitter binding (allosteric action)- either facilitates or inhibits the primary site of action
- Binding to receptor site, blocking access of transmitter to binding site (antagonistic action) - has affinity for the receptor, but little to no efficacy
describe what is occuring in this graph.
shows the dose-response functions produced by different types of drugs
-the agonist can produce the maximum possible effect by binding to the receptor
-the partial agonist has affinity to the receptor but is not able to elicit the maximum effect at any dose
-the antagonist binds to the receptor, has affinity for it, but does not produce an overt effect
-the inverse agonist produces an effect opposite to that of an agonist
explain full agonist, partial agonist, antagonist, inverse agonist along the lines of the lock and ket metaphor.
full agonst: the proper key that fits the lock
partial agonist: sometimes it sorta works and sometimes it doesnt
antagonist: fits the lock but doesnt turn it, but nothing else can get in when it is in the lock
inverse agonist: fits the lock and has an efficacy of that of the endogenous agonst
An antagonist drug by itself produces what response?
no response
It is possible to determine if a drug has an antagonistic action by
seeing if it reduces the effect of the agonist.
Acompetitive antagonist does what compared to a non-competitive antagonist?
Acompetitive antagonist binds to the same site as the agonist but does not activate it, thus blocks the agonist’s action.
Anon-competitive antagonistbinds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor
what do Irreversible or noncompetitive antagonists do to the dose response curve?
cause a downward shift of the maximum, with no shift of the curve on the dose axis
Areversible antagonistdoes what to the receptor? What about an irreversible antagonist?
Compare these to the lock and key metaphor.
Areversible antagonistbinds non-covalently to the receptor, therefore can be “washed out”.
Metaphor: a key fits into the lock but isn’t fully clicked in place so another key can kick it out
An irreversible antagonist binds covalently to the receptor and cannot be displaced by either competing ligands or washing
Metaphor: a key that fits the lock and then breaks off in it, the receptor is LOST
explain what is going on in these graphs?
shows the agonist dose-response curves in the presence of competitive (Part A) and noncompetitive/irreversible (Part B) antagonists.
The effect of a competitive antagonist is to shift the dose-response curve to the right. It takes a larger dose of the agnost to produce the same effect.
The noncompetitive/irreversible antagonist shifts the agonist curve down. Dose curve stays in the same place but the maximum effect is reduced.
Brief Summary of Pharmacodynamics?
EXAM
Agonists bind to receptors to produce a functional response.
Agonists can be full, partial, or inverse.
Antagonists block or reverse the effects of agonists.
Antagonists can be competitive or noncompetitive/irreversible.
what is the therapeutic drug index?
*one of the most important things we can get from the dose-response curves
*it is the ratio of LD50 to ED50
-TI = LD50 / ED50
*LD50 refers to the lethal dose (unwanted side effect) for 50 percent of test subjects
*ED50 refers to the drug dose that produces desired effect in 50 percent of test subjects
explain this graph
the red curve is the standard dose response curve
the blue curve is the number of patients displaying a response against the curve
it shows HUGE variability
people who are insensitive are on the right hand of the red line
people who have no tolerance will be on the left end
the POINT: the red curve is the ideal curve, however there is considerable human variability shown by the blue curve
explain what this graph is
illustrates LD50 to ED50
shows it wouldn’t be a safe drug because at the dose, 50% of patients display desired effect, but it is already hitting the lethal dose
the curves should be separated very far on X-axis and they should not overlap
explain the results of the therapeutic index
The greater the TI, the safer the drug. The difference between the desired effect and the undesired or lethal effect is larger
if two drugs produce a therapeutic effect that is desirable, the better drug (all things being equal) would be the one with the larger TI
To be safer, the TI is calculated by using the LD1 / ED99
(LD1 is death in no one)
The lower the ED50, the greater the potency, but the lower the TI, the lower the safety.
what are Nocebo Effects?
Occur as result of unintended negative suggestion by health professionals when informing patient of possible complications of proposed treatment
