3: Chemical Interactions + Agonist/ Antagonists + Partial/ Inverse Agonist

What are the four different types of chemical interactions?

1. additive

2. synergistic

3. potentiation

4. antagonism

the combined effect of two chemicals is equal to the sum of the effects of each agent alone (2+3=5) ?

additive

two organophosphate insecticides when given together will inhibit an insect’s acetylcholinesterase enzyme as a sum of both of their parts

this is an example of which chemical interaction?

additive

the combined effect of two chemicals are much greater than the sum of the effects of each given alone (2+2=20)

synergistic

two hepatotoxic chemicals (carbon tetrachloride and ethanol) produce more than additive toxicity when given together

synergism

when one chemical does not have an effect on an organ or system but when added to another chemical makes that chemical much more effective (0+2=10)

potentiation

isopropanol is NOT hepatotoxic BUT when administered with carbon tetrachloride, the hepatotoxicity of carbon tetrachloride is much greater that then given alone

this is an example of which interaction between chemicals?

potentiation

when two chemicals administrated together interfere with each other’s actions or one interferes with the action of the other

• (4+6)= 8

• (4)+(-4) = 0

• 4 + 0 = 4

antagonism

repeated administration of the same dose of a drug results in a progressively reduced effect of the drug over time

higher doses may be needed to achieve the same pharmacological response

tolerance

is it possible to have tolerance to one effect of the drug and not to another?

if so, what is an example?

Yes!

opiods: can build a tolerance to analgesia effects but NOT respiratory depression

so higher opioid will cause high respiratory depression (BAD) but not desired analgesia effects

in terms of tolerance how would you interpret a change in ED50 but not TD50 ?

tolerance to therapeutic effect( need higher [L] to reach ED50)

BUT not to toxic effect (need same amount to get toxic so higher = higher toxicity)

what are three causes of tolerance?

1. metabolism or transport

2. mediators

3. receptor systems

how can metabolism and transport lead to tolerance?

list an example?

increased degradation or removal of the drug causes you require more of the drug to achieve the same effect as you getting less than the amount you are expecting

ex. drug efflux pumps in cancer cells

what is an example of decreased mediators leading to tolerance?

reduced neurotransmitters available to stimulate receptors

______ or _________ receptors can lead to increased drug tolerance

list an example

less changed

Clonal expansion of mutated receptors on cancer cells develop resistance against cancer drugs (imatinib resistance in EGF receptors)

complete tolerance that develops rapidly after (repetitive) administration of a pharmacologically active chemical

tachyphylaxis

Tachyphylaxis usually occurs following the ______ doseS of drugs

can increasing the dose overcome tachyphylaxis?

• initial

• NO, once you develop tachyphylaxis no amount of the drug will cause you to have a response

when taking a nitrovasodilator to treat angina you must take an 18-hour break before taking another dose to prevent ___________________ (if not, no matter how much you take, you will not get relief from angina)

tachyphylaxis

property of a molecule to activate the receptor

agonist

do agonists and antagonists have both affinity and intrinsic activity?

NO

agonists have affinity AND intrinsic activity

antagonists ONLY have affinity has no effect unless a agonist is present

property of a molecule to prevent the binding of agonists and block their biological function

antagonist

do antagonists have affinity for the receptor?

do they have intrinsic activity? what exactly is meant by intrinsic activity?

YES

NO, intrinsic activity is the ability to perform a function independently. Antagonists do not decrease efficacy unless there is an agonist that they are actively blocking whether it be noncompetitive or competitive

are agonists solely drugs?

NO an internal ligand can also be an agonist

binding of an agonist to a receptor stabilizes the receptor in an active ___________

conformation

D + R ⇌ DR*

the following suggests that AGONIST binding is proportional to _________ ________

receptor activation

D + R ⇌ D + R*

↕

DR ⇌ DR*

explain the following equation

what part of this equation is unstable?

a drug and receptor may come together to form an inactive complex (DR) or a drug may simply activate a receptor (R*) both of which are unstable

OR it could form a stable ACTIVE drug-receptor complex (DR*)

D + R ⇌ DR ⇌ DR*

what does the ⇌ between D+R and DR represent

what does the ⇌ between DR and DR* represent

• —> = Kon

• ←— = Koff

• —> = Ka = rate of receptor ACTIVATION

• ←— = Kb = rate of receptor DEACTIVATION

which type of antagonist

• inactivates the agonist by modifying or sequestering it so that the agonist is no longer capable of binding to and activating the receptor WITHOUT interacting with the receptor

chemical

Protamine binds to acidic heparin to reverse excessive bleeding without interacting with its receptor

what type of agonist/antagonist is protamine?

chemical ANTAGONIST

what type of antagonist

• activates or blocks the receptor that mediates a response physiologically OPPOSITE to that of the receptor for the agonist

• doesn’t interfere with the receptor target of the agonist but instead with the receptor of a separate process that will counteract the response of the agonist

physiological/function

which antagonists inhibit the function of the agonist without binding the the target receptor of the agonist?

1. chemical

2. physiological/functional

3. dispositional

what type of antagonist

• alters ADME so that the concentration and/or duration of the agonist at the target organ are diminished

dispositional

_____________ _______________ inccreases the metabolism of many drugs by inducing hepatic microsomal enzymes which reduces the concentrations and pharmacologic responses of administered drugs

this drug acts as a _________ antagonist/agonist

anticonvulsant phenobarbital

dispositional ANTAGONIST

what are some differences between competitive and noncompetitive antagonism in terms of

• where it binds

• reversibility

• potency of agonist

• efficacy of agonist

• competitive bind onto the active site, noncompetitive binds to an allosteric site

• competitive bind REVERSIBLY so it can be overcome with a larger number of agonists (potency decreased) non-competitive bind IRREVERSIBLY once it binds it changes the conformation of the receptor which can no longer be bound to

• Potenceny: noncompetitive= no change in potenency competitive = decreased potency

• efficacy: NC= decreased Competitive= unchanged

Compeititve Antagonim

• reversible or irreversibly bound?

• effect on efficacy

• effect on potency

• shift in the graph

• can inhibition be overcome? if so, how?

• reversibly

• no change bc/ reversible

• decreased potency (right shift)— need more agonist to compete against antagonist

• right shift

• yes with increased agonist

Noncompetitive Antagonism:

• irriversible or reversible?

• effect on agonist efficacy

• effect on agonist potency

• can inhibition be overcome?

• irreversible — once it binds allosterically, the receptor can no longer be activated by agonist

• decreased efficacy — won’t be able to reach max effect of having all agonistic receptors filled

• no effect on potency (it will take the same amount of drug to get to 50% effectiveness— but effectiveness will be half)

• inhibition CANNOT be overcome since increasing the concentration won’t change the fact that there are antagonists irreversibly bound

Asprin works as a blood thinner by binding irreversibly to COX enzyme preventing the formation of thromboxane

Asprin acts as a competitive/noncompetitive antagonist or agonist?

noncompetitive ANTAGONIST bc/ binds irreversibly

does the following dose-response reciprocal plot show a competitive antagonistic relationship or noncompeitive antagonistic relationship between the agonist ?

how can you tell?

The intersection at Y-axis (E-max) shows that efficacy remains the same meaning we have a COMPETITIVE inhibitor (if we have enough agonist we can outcompetethe inhibitor and reach max effectiveness)

does the following dose-response reciprocal plot show a competitive antagonistic relationship or noncompetitive antagonistic relationship between the agonist ?

how can you tell?

noncompetitive bc/ intersection at x axis shows that [ligand]— dose— remains the same

the effectiveness (y-axis) decreases but the amount of drug it takes to reach the new max activity remains the same

which type of antagonism is altered in the presence of spare receptors?

noncompetitive

Noncompetitive Antagonism with Spares:

• LOW antagonist concentration

  • bind to receptors not needed for maximal response SO no change in ___________

  • reduction in the number of receptors available INCREASING the fraction of receptors that must be occupied to produce a 50% response SO DECREASED ____________

• HIGH antagonist concentration

  • binds to spare AND needed receptors SO _______ in potency and ________ in efficacy

• efficacy

• potency

• decrease in potency AND efficacy

In noncompetitive antagonism involving spare receptors

• what happens to the max efficiency of the agonist in LOW concentrations

• what happens to max efficiency and potency in HIGH concentrations

HIGH

• unchanged efficacy= antagonist takes up receptors that aren’t needed anyway for max effect

• decreased potency = you need more agonist to reach 50% max effect since some of the spots needed are being taken away

LOW

• decreased efficacy = antagonists begin to take the place of receptors needed to reach max effect (all are used up)

• decreased potency = need more agonist to reach 50% of max since now even more receptors are taken up by antagonist

Noncompetitive Spare Antagonism

HIGH concentration of antagonist:

• _______ efficacy

• ________potency

LOW concentration of antagonist

• ________efficacy

• ________potency

HIGH

• UNCHANGED efficacy

• decreased potency

LOW

• decreased efficacy

• decreased potency

a ______ agonist produces complete activation of a receptor at high drug concentration

full

a ________ agonist binding results in less than 100% activation even at very high concentrations

partial

________ agonists produce a response below the base line response measured in the absence of the drug

inverse

receptors can have________ activity such that a certain percentage of the response is achievable without the receptor being stimulated by a drug/ligand

CONSTITUTIVE

partial agonists are sometimes also referred to as

• partial antagonists

• mixed-agonist- antagonist

since partial and full agonists bind to ______ receptor site partial agonists can ______ the response produced by a full agonist

same

REDUCE

derivatives of trimethylammonium stimulate muscarinic acetylcholine (Ach) receptors to cause muscle contraction in the gut

the ligand is acetylcholine which is not shown on the graph

Which types of agonists are butyl, hexyl, heptyl, and octyl?

full agoninst = butyl and hexyl = reach max effect

partial agonist = heptyl and octyl = DONT reach max effect

are partial agonists lest potent than agonists?

not always

can also be more potent

ex. it takes less buprenorphine (0.3mg/kg) to get to half of its efficiency and more morphine (1mg/kg) to get to half of its efficiency but morphine has a higher max response

the stabilization of DR as well as DR* is hypothesized to to explain the mechanism of which type of agonist?

partial agonist

why it doesn’t reach max because the receptors that it does bind to aren’t activated once it becomes a complex

receptors with multiple DR* confirmations all with different intrinsic activity is thought to explain the mechanism of which type of agonist?

partial agonist

partial agonist binds to make DR* but not all DR* responds the same way, making it unable to to reach max efficiency

decreased efficiency in inducing primed conformation of receptor may explain the mechanism behind which agonist?

partial agonist

if the receptor is not primed by a partial agonist it may not be activated leading to less than max effeciency

as the number of receptors occupied by the partial agonist increases, the number of receptors that can be bound by full agonist _________ causing a decrease in ___________

• decreases

• Emax

not all bound to full agonist which would have provided 100% efficiency

_____________ inhibits overactive dopamine pathways and stimulates underactive pathways

which type of agonist is this drug?

Aripiprazole

partial agonists

what are the similarities vs differences between the noncompetitive antagonists vs the partial agonist curves?

SIMILARITIES:

noncompetitive antagonists and partial agonists BOTH decrease max effectiveness —- if there is a non-competitive antagonist present then not all of the receptors are bound to the agonist causing a decrease in EC50. if partial agonists are present and bind to receptor instead of full agonists then Emax is not going to be achieved

DIFFERENCES:

noncompetitive antagonists have no intrinsic activity without an agonist present however partial agonists can decrease Max Effectiveness even without agonists present

molecule that binds to the same binding site on a receptor as an agonist and reverses the intrinsic constitutive activity of the receptor

inverse agonist

why is an inverse agonist considered an agonist if it reduces the activity of its receptor?

agonist does not always mean enhance it can also block a response as does the inverse agonist

• the main point is the inverse agonists can elicit a response without an agonist present (whether it is increase or decrease a response)

inverse agonists can decrease the intrinsic activity of receptors unbound to drug without any agonists involved causing it to be an INVERSE AGONIST

what are examples of receptors with CONSTITUITIVE activity that are active WITHOUT having to be bound by an internal ligand or external drug?

GABA

Canaboid

benzodiazepine

Histamine

Opiod

Bradykinin

Adenosine receptors

Hypothesis: __________ agonists may keep receptor in bound, inactive complex that prevents baseline R* activity

inverse

R* unable to act on its own because it is trapped as DR

in systems that are NOT constitutively active OR in the presence of a full agonist, inverse agonists will behave like _____________ ____________

competitive antagonists

will bind to and inhibit receptor from attaching to drug

1. Full agonists stabilize ___

2. Partial agonists stabilize ____

3. Inverse agonists stabilize _____

4. competitive antagonists stabilize _____

WITH EXPLANATIONS

• DR* (activated complex— full response)

• DR* and DR (stabilize inactive as well which is why they can’t get full activity— alternate activity of DR* — primed DR)

• DR (stabilize DR prevent R* from working intrinsically)

• R (don’t allow R to bind with drug becoming DR)

1. Full agonists stabilize ___

2. Partial agonists stabilize ____

3. Inverse agonists stabilize _____

4. competitive antagonists stabilize _____

without explanation

1. DR*

2. DR and DR*

3. DR

4. R

How to Partial Agonists Work— Hypotheses

1. stabilize ____ form so there is a mixture of _____ and _____ form

2. receptor may have multiple DR* confirmations each wtih a different ________ _______

3. receptor may require a ________ change before activation. Partial agonists may be less efficient at inducing __________ conformations

1. DR DR and DR*

2. intrinsic activity

3. priming primed

How do Inverse Agonists Work: Hypothesis

1. inverse agonists may keep receptor in _______ inactive _______ preventing baseline R* activity

bound DR

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

How can you tell?

Competitive Antagonist

Can still reach Emax since antagonist is bound irreversibly and can be replaced by full agonist but potency is decreased since it will take a lot more of the agonist to be able to outnumber the competitive antagonist

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

Noncompetitive Inhibitor

Decreased Emax and unchanged potency

Can’t get to Emax because noncompetitive inhibitors are irreversibly bound, BUT 50% of the agonist will still lead to 50% max effect (new max effect) the same amount of the drug that achieved 50% efficacy will still give 50% efficacy, but it is a lot smaller than it was before

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

Noncompetitive antagonist (WITH SPARE RECEPTORS)

THE MORE ANTAGONISTS YOU HAVE THE MORE YOU ARE TAKING UP RECEPTORS THAT MATTER AND DECREASING EFFICACY AND POTENCY

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

partial agonist

Different from Noncompetitive antagonist because agonist can work on its OWN has intrinsic activity (watch out for the alone line!)

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

Partial agonist

You can see that efficacy has gone down but potency has gone UP which is not the case for Noncompetitive agonists whose potency remains unchanged

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist (which is left vs right)

Left = Noncompetitive antagonist (efficacy decreased but no intrinsic effect alone)

Right = potential agonsit (efficacy decreased but you can see that alone it has instrinsic effect)

The following illustrates the effect of a ____________ ____________ on the efficacy of a full agonist

Inverse agonist

Binds to receptor active site and decreases receptors instirnsic activity WORKS WITHOUT AGONIST PRESENT WHICH IS WHY IT IS NOT AS ANTAGONIST. if the receptor had no intrinsic activity then it would act as a competitive antagonist

explain why pentazocine is selective for KOR over MOR and DOR

the dissasociation constant (Kd) for MOR and DOR are HUGE meaning there is more independent ligand and drug then [LR]

KOR has a low Kd meaning there is a higher affinity towards KOR receptor

Kd= [L][R] /[LR]

identify the chemical interactions that are taking place

1. additive

2. synergism

3. potentiation

4. antagonism