Pharmacodynamics, therapeutics Flashcards by Cody Nelson

Drugs, receptors and pharmacological response:

What is a receptor?

Most drugs produce their effects by doing what?

What is affinity?

a macromolecule whose biological function changes when a drug binds to it.

by binding to specific receptors in target tissues.

the measure of propensity of a drug to bind to a receptor; the force of attraction between drug and receptor.

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Drug-receptor binding triggers a cascade of events known as ___________

what are the 3 types of bonds between drug and receptor?

signal transduction

Van der Waals force

ionic

covalent interactions

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Drug-receptor interaction:

When drugs bind to recepotors , in most cases, the binding is _______ .

Each binding triggers a _____ .

There are Two drugs that compete for the same receptor due to transient binding, how do you determine which will have a greater chance of binding?

transient

signal

the drug with the higher concentration

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Equilibrium between drug molecule and its receptor - _______ and _______

association and dissociation.

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Equation for drug-receptor interaction:

What is the equation at equilibrium?

Whats kd? and whats its equation?

whats Ka and whats its equation?

If you raise kd then what happens to affinity?

[D] x [R] x k1 = [DR] x k2

k2/k1 = kd (dissociation constant)

k1/k2 = ka (affinity constant)

ka decreases

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Equation for drug-receptor interation:

What is [DR] ?

what is this a measure of? and what is it denoted as?

drug response

minimal effect or efficacy, denoted as E_max

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How do we measure or quantify a drug - receptor interaction?

Dose-response curve

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a Log dose- response graph has what type of curve?

which value is compressed?

proportionate doses occur at equal intervals and its easier to analyze mathimatically.

sigmoid

dose scale is compressed

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dose response graph

Define EC₅₀:

Define Emax:

Define Efficacy(or Intrinsic Activity) :

Define Kd -

dose or concentration of a drug that produces 50% of maximal (half maximal) response

maximal effect produced by a drug. It is a measure of efficacy of a drug.

ability of a bound drug to change the receptor in a way taht produces an effect; some drugs posses affinity but NOT efficacy.

concentration of a drug that occupies 50% of the total number of receptors at equilibrium.

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What variable is a measure of efficacy of a drug

Some drugs possess affinity but NOT _____

Emax

Efficacy.

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Relative position of the dose-effect curve along the dose axis is referred to as the _______ of a drug.

This has ______ (little/alot) of clinical significance for a given therapeutic effect.

A more potent drug is clinically superior to another.

T or F?

Potency

little

False

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Low potency is a disadvantage only when….

How is Potency calculated?

the dose is so large that it is awkward to administer

potency = affinity + intrinsic activity of drug.

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Potency is generally compared between two or more drugs that ….

If you decrease the EC50 then what happens to the potency?

Rank these from most potent to least potent:

Ibuprofen

Indomethacin

Asprin

act by the same mechanism

Potency increases with a lower EC50

Indomethacin –> ibuprophen –> Asprin

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There are no spare receptors when what two values are equal?

EC50 and Kd

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What values would suggest the existence of spare receptors?

(for most organs)

EC50 > Kd

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__________ allow maximal response without total receptor occupancy. This increases the _________ of the system.

These can bind (and internalize) extra ligand and prevent what ?

Spare receptors, sensitivity

an exaggerated response if too much ligand is present.

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Agonists, partial agonists and antagonists

define an agonist:

define a partial agonist:

define an antagonist:

is a drug which binds to the receptor and produces an effect . Has affinity and Intrinsic activity.

has affinity for a receptor but less intrinsic activity (lower efficacy compared to an agonist acting at the same receptor)

is a drug which binds (thus competes for binding against other ligands), but does not activate the receptor. It has affinity but NO intrinsic activity.

An antagonist can be reversible or irreversible.

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is an antagonist reversible?

yes it can be.

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Agonists, partial agonists

A partial agonist has less _____ and a lower ____ compared to an agonist acting at the same receptor.

Give an example of an agonist:

an example of a partial agonist:

(both must act on opiod receptors)

efficacy, Emax

morphine

buprenorphine

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A partial agonist acts as a(n)_____ in the presence of a full agonist.

What are the uses of partial agonists such as buprenorphine:

antagonist

lower abuse potential

lower level of physical dependence

greater safety in overdose compared with a full agonist such as morphine.

What is Buprenorphine?

what happens with overdose?

an opioid analgesic

respiratory shutdown

Antagonist properties of a partial can be useful in what ways?

What is a clinical example of this?

provide some agonist activity and at the same time block the endogenous full agonists

clinical example: pindolol for high blood pressure and abnormal heart rythms

reduces the excessive stimulation due to the norepinephrine in a person with high sympathetic nervous system activity.

blocks adrenaline.

Pindolol is a _______ and acts on what type of receptors?

What is the effect of this drug on unoccupied receptors?

When adregnergic receptors are occupied, what is the effect of this drug?

partial agonst, a1 and B1 receptors

increase heart rate and blood pressure (not as much as full agonist)

pindolol becomes an antagonist for Norepinephrine and displaceses it, this reduces the blood pressure and heart rate.

When an agonist is alone, a lower dose can produce ______ effect. (minimal/maximal)

In the presence of a competitive antagonist what would you do to produce the same effect as previous?

What is an example of a agonist and a competitive antagonist?

maximal

introduce a higher dose of agonist to reach the required effect.

acetylcholine - agonist

atropine - competitive antagonist at muscarinic receptors

How does a dose-effect curve change with the introduction of a competitive antagonist? What happens to the EC50?

Shifts to the right increases.

Noncompetitive antagonism in the presence of a ____________ even a higher dose of agonist cannot produce maximal effect. What is an example of this?

non-competitive antagonist noradrenaline - agonist phenoxybenzamine - non-competitive antagonist at a-receptors

In the presence of a non-competitive antagonist , what happens to the Emax of the agonist? If there is "less maximal effect" then what happens to the EC50?

Emax is depressed. still increases.

# Define Allosteric Interaction:

When a ligand(B) binds to a site close to the site of an agonist (A) on a receptor and it can affect the binding and/or response to agonist A.

Benzodiazepine drugs potentiate the response to ___________ when they bind to its receptor. This is an example of a...

Gama aminobutyric acid (GABA) amplifying Allosteric interaction

when ligand B will rduce or completely inhibit the response or binding of agonist A to the receptor... this is called...

Diminishing or dampening allosteric interaction

How would you treat atropine poisoning? Is this reversible receptor?

increase acetylcholine at the receptor and acetylchoinesterase inhibitor ( eg. physostigmine) yes

Quantal dose response curve Define a frequency distribution: Define a cumulative frequency:

indicates sensitivity of a given population to the doses of a drug for a given effect. each bar shows the number of people responding at that dose. each bar shows the number of people responding to that dose and to previous doses.

What is the formula for Therapeutic index? High Therapeutic index means... Low index means...

TD50 / ED50 or LD50 / ED50 High index = safe Low index = toxic

# Define ED50: Define TD50: Define LD50: The higher a ratio for therapeutic index the ______ (toxic or safer)

Effective dose in 50% Toxic Dose in 50% Lethal dose in 50%

\_\_\_\_\_\_\_\_\_\_ reflects a plasma concentration range that provides efficacy without unacceptable toxicity. Its the difference between the minimum effective concentrations for a desired response and an adverse response.

Therapeutic window

A drug-receptor interaction that produces a response. The events involved in this response is known as..

signal transduction

What are the 4 fundamental mechanisms or types of Signal transduction mechanisms? 1. G 2. I 3. E 4. N Half of all known drugs work through what type of mechanism?

G-protein coupled receptor systems. (GPCRs, metabotropic receptors) Ion channel receptors (Ionotropic receptors) Enzymes as receptors - tyrosine kinase, serine/threonine kinase Nuclear receptors GPCRs (G-protein couple receptors)

When a GPCR is in an Resting or inactive state.. what enzyme is inactive? What is bound to the Alpha subunit of the GPCR when its inactive?

adenylyl cyclase GDP

When an agonist binds to a GPCR , what binds to the alpha subunit ? When this happens, the activated subunits shift tward what enzyme in order to activate it?

GTP Adenylyl cyclase

Pathways are activated by \_\_\_\_\_\_\_\_\_

GPCRs

What are the three major second messengers activated by GPCRs?

cAMP (cyclic adenosine monophosphate) IP3 (inositol trisphosphate) DAG (diacyl glycerol)

What structure/enzyme is activated in order to release Protein kinase A? What structure/enzyme is activated in order to release Protein kinase C? What structure /enzyme is activated in order to release Ca2+ and increase its concentration? What channel is directly opened by an Activated G protein?

Adenylyl cyclase --\> cAMP --\> protein kinase A Phospholipase C-b --\> DAG --\> protein kinase C Phospholipase C-b --\> IP3 --\> increase in Ca2+ K+ channel

cAMP is used in bronchioles to cause \_\_\_\_\_\_\_\_\_ and is used in the heart to cause \_\_\_\_\_\_\_\_ IP3 causes an increase in \_\_\_\_\_ DAG causes an increase in ______ from storage.

relax contract Ca2+ Ca2+

Which enzyme receptor consists of a pair of protein molecules(monomers) that are _separate when inactive?_ When an agonist causes them to interact what happens? What are some examples of this ?

Tyrosine kinase receptor They form a dimer. The i_nteraction phosphorylates tyrosines_ in the intracellular region of the receptor and the receptor becomes an active enzyme. The active receptor enzyme then activates a number of other enzymes that interact with the active tyrosine of the receptor. Insulin receptor, growth factor receptors

What type of receptor is a protein with a channel center? What causes the channel to open? Whats an example of this type of receptor and what does it conduct?

Ion channel receptor an agonist EG. Nicotinic acetylcholine receptor - conducts Na+ ions - causes muscle depolarization and contraction. Gamme aminobutryic acid (GABA) receptor - conducts Cl- ions -inhibits neurotransmission

What type of signal transduction mechanism/receptor is the fastest? Which is slowest?

ion channel Nuclear receptors

Where are Nuclear receptors located? What happens when an agonist binds to the receptor? What does this lead to? how long does this kind of signal transduction extend to? What is an example of a Nuclear receptor?

cell cytosol the drug-receptor complex then enters the nucleus and stimulates _gene transcription_ synthesis of new proteins and enzymes hours / days receptors for steroids, retinoids, thyroid hormones

What do agonists tend to do to receptors? Eg. Asthma What do antagonists tend to do to receptors?

desensitize receptors - treatment of bronchial asthma with B-receptor agonists (such as salbutamol) causes desensitization of receptors. they tend to regulate receptors - treatment with a B-receptor antagonist causes a withdrawal rebound effect when the antagonist treatment is stopped suddenly. IE treatment must be stopped GRADUALLY