Pharmocology Exam 2

Year 2 Semester 1

what is pharmacodynamics

what the dryg does to the patient based on target interaction and downstream signaling

what is required for a clinical efffect

PK and PD- enough drug has to reach the target and then produce desired response

define onset

how quick can the target change cell function

define selectivity

which tissues express the target, and what else can the drug bind

define adverse effects

what predictable responses occur on non-target tissues

define interactions

do other drugs converge on the same target or system?

list and explain 2 general ways drug produce effects

• prediction

• dose

1. target mediated

• target distribution and affinity shape the effect

• higher dose often recruits additional targets

• predictable

2. Physiochemical

• location and physical chemistry shape the effect

• dose effects may be broad but local delivery focuses them

major molecular targets

1. receptors

2. ion channels

3. enzymes

4. transport proteins

5. DNA and structural proteins

relationship between drugs and receptors

• receptors usually work only on endogenous mediators

• drugs can activate or block the receptors

• same receptor may have desired effect in one tissue and adverse effect in another

name 4 receptor superfamilites

1. ligand-gated ion channel

2. G protein coupled receptor

3. enzynmes linked receptor

4. intracellular receptor

what recepotor class is neuromuscular blockage, explain

ligand gated ion channel

• rapid

• atracurium antagonize nicotinic ACh receptors

what recepotor class is sedation and anxiolysis, explain

.ligand gated ion channel

• benzodiazepine positively modulate GABA receptors

• rapid

what recepotor class is dissociative anesthesia, explain

ligand gated ion channel

• rapid

• ketamine block NMDA-type glutamate receptors

does fast signalling guarantee immediate clinical effect

no, route, perfusion, and distribution determine when the drug reaches the receptor

what recepotor class is andrenergic receptors, explain

GPCR

• sec to min

• epinephrinephrine support blood pressure and bronchodialation

what recepotor class is alpha 2 receptors, explain

GPCR

• sec to min

• dexmedetomidine produces sedation and analgesia

• atipamezole reverses it

what recepotor class is opoid receptors , explain

GPCRs

• seconds to mins

• moprhine and fetanyle provide analgesia but can depress respiration

example of enzyme linked recepotrs and how long it takes for a response

• insulin receptor: tyrosine kinase

• mine: signal promotes glucose uptake and alters metabolism

• hours: changes in gene expression influence growth and longer term adaptation

does one receptor work only on one time scale

no, one recpetor can generate effects on more than 1 time scale

describe function of intracellular recepotrs with lcoation, mecahnism, and clinical implications

• alter gene transcription in hours to days

• location: cytosol or nucleus

• mechanism: receptor ligand complexes regulate transcription and protein synthesis

• clinical implications: anti-inflammatory effects develop over hours

what determines onset

• target signaling

• PK: drug delivery and patient factors

mechanism sets. the biological top for speed

PK determines when target engagement occurs

what does sensitivity depend on

concentration

• at lower concentration, drug can mainly occupy high affinity target

• increase concentration, go to off target effects = more likely adverse effects

• not specific

define allosteric ligand

bind at distinct site and changes receptor behavior ex. midazolam binds at seperate site and strengthens receptor’s response to GABA - not replace GABA

define orthosteric ligand

binds at endogenous agonist site, competes with endogenous ligand

example of drug working on voltage gated channels

• dependence of channels

• toxicity

• administration

lidocane blocks voltage gated sodium channels and prevents action potential propagation- because cannot get polarization = animal does not know what is happening there

• channels that open frequently can be blocked more effectively

• excess exposure can cause impact on cardiac and CNS sodium channels

• local administaration concentrates effect near intended nerves and limits systemic exposure

define drug action: target mediated

drug has receptor it is working on selectively

define drug action: primarily physiochemical

drug does not have a direct target but causes changes

3 examples of enzynme inhibition changing mediator production or breakdown

1. COX inhibiotrs: carprofen or meloxicam reducing prostanoid synthesis

2. acetylcholinesterase inhibitors: slow acetylcholine breakdown

3. phosphodiesterase inhibitors: slow cAMP breakdown and other actions

what does the enzyme inhibitor that changes mediator production or breakdown depend on

mediator turnover and downstream physiology

how is enzyme inhibition used for myasthenia gravis

• used for diagnosis becuase disease attacks nicotinic ACh receptors

• acetylcholinesterase inhibitor drug raising acetylcholine at the junction by reducing the amount destroyed

• observe increase in strength = diagnosis

• short acting so not therapeutic

• excess stimulation causes weakness and muscarinic signs

give examples of how transport proteins control extracellular and intracellular concentrations

1. fluoxetine: block serotonin transporter, increasing extracellular serotonin

2. digoxin: inhibit Na/K ATPase increasing intracellular Ca in cardiomyocytes

note: all these require build up and time to get there for symptoms

examples of anticancer drugs targeting DNA processing or cell division and major concenrn

1. doxorubicin

2. vincristine

concern: high efficacy against dividing cells explains damage to normal tissues with rapid turnover

give 4 examples of physicochemical actions and what is required for them all

1. mannitol: raise tubular or plasma osmolarity

2. antacids: neutralize gastric acid

3. activated charcoal: absorb many toxins in GI tract

4. chelators: bind metals and promotes elimination

5. protectants: form local barrier

differences of ionophore use in species

• monensin binds to sodium and carries across membranes

• disrupts electrochemical gradients without active transport

• used for benefits in cows

• can be very harmful in horses

patient factors altering pharmacodynamic response

1. species sensitivity

2. disease state

3. age

4. physiology

5. tolerance

6. adaptation

why would you want to use epinephrine over dexamethasone in an emergy situation

epinephrine: active GPCRs which is rapid

Dex: activate intracellular glucocorticoid receptors which takes a long time

why can highly selective drugs still cause adverse effects at therapeutic dose (3)

1. the intended target may also be expressed in non target tissues

2. the desired physiological response may become excessive

3. higher exposure may recruit additional targets

how do drugs bind to receptors

shape and chemical complementarity forming a reversible complex that produces a biological effect

how do agonists work

• bind and activate the receptor

• stabilize active conformation

• produce response

how do antagonists work

• bind receptor but do not activate

• prevent response

define affinity

ability to bind to receptor

• high = bind tight and stay bound even at low concentrations

• low = bind weak and lets go easily, needs higher concentrations to bind

define intrinsic efficacy

ability to activate the receptor

describe the difference between partial and full agonist

partial: slightly activate = low efficacy

full: fully activate = high efficacy

what are the 3 levels of efficacy

1. receptor: how well the drug activates the receptor

2. cellular: how well that action produces a cellular response

3. clinical: how well the drug produces a therapeutically useful effect in the whole animal

what is the efficacy of antagonist

none, no intrinsic efficacy becuase they do not activate a receptor though they can still produce an effect on the whole animal (real clinical efficacy)

does antagonist have affinity

yes, just no efficacy

what is the measure of affinity

Kd

• the concentration of drug required to occupy 50% of the receptors at equilibrium

• dissociation constant

what does a lower Kd mean

higher affinity

• less drug is needed to fill half the receptors meaning the drug binds more easily

what does the rate of affinity depend on

concentration, more drug and receptor present, faster they combine

are most drug binding permanent

no, most are reverible/ non covalent

1. ionic interactions (strongest)

2. hydrogen bonds

3. hydrophobic interactions

4. van der waals forces (weakest)

when are drug bindings perminant

with covalent bonds- lasts until the body makes new receptor or enzyme not until the drug is cleared

• organophosphates

• asprin

why does drug binding follow the law of mass action

because many weak bonds togetehr hold the drug in place and let it go again

what does Kd tell you

• affinity of the drug fro its receptor

• inversible proportional to affinity

• concentration where 50% of receptors are occupied

what does Kd tell you about efficacy

nothing

do antagonist or agonists have Kd

both

what does potency refelect

drug and receptor binding and what happens after the drug binds, not the affinity

what is efficacy

max possible effect a drug can produce regardless of the amount given

how is efficacy measured

Emax

• higher = more efficacious

why would you want. to use a partial agonist instead of a full agonist

sometimes the partial is enough effective and has less adverse effects

when does binding = effect

not always

Kd=EC50

• half the receptors occupied gives half the effect

Kd>ED50

• full effect before all the receptors are occupied

Kd<EC50

• no effect until most receptors are occupied

how is effect measured

EC50

what does Kd>EC50 usually suggest

agonist

what does Kd<EC50 usually mean

antagonist

• needs to displace and agonist to get effect

• must block most receptors

or enzyme inhibitor at non rate limiting step that must block enzyme first

antagonist EC50

do not have one because their effect is inhibition

• use IC50= concentration that blocks 50% of an agonist response/ half maximal inhibitory concentration

what does a lower IC50 mean

higher potency - less drug needed

what does IC50 measure

function inhibition not binding affinity

define potency

how much drug is needed to produce given effect

how is potency measured

EC50 (50% the max response), lower= more potent

which drug is more potent and which is more effective

potent: A

effective: all the same

which drug is more potent, which is more effective

potent: A

effective: B

difference between potency and clinical efficacy

potency: concentration of drug needed to produce effect depending on EC50 and if the drug gets to the receptors

clinical efficacy: if the response solves the problem depending on size of max response

can a low potency drug ever cause the same effect as a high potency drug

yes, just at a much higher dose

advantages of high potency drugs

1. smaller mounts needed for effect

2. useful when injection volume is limited: darting

3. more convenient and cost effective

disadvantages to high potency drugs

1. higher risk of toxicity/overdose

2. narrower margin of saftey

3. dose errors can have serous consequences (require careful dosing, easy to overdose)

what does potency depend on

affinity and efficacy

out of affinity, potency, and efficacy, which is most important clinically

efficacy because potency only sets the dose

define selectivity and how changes can shift it

• drug prefers some receptors to other for binding

• dopamine receptors are highly sensitive but adding a tiny OH can change the receptor choice completly

how does the fit of drugs affect potencies

• poor fit = must less active with different stereoisomer potencies

significance of levamisole

anti-nematode agent that makes a cocane high feel higher

2 rules of drug selectivity

1. nothing is totally selective

2. some drugs are more selevtive than others (more selective = wider gate between effective and toxic concentrations)

3 key characteristics of receptors

1. allosteric proteins: binding at one site changes conformation and activity

2. shift between inactive and active conformations

3. most unoccupied receptors are inactive (resting) state

difference in speed of ligand gated ion channel and G protein coupled receptor

ion channel is faster because just have ligant bind and then channel opens (milliseconds)

G protein coupled receptor is slower because it causes a cascade of effects

ionotrophic receptor- describe channel and mechanism

• channel is the receptor with a central pore

mechanism: ligand binding changes receptor shape so pore opens

common effects of ionotropic receptors

Na or Ca causes depolarization (excitatory)

Cl- in causes hyperpolarization (inhibitory)

what is long term potentiation

after strong activity, a synapse responds more strongly to the same signal (cellular biased memory)

1. insertion of receptors

2. modify receptors to be more efficient

3. increase neurotransmitter

speed of metabotrophic receptors

slower, but greater amplitude, many G proteins activated at once

speed of intracellular receptors

hours to days, but long lasting effects

speed of enzyme linked receptors

minuets to hours, control growth, survival, plasticity

define partial agonist

binds and activated the receptor, produces less than maximal response even when every receptor is occupied (lower efficacy)

what is the ceiling effect on an agonist

after a certian dose, more drug adds no more effect

effect of partial agonist next to full agonist

acts like an antagonist becuase it occupies receptors but only partially activates them so there is a decrease in full agonist effect

describe function of inverse agonist

binds and stabilized inactive conformation, shifting the balance away from the active state

what is the difference between an inverse agonist and a neutral antagonist

neutral antagonist blocks agonists but leaves baseline activity unchanged

inverse agonist pushed activity below the baseline

3 ways antagonists block a drugs effect

1. Pharmacological: on the same receptor: bind receptor without activiating it so the agonist cannot

2. physiological: activate a different receptor or pathway to produce the opposite effect, same tissue, different pathway, different organ

3. pharmacokinetic: keeps the drug from reaching the target through binding, blocking absorption, or speeding up elimination

what can an antagonist do on its own

nothing, only shows effect when agonist is present

compare affinity and efficacy:

agonist

partial agonist

antagonist

agonist: affinity and efficacy

partial agonist: affinity and some efficacy

antagonist: affinity, no efficacy

describe funciton of competitive antagonist

binds the same site as the agonist, binding is reversible and enough agonist can outcompete it

describe funciton of non competitive antagonist

bind irreversibly or at a different site from the agonist

• the agonist cannot compete it off

example of physiological antagonist to histamine

histamine on H1 receptor causes airways to narrow

epinephrine on beta2 receptor causes airways to open

when are physiological antagonists useful

when the cause is unknown- don’t know what drug is causing the signs, just want to cause opposite physiological effect