How a drug changes the tissues physiology or chemistry to have an effect after it has reached the site of action

Mechanism of drug action

by binding to endogenous molecules

• binding happens because there is affinity between drug and endogenous molecule
• binding is specific
• when drug binds the conformation of endogenous molecule changes
• changes alter function
• alteration in function makes drug effect 

-strength of attractive force that draws a drug molecule to an endogenous molecule

Magic Bullets

-name for durgs that only specifically target certain cells (often pathogens) to kill them

spatial arrangement of atoms that make up molecule shape

-changed when drug binds to receptor

Paul Ehrlich made the discovery

-working on biological stains and found they stick specifically to certain cells and parts of cells

Important bc it showed specificity of interactions

1. Osmotic diuretics: promote urine by decreasing H20 in tubes
2. Traditional antacids: bind H ions to decrease H and neutralize acid
3. Chelating agents: move heavy metals from body, binds to lead and makes them easier to get out of body 

1. Regulatory proteins: carries messages from one part of body to another, usually gene trascription 
2. Enzymes: catalyzes
3. Transporters (carriers): uses energy to move across a membrane or gradient
4. Ion channels: embedded in membrane and lets stuff cross in specific ways

Almost all psychotropic drugs use one of these 4 types

Agonist: binding + intrinsic activity

-intrinsic activity means it mimics endogenous molecule

Antagonist: binding, but no or low intrinsic activity

-block or reduce effects of other drugs or endogenous ligands

Intrinsic activity is a seperate construct from binding

• Proposed by Clark
• Applied the "law of mass action" to kinetics of drug/receptor interaction
• Law of mass action: rate of a reaction is proportional to the concentrations of reactants and products
• Says the reactants are "free" drug and "free" rececptors and the product is a drug/receptor complex

1. Explains relationship between binding & response

2. explains kinetic component about binding and drug/receptor

[D] [R] ---->[DR]

[]=concentration, d=free drug, r=free rec, DR=complex

-lots of free drugs and receptors @ administration so rate of reaction is high (lots of complexes forming)

-over time, less free so less complexes formed and lower reaction

[image]

Reversible or irreversible

• Affinity is determined by reversibility
• high affinity = irreversible=don't dissociate
• low afinity=reversible=drug spontaneous dissociates 

Forward Reaction: association of free drug and free receptor to form drug/receptor complexes (high rates initially then it evens out)

Backward reaction:Dissociation of drug/receptor complexes, happens more as time passes (more [DR] there are the more there are to dissociate)

Eventually both even out to the Binding Equilibrium

Concentration of [D], [R], and [DR] are fixed

-forward and backward reactions keep happening but the amount of each remains about the same

-does not mean there are the same amount of each, just that they stay stable

If reversible, affinity determines relative amounts of free and bound drugs

• Low affinity: high free drug and receptor, low concentration of complexes
• High affinity: low concentrations of free drug and recep, high concentration of complexes 

Assumes magnitude of response is directly proportional to fractional receptor occupancy

Law of mass action can determine the relationship between drug concentration and fractional receptor occupancy

Relates affinity , concentration, and % occupancy

Rate of forward reaction: Rate_f=K_f [D] [R]

Rate_b=K_b [DR]

K_f=association rate constant

K_b=dissociation rate constant

Rate_f=Rate_b

so

K_f[D][R]=K_b[DR]

so

K_b/K_f=[D][R]/[DR]

so

K_b/K_f=equilibrium dissociation constant or K_d=index of affinity

so

Affinity = recipricol of index of affinity=1/K_d

K_d increases as affinity decreases

-low affinity means large [R] & [D] and little [DR] so K_b is bigger then K_f

-K_b/K_f or K_d is high so K_d is high and affinity (recipricol) is low

K_d decreases as affinity increases

-high affinity means more [DR] so K_f is bigger than K_b

-K_b/K_f is small so K_d is small and affinity (reciprocal) is large

r=[D]/(K_d+[D])

r=% of receptors occupied

Get to this point by calculating total receptors to determine % occupied

[R_t]=[R]+[DR]

fractional receptor occupancy is related to affinity and concentration of free drug

Kd increases=r decreases

[D] increases =r increases

K_d=concentration of free drug where 50% of receptors are occupied

When Kd=[D] then r =50%

According to occupation theory K_d will equal the EC₅₀

EC₅₀ is the concentration that will produce q/w of the effect (median effect)

Not true cause of problems with the theory

Doesn't account for:

1. intrinsic activity
2. spare receptors
3. inverse agonists
4. allosteric modulation (drug can stick to other, nonactive sites & effect action of ligand that is on the active site )

intrinsic activity: degree to which a drug bound to receptor alters the physiological functin of the receptor

Full agonist: intrinsic activity =1

Partial agnoist:between 0 and 1

Pure antagonist=0

Sometimes you get maximal response w/out filling up all receptors

(ones you don't need are called spare receptors)

Occupation theory doesn't account for Partial agonist or antagonist (even if 100% of receptors are occupied, max response won't happen)

Doesn't account for inverse agonist: has affinity but produces opposite effect

Two-state receptor model

• proposes that receptors exist in dynamic equilibrium between active and inactive states (states exist naturally)
• agonists have differential affinity for the 2 states
• affinity to active state=increase reaction
• affinity to inactive state=decrease response (inverse agonist)
• antagonists have no preferential affinity

Why dose is related to response

• response related to % of receptors occupied
•  % of receptors occupied is related to concentration at site of action
• concentration at site of action is related to plasma concentration
• Plasma concentration is related to dose

1. relates dose to observable effect (response)
2. response can be graded (range of values) or dichotomous (all or none)
3. dose scale can be linear or logarithmic
4. Position on dose axis=potency, further left means higher potency
5. peak=maximal effect=efficacy, higher the upper most point means higher efficacy
6. slope=size of response change produced by a given dose change, steeper slope meansbigger change in response w/ change in dose

Amount of drug needed to produce a given effect

-can only talk about potency in relation to a certain effect

Typicall defined as amount needed to produce 50% of maximal effect

Farther curve is to the left the more potent the drug is

Efficacy is usually the most important for drugs

Potency diff between 2 drugs can depend on efficacy

(Drug A may be more potent then Drug B at getting 50% of response, but if A never gets to 100% of response then it is irrelevant in regards to potency compared to a drug that does reach 100%)

• Drug effects may be inherently quantal (all or none)
• Graded variables can be dichotomized
• Ind diff in response to a dose provided basis for quantal dose-response analysis
• % of individuals that show a certain response varies with dose

X axis = dose

Y axis=percent of individuals showing effect

ED50=dose that gives desired effect for 50%

LD50=dose that is lethal for 50%

TC50=dose that produces a certain toxic effect for 50%

(want ED50 far away from LD50 and TD50)

Derived from quantal responses

Therapeutic Index=LD50/ED50

-cruce measures since it doesn't consider bad effects other than death

Toxic Index=TD50/ED50

want both indexes to be really high

Antagonism: 1 drug interferes w/ affect of another drug

1) Pharmacokinetic: 1 drug effects another by altering pharmacokinetic properties (eg changing metabolism or distribution)

2) Physiological: 2 drugs working @ different sites initiate opposing physiological processes

3) Pharmacological: drug that binds to receptor but has weak or no intrinsic activity

-competitive (reversible)

-noncompletitive (irreversible)

• 2 drugs (ie agonist and antagonist) compete (reversibly) for binding to the same receptor 
• Fraction of receptors occupied by each drug is related to each drug's:
• Affinity (increased affinity=increased occupation of recptor)
• Concentration (increased concentraion = increased occupation of receptors)
• Dynamic process with drugs binding and releasing but average will equal concentration of each if affinity is the same

• If you keep agonist dose the same and increase antagonist dose (X axis) the maximal response with diminish (Y axis)

• If you keep competitive antagonist dose the same and increase agonist dose (X axis) the response (Y axis) you can still get the full response, you just need more of agonist
• Competitive antagonists decrease potency but does not affect efficacy
• Competitive antagonists display surmountability (competitive antagonism can be overcome by increasing agonist)
• [image]

• often reduces potency and efficacy for irreversible antagonism
• irreversible antagonism is not surrmountable unless there are spare receptors
• doesn't reduce efficacy if there are spare receptors
• eg 50% spare, antagonism is blocking 40% then agonist can still have full effect
• [image]

Partial agonist can serve as an antagonist to a full agonist

-keep full agonist dose the same and increase partial agonist, eventually decrease efficacy to the dose of the partial agonsist effect

[image]

Translation of extracellular messenger (drug) into an intracellular response

2 aspects of transduction and of receptors:

-binding component

-effector: molecular machinery that starts biological response, does the transduction

Binding and effector can be part of the same or separate molecules (makes defining a receptor difficult)

• Amplification:small extracellular signal can be amplified to strong intracellular response
• Specificity: diff ligands produce diff intracellular response so cells can identify diff types of ligands
• Pleiotropy: diversity, multiple responses from activating a single receptor
• Integration: adding together of diff transduction pathways
• Can have immediate or slow developing effects (can be short-lived or permanent)

• Open or close ion channels
• activate or block intracellular enzymes
• activate or block transporters carriers
• alter gene expression (LT changes)

• Necessary to understand brain physiology
• Imp for understanding pathogenesis of disease (mental illness)
• signaling pathways may be useful targets for drugs 

Signals that act on cel lmembrane (most common)

-can be ionotropic or metabotropic

Signals that can intracellularly

-all are metabotropic

Ionotropic: receptor that directly opens & closes ion channels

-binding site & effector ar the same structure (effector is the opening in the membrane

Metabotropic: produces metabolic changes inside the cell

-doesn't directly open ion channels

-ligand attaches, protein attaches to receptor, enzyme on receptor changes it

-ligand attaches, activates another enzyme in the cell, that seperate enzyme changes protein

-G protein coupleced: G is seperate from receptor

-drug binds and releases G which bomines w/ effector to alter a molecule

• Ligand gated ion channel
• can open like a shutter or chains blocking it
• Includes channels for Na+, K+, Ca++, & Cl-
• Directly alter membrane potentials (change charge)
• Produces EPSPs, IPSPs, and act pot
• effects are really fast
• can be regulated by multiple extra & intracellular signals 

Pentameric (5 subunits)

Each subunit has 4 trans-membrane (i.e., membrane spanning) helixes

• ligand binds, ion channel opens
• 2 binding sites, ligand at both needed to open receptor 
• 1 ligand opens channel and other ligand lets enough (+) ions into the cell to unblock the channgel from Magnesium
• imp process in synaptic plasticity (learning)
• Modular channels w/ 3 sites
• 1 ligand opens channel, if others attach you get a bigger or longer opening

• initiate metabolic processes in cells
• response is slower than ionotropic
• response is longer lasting, ST permanent
• can produce diverse intracellular response (pleiotropy)
• can open & close ion channels 
• most imp class of receptors bc they mediate a lot of signals produces by NT

• Neurotransmitters
• hormones
• light (receptors in eye)
• odorants
• pheromones
• calcium 

Single subunity w/ 7 transmembrane domains

One end has an amino group (N-terminus) and the other has a carboxal group (C-terminus)

peptide bond: is when these two groups unite

Binding component & effector are spatially seperated, G-protein connects them so they can be functionally related

1. Inactive state, G protein alpha subunit has GDP attached to it (GDP seperate from binding site)
2. Ligand binds and changes form
3. G protein binds to receptor 
4. G protein changes form
5. alpha can't hold onto GDP so GDP goes away
6. affinity b/ GTP & alpha subunit occurs and they join
7.  alpha changes, leaves β/γ subunits
8. GTP hydrolisizes back to GDP
9. G protein is deactivated and alpha rejoins β/γ (ready to start process again)

• Adenylyl cyclase system
• Activated by the alpha subunit of G_{s(stimulatory)} protein
• alpha from G_i  will inhibit adenylyl cyclase
• Adenylyl cyclase changes ATP to cyclic AMP (cAMP)
• 2nd messenger, bcligand tranduces to intracellular signal then cAMP carries message somewhere else
• cAMP binds to cAMP dependent protein kinases (protein that phosphorleates other proteins)
• catalytic subunit leaves protein kinase to phosporelate
• may phosphorelate CREB in nucleuse
• cyclic AMP response element binding
• Kinase has 2 catalytic subunits so it can phosphorelate the bistructure of CREB
• CREB alters DNA transcription (DNA-->RNA)

• 2nd messenger systems
• one enzyme can make 2 diff messengers
• IP3 allows release of calcium from endoplasmic reticulum (ER)
• activation of calmodulin
• activation of protein kinase C

Example of a transmembrance receptor that is an enzyme (not G protein coupled)

-inactive state are monomers (single subunit), when ligand binds they join & becomes a dimer that are functionally connected 

-tyrosine residue (single amino) becomes catalytically activate and change other phosphates

-important for growth factors

-related to BDNF (related to derpession)

Transmembrane receptors that activate separate tyrosine kinase receptors

• tyrosine residues are phosporilated but they aren't the active component here
• instead they bind to JAC molecule which create STAT
• Stat releases and goes to nucleus to alter genetic expression
• JAC=janic kynases
• STAT=signal transucing and activation of transcription

• arachidonic acid: stimulates protein kinase C
• precursor of eicosanoids(e.g., prostaglandins)synthesized by tissue damage and causes inflamation & pain-paind meds work here
• precursor of endocannabinoids 
• nitric oxide: activates guanyly cylase
• causes vasodialation
• corticosteroids: released by adrenal cortex
• imp for stress/emergency reaction (imp for mental ill
• cortisol (corticosteroid stress hormone)
• made from cholesterol (real lipid soluble so diffuses across membrane easily)

• Binds to glucocortichoid receptor (GR)
• GR seperates from HSP (HSP is activated by stress)
• HSP is a chaperone bc it can unfold proteins and alter their activity
• GR enters nucleus and alters genetic transcription