Pharmacodynamics & Introduction to Autonomic Control

what is a drug

any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient

how do drugs cause its effects

• the target the drug interacts with

• how the drug binds to the target site(s)

• how binding translates to a biological effect

what are the 4 main ways a drug may interact in the body

May interact through:

• receptors - ligand/receptor interaction

• ion channels

• enzymes

• carrier channels/transporters

what is a ligand & what aspects determine its binding

substance that binds to a receptor, can be a ‘drug’ or endogenous factor

binding depends on:

• shape & size

how does affinity of a drug effect its binding

forces of attraction

weak & reversible:

• hydrogen bonds

• ionic bonds

• dispersion forces

strong & potentially non-reversible

• covalent

how does the law of mass action relate to drug-receptor binding

the principle that the rate of a chemical reaction is proportional to the concentrations of the reacting substances / reactants

• more drug (limiting reagent) + receptor = drug-receptor complex

what are the different K values for the drug-receptor complex

K_on = association

K_off = dissociation

therefore, [D] x [R] x K_on = [DR] x K_off (this is true at equilibrium)

NOTE: ↑ [DR] = ↑ response

what is measure of affinity

when 50% of receptors are occupied: [R] = [DR]

therefore, [D] = K_d = measure of affinity

e.g. K_d = 1nM (means that only 1nM is required to occupy 50% of receptors)

what are competition binding assays/experiments

experiments used to determine the K_d/IC₅₀ (inhibitory curve at 50%)

• starts with a radioligand (radioactive ligand) mixed with a sample of receptors until saturated

• drug of interest (non-radioactive) is added to the mixture, the drug displays the radioligands thus decreasing the % of radioligands bound

• this is illustrated by a graph (inhibitory curve)

NOTE: IC₅₀ = K_i = K_d

how are Ki valves reported

as pKi values:

• pKi = -log₁₀(K_i)

• higher pKi = greater affinity

what are some of the different receptor types

• ligand-gated ion channels

• G-coupled protein receptors

• kinase-linked receptors

• nuclear responses

what are agonists & antagonists

agonist - a drug/molecule that activates a receptor (denoted: DR*), mimics the effect of original ligand

antagonist - a drug/molecule that inhibits the activation of a receptor

• has affinity but NO efficacy

what is efficacy

the ability of a drug, once bound, to activate the receptor to cause a response

• refers to effect as a result of receptor activation

what is clinical efficacy

refers to the therapeutic effect of a drug

what are concentration-response curves

curves that display the relationship between [D] & % response

• E_max = maximum response = efficacy

• EC₅₀ = agonist concentration that produces a response 50% of maximum = potency

what is potency & how is it measured

measure of how much of a drug is required to produce a particular effect

• measured as pEC₅₀ = -log₁₀(EC₅₀)

• greater pEC₅₀ = greater potency

what is selectivity

the degree to which a drug acts on a given site relative to other sites.

• e.g. a drug has high selectivity for kidney but low for brain

what is therapeutic index

relates the dose causing adverse effects to the dose causing desired effect

i.e. dose that cause good effects vs dose that causes bad effects

what is the natural state of receptors

normally in the inactive form but become active via a ligand that forces a conformational change in shape

what is important to note about the location of sympathetic nerves

located within the spinal cord, in which axons branch out to differnet parts of the body

how is noradrenaline formed

formed from tyrosine which enters neuron via a transporter

• tyrosine → DOPA (tyrosine hydroxylase)

• DOPA → dopamine (DOPA carboxylase)

• dopamine is moved into VMAT vesicle

• dopamine → noradrenaline (dopamine β-hydroxylase - only in synaptic vesicles)

what is vesicular monoamine transport (VMAT)

storage vesicle that takes up dopamine (& noradrenaline) for storage & re-release

• ATPase drives H+ into vesicle

• H+ is released for vesicle in exchange for dopamine

• NA formed is bound to the membrane of the vesicle

what is the process of NA release & recycling

exocytotic release:

• AP propagates through cell activating Ca2+ channels

• calcium facilitates the movement of VMAT to nerve terminal where its released

termination/recycle:

• NA in synaptic cleft is taken up by a transporter

• NA is reloaded into VMAT vesicles ready for re-release

what enzymes breakdown or degrade NA

MAO = monoamine oxidase

• found in nerve terminal

• degrades NA

COMT = catechol-o methyl transferase

• metabolises NA that is taken up by the smooth muscle cell

what is adrenal

a hormone from the medulla of the adrenal glands

• travels through bloodstream to act on structures like the bronchi

• synthesised from noradrenaline by PNMT (phenylethanolamine N methyltransferase)

what are some differences between α & β receptors

α-receptors: noradrenaline >= adrenaline

• mainly regulated cardiovascular system: contracts vessels

β receptors: adrenaline >= noradrenaline

• heart rate (increases force & rate)

• gut activity (slows & relaxes)

• smoot muscle (dilates to increase blood flow)

what are some different β-receptors

β₁-receptors: cardiac muscle, liver, skeletal (↑force & rate)

β₂-receptors: lungs, blood vessels (relaxation ↑blood flow & O₂ delivery)

β₃-receptors: adipose tissue (lipolysis)

what type of receptor is β adrenoceptors:

G-protein coupled receptors

• thus β adrenoceptors activate adenylyl cyclase

• this produces cAMP

• cAMP activates protein kinase A

• protein kinase A phosphorylates activates other enzymes

NOTE: this examples why receptors on different cell cause different effects since they phosphorylate different intracellular proteins