pharmacodynamics (pharm 2)

drug dose and graded dose response curves

how do we quantitate the drug dose necessary to produce the correct therapeutic response? - graded dose response curves describe the relationship between drug concentration and response - AFFINITY determines how much drug is necessary (need LESS of a HIGH affinity drug to occupy receptors --> more potent, need MORE of a LOW affinity drug to occupy receptors --> less potent) - factors that can determine curve potency, efficacy, partial vs full agonist, competitive vs irreversible antagonist, spare receptors

1. intracellular receptors

- gas (smooth muscle relaxation, memory?): nitric oxide activates guanlyl cyclase which deactivates MLC-K by phosphorylating it (inhibits) - steroid receptors (long lasting): corticosteroids, mineralocorticoids, sex steroids, vitamin D, thyroid hormone therapeutic implications: - lag period - effects can last for days - effects not related to plasma levels

definitions

- hyporeactive - low intensity response - hyperreactive - patient with a big response - tolerance - decrease in drug effect when administered chronically - tachyphylaxis - rapid decrease in drug response after just a few doses - hypersensitivity - allergic response

4. ligand gated ion channels

peripheral and central nervous ion channels: - forms a hole that create flow of ions - nicotonic acetyhlcholine - gamma-amino butyric acid - glycine - excitatory amino acid channels (aspartate, glutamate) -mechanism --> increase in ion flow (conductance)

molecular targets

receptors: - 1. mediate the biologic response of most drugs: - 2. influence drug dose (maximal effect of a drug = # of receptors) receptor affinity is the ability to bind to receptor - 3. provide drug selectivity: receptor = lock and drug = key (molecular size, shape, electronic charge), cellular localization and prevalence, toxicity - 4. mediate effects of antagonist

family of G proteins (commit to memory) structural and functional families of receptors

- Gs: beta adrenergic, increase adenylyl cyclase --> increase cAMP --> increase PKA, contract cardiac myocytes, relax smooth muscle via phosphorylation of MLCk, activate glucose production in liver via phosphorylation of reg enzymes, activate renin production in kidneys - Gi: alpha 2 adrenergic and muscarinic- 2 (and more), decrease AC --> decrease cAMP, decrease cAMP --> increase K+ efflux --> hyper polarize cell (inhibitory), decrease release of NT in nerves, slow cardiac - Gq: muscarinic (1 and 3) and alpha 1, increase PLC --> increase IP3 and DAG --> increase Ca2+ --> increase PKC, activate smooth muscle activation via increased intracellular Ca2+ (binding to calmodulin?) - Golf: odorant receptors, increase AC --> increase cAMP - Gt: photons, cGMP phosphodiesterase --> decrease cGMP - Go: NT in brain, unclear

3. cytokine receptors (growth and cellular differentiation)

- also transmembrane proteins - growth hormone - erythropoietin - interferon - dimers that activate JAK which activate STAT (active nuclear transcription) which then enter the nucleus and alter gene expression

competitive and irreversible antagonist

- antagonist work by blocking function of agonist --> no conformational change in receptor - antagonist have no intracellular effects when given alone - antagonist function to block agonist or endogenous ligands from binding to the ligand binding pocket of receptor - two types are competitive antagonist and irreversible (noncompetitive) antagonist

competitive antagonist

- block binding pocket of receptor - same binding properties as agonist - ability to bind to receptor pocket or its affinity with it determines how effective the antagonist will be - shifts agonist dose-response to the right --> increasing the antagonist concentration increases the agonist d-r curve more to the right (same Emax) - competitive antagonist can be overcome with adding more agonist clinical response and relevance: - antagonist effect depends on antagonist concentration and its affinity to receptor C' = C(1+[I]/K(I)) - Schild equation C' = concentration of agonist required to produce effect in presence of antagonist [I] = concentration of antagonist K(I) = rate (affinity) of antagonist - duration of action is dependent of [plasma] - effected by drug clearance and excretion - varies form patient to patient - levels of endogenous agonist vary between patients and subsequently the effect of the antagonist

2. ligand-regulated TM (transmemrbane) enzymes

- cause some sort of phosphorylation cascade on inside growth factor families (metabolism and growth): - - tyrosine kinase --> insulin, EGF (epidermal growth factor), platelet derived growth factor (PDGF) - guanylyl cyclase --> atrial natriuretic factor (ANF), vascular tone - serine kinase --> transforming growth factor-beta (TGF-b) dimers that phosphorylate?

receptor regulation and desensitization (IMPORTANT) explain the cause and effects of receptor up regulation, down regulation, and desensitization

- common with G protein coupled receptors - the effects of agonists are generally short lived - desensitization: continual exposure results in less than maximal effect - desensitization --> can uncouple G protein from receptor via conformational change (reversible and short lived) - down regulation --> the receptor-agonist complex can be endocytosed into the cell via coated endosomes (originally from membrane) and transported to lysosomes for digestion or sent back to the membrane for recycling (long effect) - 1. homologous desensitization: - desensitization - covalent modification of receptor (e.g bARK - phosphorylation of G protein binding site prevents G protein binding) - downregulation - destruction of receptor or internalization of receptor - 2. heterologous desensitization: - common point in effector pathway (like G protein like removing the Gq) - input from converging systems clinical relevance: - lose response, drug no longer effective - hypersensitivity (withdrawal rebound effect)

coupling identify steps in the common intracellular second messenger signaling cascades: be able to describe how an external agonist stimulates production of the intracellular second messengers, be able to describe major intracellular receptor second messenger cascades, be aware of other types of receptor effector coupling

- coupling outside event and inside event --> occupancy - bound receptors = biologic response - coupling = occupancy of receptor by drug produces a response (conformational change in receptor structure, coupling efficiency = amount of conformational change (partial vs full agonist) and if there are spare receptors - primary messenger (agonist, NT, peptide hormone, etc) --> bind to receptor --> activate intracellular cascade via intracellular 2nd messenger

(efficacy) graded dose response curve

- different Emax - potency = ease of drug binding to receptor = drug concentration (EC50) or dose (ED50) required to produce 50% of drugs maximal effect --> depends on affinity (Kd) of drug-receptor binding and determines the dose necessary to administer to patient (clinical relevance) --> degrees of potency are comparable along the x-axis (concentration of drug) - efficacy = amount of change produced after drug is bound = magnitude of response produced by drug --> clinically more important than potency when selecting a drug --> degrees of efficacy is comparable along the y axis (%maximal effect)

beneficial vs toxic effects

- drug choice and dosages is often the clinicians value judgment based upon the beneficial versus toxic effects D + R = DR receptors --> effector X --> toxic/beneficial response (autonomic drugs, anticoagulants, antineoplastic drugs) D + R = DR receptors --> X and Y effectors, X --> toxic response and Y --> beneficial response (digoxin, ACh inhibitors) D + R1 or R2 = DR1 or DR2 receptors --> DR1 --> X effector and DR2 --> Y effector, X --> toxic and Y --> beneficial (antihistamines, aspirin, autonomic drugs, many CNS drugs) Paracelsus - "all substances are poison; there is none which is not a poison. the right dose differentiates a poison from a remedy"

efficacy and potency

- efficacy is determined and comparable by observing the EC50 (x-axis concentrations) - potency is determined and comparable by observing the Emax (y-axis effect)

paul erlich

- father of pharmacology - antiparastic drugs were specific to trypanosomes and curare inhibited muscle contraction caused by nicotine but not electrical stim --> these drugs must be binding to some specific receptor in body

spare receptors

- increase sensitivity to drug - mechanisms: temporal (effectors once stimulated continue to work) or spare in number (unoccupied receptors) clinical importance: - spare receptors allow low affinity agonist to produce full response at concentrations less than what is required to occupy all receptors (increase cellular sensitivity by mass action) - ligands with low affinity, dissociate faster from R allowing rapid termination of biologic response (good if you want short acting drugs) - example: in the heart 90% blockade of B receptors does little to slow down heart rate which can effect the dose required of irreversible antagonist without spare receptors: - KD (half bound) = EC50 (half max effect) - KD = 1/2 receptors are bound EC50 = 1/2 maximal response = 1/2 receptors are bound = 1/2 maximal response with spare receptors: - allows same response from low affinity (fast on/off response) ligand or less concentration of a high affinity ligand - KD = k2/k1 - k1 is very large (with spare receptors) thus KD is very small --> thus the concentration of drug at KD (when half receptors are bound) is much greater than the concentration of drug at half max EC50 --> KD>>>>EC50

therapeutic principles

- individual patient variability - causes for variable (idiosyncratic) drug responses --> genetic, immune, age, wt, sex, disease state, kidney and liver function - importance of quantal dose response curves - beneficial vs toxic effects

irreversible (noncompet) antagonist

- ligand that binds to the receptor with an affinity that may be so high that the receptor will be no longer avail to bind to any agonists (knocking out receptors) - ligand covalently linked to receptor - effects cannot be overcome by adding more agonist - lowers the Emax (however when spare receptors are present the maximal effect could remain at the initial value depending on the concentration of antagonist, however the curve will be greatly shifted to the right and possibly look like competitive) clinical use of irreversible antag: - pros - duration of action is not dependent on rate of elimination, long lasting effects (if wanted) - cons - more dependent on receptor turnover rate, overdose problem - example: aspirin has lon duration of antiplatelt effects even though its half life is 15 minutes

5. G-protein coupled receptors

- most predominant - called GTP because it binds GTP - family of similar proteins (700 GPCR in human genome) - all have similar AA sequence homology and general morphology - 7 transmembrane domain serpentine motif - when bound to agonist they all transmit info to inside of cell via activation of G proteins - G protein activation produces changes in effector enzymes which produce send messengers resulting in cellular response - G protien signaling involved in 1/2 of non-antibiotic drug action

partial agonist

- partial agonist - produce a lower response than full agonist when all receptors are bound (less efficacious but could be more or less potent) - this effect has nothing to do with affinity of the drug for receptor - partial agonist can act as antagonist - the net response is a result of the contribution of the full agonist and the contribution of the partial agonist - example: pindolol use in hypertension - used when you don't want the full volume of effect of a full agonist

other types of antagonism

- physiologic antagonist - a drug that binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing - e. g epinephrine (bronchodilation (B2) and vasoconstriction (a1)) counteracts histamine (bronchoconstriction, vasodilation (H1,2)) - chemical antagonist - a drug that interacts directly with the drug being antagonized to remove it or prevent it from reaching its target (independent of agonist-receptor interaction)

quantal dose response curves quantal dose response curves: define ED50 and LD50 in a quantal dose response curve, be able to calculate therapeutic index and know why this value is important

- potential variability between individuals - quantal dose response curves represent large number of individual paints or experimental animals response to various drug concentrations while observing a single set data point (lower bp, sped HR, etc) it is useful in determing a drug concentration that 50% of the population will respond to in the expected therapeutic end point - ED50 - median effective dose (dose at which 50% of individuals exhibit specific effect) - TD50 - toxic effective dose - dose required to produce a particular toxic effect in 50% of animals tested - LD50% - lethal effect dose - 50% death - therapeutic index = LD50/ED50 - a rough measure of drug safety margin - warfarin - small therapeutic index (ED50 and LD50 are close) - penicillin - large therapeutic index (ED50 and LD50 are far apart)

GPCR second messengers

- produced upon receptor binding to agonist - amplify orignial signal - mediate the activation of kinases - phophorylation of intracellular proteins results in biologic response - main second messengers: cAMP, calcium, IP3, cGMP

drug receptor

- the molecule inside the body that binds to the drug resulting in the physiologic changes after administration of the drug - a therapeutic response to a drug is achieved when it bind to an endogenous protein (receptor) in the body thus altering the biologic pathway that the receptor is involved in

efficacy

- volume of effect - drug A produces a conformational change in receptor that activates intracellular signaling cascades more readily than drug B (or, its receptor occupation is more efficiently coupled to intracellular signaling cascades, or receptor conformation that dug binds to favors activating intracellular cascades)

different receptors

-1. transport proteins and ion channels: e.g cardiac, CNS acting and diruetic medications - 2. regulatory proteins: NTs, autocoids, and hormones, most drugs - 3. enzymes: e.g many abx, antineoplastic agents, aspirin and much more - 4. structural proteins (connected to plasma membrane) - 5. lipids: e.g alcohol, anesthetics - 6. nucleic acids: inside nucleus

concentration effect curves (graded dose response curves) graded dose response curves: compare various drugs and determine which drugs are more potent or efficacious on a graded dose response (describe what these terms mean at the molecular level), be able to describe the differences between Kd, EC50, Bmax and Emax on a graded dose response curve, be able to explain why Bmax does not equal Emax when spare receptors are involved

drug (C) + receptor (R) <--> CR --> effect -k1 (rate) --> C + R --> CR - k2 (rate) --> CR --> C + R - K(D) = k2/k1 = equilibrium constant --> measure of the AFFINITY of the drug to receptor - when half the receptors are filled -initially, more drug = greater effect - response then diminishes with more drug - finally at higher concentrations, drug produce little additional effect --> Capacity saturated when studying response to drug: E = (Emax x C)/ (C + EC50) E = effect at C Emax = when all receptors are occupied C = concentration EC50 = C that produces 50% of the maximal effect when studying receptor-drug binding: B = (Bmax x C)/(C + K(D)) B = bound drug to receptor Bmax = all receptors bound C = free unbound [drug] K(D) =equilibrium dissociation constant (potency) - is when the concentration of free drug is at half maximal binding or the concentration of drug in which half the receptors are filled - EC50 is when drug effect (E) is 50% and when drug bound to receptor (B) is 50% (when there are no spare receptors) - use log conversion to allow broader comparison between drugs (creates a more S shaped curve) - direct relationship between binding of drug to receptor and effect produced --> more receptors bound --> bigger effect or the more drugs taken --> the larger the response

outline of pharmacodynamics and objectives

drug dose --> molecular targets --> efficacy --> potency --> toxicity --> individuals introduce receptors: - differentiate between a receptor agonist, irreversible/noncompetitve, or competitive antagonist, partial agonist (be able to identify each of these ligands on a dose response curve) -describe the following: competitive antagonist, irreversible/noncompetitive antagonist, phyiologic antagonist, chemical antagonist, spare receptors, partial agnoist, affinity, potency, efficacy interplay between receptor occupancy, signal transduction and therapeutic or toxic effect

variation in drug responsiveness

effect of drug varies with: - drug concentration reaching target organ - pharmacokinetic variability (absorption, metabolism, excretion) - effect of drug at target organ - pharmacodynamic variability (endogenous ligand levels, receptor number) - changes in components of response distal to receptor (age and health, compensatory feedback regulatory changes)