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45 Cards in this Set

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drug development and approval rough stages

starts with drug discovery or synthesis, understanding its mechanism, and development of a compound with enhanced selectivity and potency; in vitro studies; in vivo metabolism and safety in animals; phases 1, 2, 3 human trials and phase 4 post approval; costs 15-900M to reach market and 30% of those return their investment cost; 10% of US healthcare $$ are spent on prescription drugs; global market is 640B

possible approaches to drug discovery

ID of new drug target; rational design of a new drug; chemical modification of known molecule; screening of libraries of compounds; biotechnology and cloning; combine known drugs for additive or synergistic effects or reposition a known drug for a new use

synthesis of novel chemical compounds derived from where

plants (cardiac glycosides), animal tissues (heparin), microbial cultures (PCN G), human cell cultures (urokinase), genet technology (human insulin); increased insight into structure-activity relationships permits a more focused search for new compounds

precilinical safety and toxicity testing

all drugs are toxic at some dose; assess risk by identifying potential human toxicities; no effect dose, minimum, and median lethal doses; the chosen human test dose will be about 1/10 to 1/100 of the preclinical no effect dose; the complete precilinical toxicity studies and estimates of therapeutic index may take 2-6 years

3 major confounding factors for transitioning the investigative drug to human evaluation

variable natural history of most diseases which requires large number of subjects and long period of study; presence of other diseases and risk factors or need to obtain accurate histories and properly randomize groups; patient and observer bias so need to have single and double bind designs

what does the FDA do

oversees the drug evaluation process (safe and effective) and grants approval of new drug products; complete absence of risk is impossible to demonstrate; it is possible to identify most of the hazards and their frequency in the study population so safety is based on the nature and incidence of hazards compared with the hazard or nontherapy of the target disease

what is an IND

notice of claimed investigational exemption for a New Drug; it is filed when a drug is ready to be tested in humans; it contains composition, source, chemical and manufacturing info, animal data, proposed protocols, names of physicians who will conduct trials, and compilation of key data relevant to study in humans

phase 1 clinical testing

dose-effect relationship established in 25-30 healthy volunteers; the goal is to find the max tolerated dose and see if humans show significantly different responses from animals; trials are nonblind; many toxicities are detected and pharmacokinetic measurements of absorption, half life, and metabolism are made; see if effects on body functions observed in animals occur in humans

phase 2 clinical testing

therapeutic efficacy assessed in 100-200 pts with the relevant disease; single blind; placebo, positive control, test drug; assess safety, efficacy, dose, additional toxicities, pharmacokinetics; if benefit is evident and any toxicity is acceptably small then phase 3 is entered

phase 3 clinical testing

larger pt groups (1000s) to further establish safety and efficacy; comparison of the new drug with standard therapy; some toxicities may first become apparent here; double blind and crossover designs often used; these trials must be approved by institutional ethics committees (IRB); phases 1-3 take 4-6 yrs; most drugs are revealed to be unusable; about one drug survives for every 10,000 newly synthesized compounds (0.01%) so 1/10 that begin phase 1 makes it through phase 3

what happens after phase 3

the manufacturer may submit an NDA to the FDA who review it over the course of months to years; must show that preclinical and clinical data provide evidence for meeting safety and efficacy criteria and that product formulation meets quality control standards; following approval to market the drug phase 4 begins

phase 4

regulatory surveillance continues in the form of post licensing studies; monitoring of safety under actual conditions of use in very large numbers of pts; low incidence effects are usually not detected prior to phase 4; this is the only way to assess the long term risk benefit ratio and true therapeutic value; cost benefit evaluation may also be warranted for drugs with little benefit over older ones; adverse reactions in susceptible populations include tolerance, idiosyncracy (genetic origin), and allergy (immunologically mediated); during phase 4 serious and unexpected events (overdose, accident, withdrawal, adverse effects not listed in labeling) must be reported to FDA within 15 days

phase 4 patent expiration

occurs 20 yrs after IND; since it takes about 5 years from IND to FDA approval of the NDA that leaves no more than 15 years of patent protection; after that any company can produce the drug, file an abbreviated NDA, demonstrate equivalence, and with approval market the drug as a generic product

types of bonds and attractive forces pertinent to drug-receptor binding in order of decreasing bond strangth

covalent (irreversible; least common), ionic (+/-), hydrogen (H-O), hhydrophobic interactions, van der walls (dipole interactions)

characteristics of classical receptors

span the membrane; amphipathic (have polar and nonpolar regions); alpha helices form the nonpolar transmebrane regions

receptor characterization

depends on ligand binding specificity; radioligands (labeled drugs) are used to obtain measures of receptor-bound and free drug; after equilibrium binding, receptor bound (LR) and free unbound (L) drug are separated; concentrations of bound ligand (LG) and free ligand (L) are determined

Kd=

[L] [R] / [LR] = k2/k1 = Kd; [L] and [LR] can be measured but [R] cannot; [R] = [RT] - [LR] so [LR] / [L] = [RT] / Kd - [LR]/Kd; another way to say this is that [bound]/[free] = [boundm]/Kd - [bound]/Kd which can then be graphed in what is known as a scatchard plot; don't really need to know this slide; know the smaller the Kd the higher the binding affinity (Kd is the dissociation constant= the concentration needed for 50% binding)

scatchard plot

[B/F] is the y axis and [B] is the x axis; slope = -1/Kd and x intercept = Bmax

determination of specific binding

[specific receptor binding] = [total binding - nonspecific binding]

what is specific binding

saturable high affinity binding

what is nonspecific binding

nonsaturable low affinity binding

drugs acting at the call membrane produce transmembrane signals by regulating one or more of the following

ligand gated ion channels (aka receptor-operated channels); G proteins and second messengers; transmembrane enzymes

transmembrane signaling mechanisms

ligand gated ion channels; G protein coupled receptors (GPCRs); ligand regulated transmembrane enzymes= receptor tyrosine kinases and cytokine receptors; intracellular actions (regulation of gene transcription)

how to ligand gated ion channels work

neurotransmitters GABA (A type), ACh (nicotinic), 5-HT (5-HT3), and EEAs (e.g. glu) bind in part to ligand gated channels; increased memrbane conductance occurs by the opening of gated channels for specific ions (Na+, K+, Ca2+) which then follow their electrochemical gradients

how do G protein coupled receptors (GPCRs) work

membrane receptors associated with G proteins, an effector enzyme, and diffusible second messengers; G proteins are inactive when GDP is bound and active when GTP is bound; G proteins consist of an alpha, a beta, and a gamma subunit; the alpha subunit interacts with the activated receptor, with GDP/GTP and with the effector enzyme (or channel); types of G proteins are Gs, Gi, Go, and Gq; so binding of drug (i.e. ligand) to receptor, then receptor activation of a G protein, then G protein regulation of an enzyme or ion channel, then change in the concentration of a second messenger

the effector and second messenger in the calcium phosphoinositide pathway

phospholipase C for the effector and calcium, DAG, and phosphoinositide for the second messenger

the effector and second messenger in the cAMP transduction pathway

adenylyl cyclase (AC) for the effector and cyclic AMP (cAMP) for the second messenger

the cAMP second messenger system

the linked G protein is either Gs or Gi depending on the receptor subtype; this is an important concept for their system= stimulation of the receptor will cause either enhanced AC activity or decreased AC activity depending on whether the receptor complex is associated with Gs or Gi; a given receptor subtype is linked to one or the other but a cell may express multiple receptor subtypes; activation of AC results in synthesis of the secondary messenger cAMP from ATP; cAMP activated protein kinase A

cAMP dependent protein kinases are made up of what and what do they do

aka protein kinase As; regulatory and catalytic subunits; catalytic subunits are inhibited when associated with the regulatory subunits; cAMP combines with the regulatory subunits to cause dissociation from catalytic subunits, allowing activation of enzymatic activity; cAMP binds to regulatory domains of PKA liberating the catalytic subunits, Ca/CaM binds to the regulatory domain of CaMKII resulting in exposure of the catalytic domain; DAG, Ca, and PS are involved in activation of PKC

inactivation mechanisms in the cAMP pathway

inactivation of G proteins (GTPase); inactivation of second messengers (phosphodiesterases for cAMP); inactivation of protein kinases by phosphatases

calcium phosphoinositide second messenger system

G protein linked, Gq; activation of phospholipase C results in hydrolysis of phosphotidylinositol-4,5-bisphosphate (PIP2) into 2 second messengers (diacylglycerl (DAG) and inositol-1,4,5-triphosphate (IP3)); DAG activated protein kinase C; IP3 mobilizes stored intracellular calcium

norepinephrine stimulation of G proteins results in an increased intracellular concentration of calcium; this increase is not reversed by the extracellular calcium chelator EGTA; which of the following is the most likely source of the increased intracellular calcium concentration: a. ER b. golgi c. lysosome d. nucleus e. plasma membrane

a. ER

ligand regulated transmembrane enzymes: receptor tyr kinases= where does the drug bind, what is the effect, what agonists

drug or hormone binds to extracellular domain; allosteric effect with dimerization and autophosphorylation of intracellular domains; phsophorylated form phosphorylated substrate proteins; agonists include insulin, EGF, PDGF, other growth factors

ligand regulated transmembrane enzymes: cytokine receptors= where does the drug bind, what is the effect, what agonists

drug or hormone binds to extracellular domain; allosteric effect with dimerization and autophosphorylation of tyr residues on intracellular domains; phosphorylated form phosphorylated JAK tyr kinases, which in turn phosphorylated 'signal transducers and activators of transcription' STAT molecules; agonists are growth hormone, interferon, erythropoietin, and other growth factors

what is homologous desensitization

affecting responses elicited only by the stimulated receptor

what is heterologous desensitization

acting on several receptors or on a pathway common to many receptors

cytosolic receptors

steroid hormones cross the cell membrane and bind to cytosolic receptors; the complex is transported to the nucleus and binds DNA sequences near the gene whose expression is to be regulated

nuclear receptors

thyroid hormone enters the cell and passively enters nucleus to bind its receptor (part of chromatin)

which of the following most accurately describes the transmembrane signaling process involved in steroid hormone action? a. action on a membrane spanning tyrosine kinase b. activation of a G protein which activated or inhibits adenylyl cyclase c. diffusion into a cell and binding to an intracellular receptor d. opening of transmembrane channels

c

presynaptiv reuptake

major mechanism for terminating action of the monoamine transmitters; some drugs interfere with this mechanism by blocking reuptake carriers (TCAs, cocaine); some drugs can cause release of stored transmitter (amphetamine)

most transmitters are stored where

in intracellular storage vesicles

reserpine

interferes with this mechanism and prevents storage causing depletion

extracellular sites of action examples

the antocoagulant heparin and its antagonist protamine; chelating agents EDTA, penicillamine, and dimercaprol bind toxic metals (lead, copper, and mercury); antacids; laxatives

the ED50

the effective dose; the dose at which 50% of people have the desired effect

the LD50

the lethal dose; the dose at which 50% of people die