Exam 3

H+K+-ATPase pump

• enzyme known as the proton pumo

• exchange is stimulated by secondary messengers (Ca++ and cAMP) from GPCR activation_

basal, stimulated

inhibitors of the proton pump will block both ____ scretion

PPI backbone

conjugate base

PPIs are formulated with their ____

PPI MOA

• prodrugs that are trnasformed within the acid compartment of the parietal cell, into an inhibitor that reacts with an essential thiol group on the enzyme

• at neutral pH they are inactive, chemically stable, lipid soluble, weak bases

• they reach the parietal cells from the blood, then diffuse into the secretory canaliculi where they become protonated, and thus trapped

PPI covalent attachement 

• at least 2 molecules of the sulfenamide react with thiol gorups in the active site of H+/K+ atpase

• one is Cys-813,

• full inhibition occurs when 2 molecules of inhibitor react with one molecule of enzyme ****

permanent inhibiton

administration of omeprazole results in ___ of enzyme activity in vivo

PPI formulation

• formulated as enteric coated microcapsules or granules designed to withstand gastric acid and ensure release in the intestine.

absorbed from the systemic circulation

how do PPIs enter the parietal cells of the stomach?

A

which best depicts solubility of an enteric coating as a function of pH?

intestines

which location are PPIs most likely absorbed?

acidic pH

what drives activation of a PPI?

PPIs are bioactivated in parietal cells because of a low pH

PPIs are bioactivated into an electrophile, which can be toxic (like acetaminophen), why then are PPIs safe?

2

how many molecules are depicted in the following structure?

A

which location is acidic?

True

T/F PPIs block both stimulated and basal gastric acid secretion

eicosanoids

• structurally simple but highly biologically diverse, endogenous substances

• all structurally similar 20-carbon molecules

• derived from oxidation of lipids

• all are unstable ****

• prostaglandins, thromboxanes, prostacyclins, leukotrienes

local

eicosanoids are ___ hormones

local hormone

• unstable, very potent, synthesized specifically near the action site, quick response, rapid degradation

• ex: eicosanoids

uniquitous

eicosanoids are ___ in the body

mediators of inflammation

eicosanoids are the most important _____

how do eicosanoids work

• as chemical messengers through ecosanoid receptors

• a particular PG may have different effects in different tissues, depending on which receptors are expressed

prostaglandins (latanoprost)

• block w oxidation

• limited success- instability and off target effects, best for local adminisratoin

• agonists- goals are to increase stability and increase selectivity

1. add a phenol group - block w oxidaiton

2. reduce a double bond

3. prodrug (increase lipophilicity)

• indication- glaucoma

prostaglandins (carboprost)

• block dehydrogenase

• agonists- goals are to increase stability and increase selectivity

1. add a methyl in place of the hydrogen. this will block oxidation at carbon 15 by dehydrogenase

• uses: abortion, treat postpartum hemorrhage

prostaglandins as drugs

• block w oxidation

• block dehydrogenase

• target PG receptors

• all are agonists= goal is to increase stability and increase selectivity

leukotrienes

• mediators of inflammation

• potent hypotensives

• potent bronchoconstirctors

• act via specific GCPRs

  • cysteine leukotriene receptors→ CysLT1, CysLT2

• zafirlukast, montelukast, zileuton

• important target for asthma

agonists or antagonsts

therapeutics based on eicosanoid signaling can act as ___

local delivery

typically ___ is required for eicosanoids due to cell specific expression of receptors

GCPRs activated by eicosanoids are tissue specific

how do eicosanoids achieve different effects in different tissues?

omega 6

the following is which type of fatty acid?

hydrolysis

membrane phospholipids are cleaved by phospholipases by which metabolic process?

completely block oxidation

how would the following modification influence oxidation on carbon 15?

increase

would the following increase, decrease, or have no effect on stability?

no effect

would the following increase, decrease, or have no effect on stability?

increase

would the following increase, decrease, or have no effect on stability?

B

which would have a higher corneal permeability?

analgesic

acting to relieve pain

antipyretic

prevent or reduce fever

anti-inflammatory

a substance or treatment that reduces inflammation or swelling

tNSAIDs

• traditional, inhibit both COX-1 and COX-2

NSAIDS

new, selectively inhibits COX-2

cyclooxygenase

prostaglandin G/H synthase enzymes are also known as this

COX-1 inhibiton

• unwanted side effects in the gastrointestinal tract

COX-2 inhibtion

• antipyretic, analgesic, and anti-inflammatory actions

arginine 120

is important for binding in the NSAID MOA

functional groups

NSAIDs are classified based on __

NSAID classifications

• salicylic acids (aspirin)

• para-aminophenols (acetaminophen)

• acetic acids (indomethacin)

• propanioc acids (ibuprofen)

• enolic acids (piroxicam)

• diarylheterocyclics (celecoxib) → cox-2 selective

salicylic acid (aspirin)

• NSAID

• irreversible COX inhibition → covalently modified COX

esterase, CYP3A4, UGT, NACt

how are salicylic acid derivatives metobolized?

diflusional

salicylic acid derivative not metabolized by phase 1 systems

para-aminophenol (acetaminophen)

• not as NSAID***

• not a good COX2 inhibitor therefore has very weak anti-inflammatory effects

• extremely toxic at higher doses due to quinone

acetic acid derivatives

propanoic acid derivatives

enolic acid derivatives

COX 2 selective inhibitors

COX selectively

• no real advantage for it

• selectivity increases toxicity for other liabilities

D

which NSAID is a prodrug?

C

which NSAID is not likely metabolized by phase 1 systems?

D

which NSAID is most suitable for topical administration?

A

which NSAID covalently binds to COX?

carboxylic acid (usually)

which functional group is essential for NSAID activity?

3

which metabolite of acetaminophen is toxic?

cyclooxygenase

which enzyme do NSAIDs inhibit?

false

T/F NSAIDs that are bioactivated outside of the GI tract do not cause GI toxicities

carboxylic acid

Nabumetone is an NSAID that requires bioactivation. which functional gorup is nabumetone missing to be an NSAID?

false

T/F the anti-inflammatory effect of NSAIDs is through COX-1 inhibiton

C

what is the most likely phase 1 metabolite of diclofenac?

3

which is most likely to have the highest topical absorption? (numbered left to right 1-3)

dopamine hypothesis of schizophrenia

• exact cause is unkown

• current hypothesis- the accepted hypothesis is that it is caused by an increase in dopaminergic neurotransmission

• schizophrenia is a disease that is treated with medicine derived from a working hypothesis

secondary amine

functional group that common neurotransmitters share

schizophrenia

• disease that is attributed to abnormal dopamine signaling in the CNS

  • increased signaling through the D2 receptor

antipsychotic classification

• phenothiazine class

• benzamide class

• benzazepines

• benzisoxazole and benzisothiazole

• all work by modulating dopamine signaling

phenothiazine antipsychotics

• based on phenothiazine core

• slightly bent and not planar

• chlorpromazine, promethazine, diethazine, ehtopropazine

• can be short or long acting, depending on structure

short acting phenothiazine

long acting phenothiazine

benzamide antipsychotics

haloperidol

• long acting benzamide

• duration is 4-6 weeks for compliance

• prodrug→ fatty acid ester cleaved by hydrolysis

• can become toxic through bioactivation → HPP+ is neurotoxic to dopaminergic and serotonergic neurons

• caused tardive dyskinesia, which is repetitive, involuntary movements

chronic haloperidol toxicity

• bioactivation creates HPP+ → neurotoxic to dopaminergic and serotonergic neurons

• severity of toxicity is associated with an increase in HPP+ to haloperidol

• causes tardive dyskinesia, which is repetitive, involuntary body movements

• patients frequently exhibit extrapyramidal symtoms (EPS)

benzazepine antipsychotics

• synthesized based on imipramine (TCA)

• less EPS toxicity

• substitution of the amine target specificity → 3 amine and not secondary

• efficacy of this class challenges the dopamine hypothesis of schizophrenia

clozapine

• benzazepine class antipsychotics

• bioactivation created toxic metabolite

• catalyzed by peroxidases in neutrophils

• reactive metabolite responsible for covalent binding in neutrophils

• agranulocytosis occurs in 1-2% of patients from neutrophil toxicity

benzisoxazole and benzisothiazole antipsychotic

• generate compounds with D2 and 5-HT2A activity

• phenothaizine + benzazepine ?

• aripiprazole

• paliperidone palmitate

aripiprazole

• benzisoxazole and benzisothiazole antipsychotic

• high affinty antagonists for D2 and 5HT2A

• reduce extrapyramidal receptors

• 5HT2C agonist help reduce weight gain

typical antipsychotics

• first generation

• based on blocking D2 receptor signaling

• phenothiazine class

• benzamide class

atypical antipsychotics

• 2nd genration

• based on blocking D2/5HT2A receptor signaling

• benzazepine class

• benzisozazole and benzisothioazole class

sedatives

• reduce anxiety and exert a calming effect

anxiolytics

anything that inhibits anxiety

hypnotics

produces drowsiness and facilitates the onset and maintenance of a state of sleep (not necessarily healthy sleep)

GABA receptor complex

• barbituates

• benzodiazepines

• z drugs

GABA system

• drug binding leads to increased GABA binding to GABAA receptors

• drug binding inhibits firing of the neuron

gamma amino butyric acid (GABA)

• a major inhibitory neurotransmitter in the CNS

benzodiazepines

• bind the alpha and gamma subunits

• increase GABA binding

• causes greater influx of chlorine into the neuron

• decrease the rate of firing of the neuron

• CNS depression, helps lower anxiety

barbituates

• cyclic diacylureas

• substituted derivates of barbituric acid- generally, only the 5,5-disubstituted barbituric acid derivatives are active ***

• depending on the dose, can produce→ sedation, hypnosis, anesthesia

• the long acting are often used as anticonvulsants ***

• in order to possess hypnotic activity, must enter the CNS

issues with barbituates

• decrease REM sleep and dream time → not “natural sleep”

• tolerance develops

5 mono-substituted barbituric acids

• inactive

• too acidic to cross the blood brain barrier

• ionized in blood, no CNS penetrance, no activity

5,5 disubstituted barbituric acids

• active

• imide NH pKa= 7.1-8.1

• have CNS distribution

• ex: phenobarbital

barbituate SAR (5 carbon)

1. both C-5 H atoms must be substituted

2. as the number of C5 substituent atoms increases, lipid solubility increases (increases potency, volume of distribution, shortens duration of action)

3. halogens on alkyl groups at C5 increase lipid solubily

4. polar functional groups at C5 decrease potency (decreased lipid solubility)

barbiturate SAR (2 carbon)

• replacement of O with S gives increased lipid solubility, faster onset, and shorter duration

• maximal brain levels of thiobarbiturates are rapidly achieves, this, they have been used as IV anesthetics

why is barbiturate duration so short?

• large volume of distribution

• rapid absorption and distribution into the CNS followed by rapid redistribution to other sites

ultra short acting barbiturates

• thiopental

• methohexital

thiopental

• barbiturates used in lethal injection

• autopsies of executed inmates showed the level of thiopental in their bloodstream was insufficient to cause unconsiousness