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89 Cards in this Set
- Front
- Back
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Drugs that penetrate the CNS face difficulties with bio-availability. How? what are the three important contributions? |
Drug has to pass the BBB and squeeze through tight junctions in the brain. These drugs bind too proteins, come off , and then bind again.
Three important contributions are : 1. lipophilicity (balance) 2. Protein binding 3.affinity for efflux transporters (P- glyco protein)
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CNS drug penetration is driven by: |
Lipophilicity.
Log P supports: -Aq solubility -Oral absorption (Ideal 0.3-6) -CNS penetration (log 1-4) This promotes good penetration in the pain. Higher log P=higher cps penetration but not too high will get stuck in fatty membranes around capilaries. Every drug has a sweet spot log P
***Drugs have to get through the membrane partition so it can bind to the receptor.
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Sleep is controlled by the reticular formation via |
RAS, reticular activating system. Circadian rhythms dictates the sleep wake cycle which is controlled by the Superchiasmatic Nucleus which is part of the hypothalamus. This system has visual input since circadian rhythm responds to light and dark. |
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As you get older your melatonin receptors |
go down |
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Sedatives |
produce calm effect / little to no effect on motor or mental functions |
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Hypnotics |
produce drowsiness |
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OTC drugs for sleep are primarily |
1st generation H1 antagonist . hit brain and make you sleepy |
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The GABA receptor system |
circles are a release of GABA. Inhibitory effects makes post synapse less likely to fire.
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Gaba basically hyper polarizes (more negative than normal an undershoot due to CL- influx ). the neuron so an action potential can't fire. It can't respond to normal excitatory input. Thanks GABA |
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This is the Gaba receptor which is also an ion channel. 2 GABA binds between A1 and B2and the channel opens and we get an influx of Cl-. i.e.: Ethanol is a Gaba agonist. It stimulates pos effect of GABA and action of Cl. |
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A1B2Gamma2 are typical sub units for what drug |
Hypnotic/amnestic/seizure . Type 1 |
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A2B2Gamma are typical subunits for GABA seen is what drugs? |
Anxiety/Muscle relaxation . Type 2 |
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What drug ? What does it do ? What type?
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This be Chloral Hydrate a sedative that has amnestic effects. - "Mickey Finn" The water turns the tricholoracetadehyde into chloral hydrate which is a solid. BASICALLY RUFFIE--> put in drink.
Dont remember what happened the night before does not effect REM sleep |
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-Life cycle of Chloral Hydrate Explain - What does it start as? |
Metabolisim of drug will be how long active metabolite acts and the duration of action. This drug has an early lipophilic effect from the CHLORAL HYDRATE and early hypnotic effects seen. The later effects are from the TRICHLORAL ETHANOL which is more hypnotic. It ends up as Trichloroacetic acid which is NOT a sedative and is excreted and irreversible. |
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-Side effects of CL hydrate -Indications of CL Hydrate - Is it still used?? |
Take too much body gets tolerance/ ADDICTED -Its a schedule 4 -Can mss up anti coags. Both are highly bound protein drugs. It might knock warfarin off of plasma protein. And we have more free warfarin!! - RASH GI problem CL hydrate is addictive USED FOR : Short term use for insomnia - pre surgery Not used any more it was replaced by BARBITUATES. |
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Barbiturates explain /where does it bind to / |
Barbiturates is a positive Allosteric MOdulator. It increases the duration of CL- channel opening. Increase channel opening time. X can be different things. Barbiturates bind to Beta subunit on the GABA receptor. -ANTI SEIZURE MED |
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Barbiturates work as : - Do high and low doses do the same thing?
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Hypnotcs but has a CNS depressed effect thus being a sedative too. -Depressant effects the cerebrospinal axis -Skeletal , smooth muscle and cardiac muscle activity. ALL MUSCLE ACTIVITY -HIgh dose gives excitatory -Low Dose give sedative and hypnotic This is called a BI- PHASIC EFFECT -Used also as pre anesthetic and for the WADA TEST prior to ablative surgery for epilepsy. Done to see what will happen if they cut out certain parts of brain. Injected into common carotid and do cognitive test on pt... |
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Barbiturates have certain structural req : |
The N-H hydrogens are WEAKLY ACIDIC and in vivo at physic ph, only one ionization can take place. Left in monolactam form from barbituric acid form. IF N3 it will only Ionize once. |
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Whats goin on with these barbs ? |
Must have good Aq solubility, oral absorption, and cns penetration. A log P of 1.3 is good (2nd to last). Drug needs to balance between property and activity. The one next to it is bad, the 4th alkyl group does not allow it to be ionized also PKA is ridiculous. |
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There are different barbiturates. Depending on _______ the bio availabity changes and depending on ______ the duration of action changes |
1.Lipophilicity 2. Metabolisim
Ultra short acting is used for pre anesthesia -->Thiopental Short acting -> pheno barb used for seizures and capital punishment Long acting pheno barb don't get into brain very well and is used for seizures mainly
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BIOAVAILABILITY IS AFFECTED BY |
Solubility / Oral absorption / and CNS penetration. ALL THESE MUST AGREE |
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What groups need to be there for optimal activity? |
-Stay away from polar groups! it lowers log p -Lipophilic groups can sometimes get YOU TOO LIPOPHILIC. CL- especially! -Important to have 5-8 carbon spacer, its best for lipophilictity -Alkyl groups get into brain faster thus decreasing onset of action (GOOD!) @ R3. ANYTHING GREATER THAN METHYL will give you CONVULSIVE PROPERTIES. you go from anti- convuls to convulsive. - 2 Alkyl groups on top, R1 and R2 are the best for the drug. R1&R2. -If you take the Nitrogens off you will get inactivity. - You can increase duration of action even FASTER if you add a sulfur it increases lipophilicty and gets into brain faster but then its metabolized quickly. (X)
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Visual |
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This describes the log P and again , how important it is for penetration into the brain!! The fastest one is? Name Log P and DOaction |
Thiopental with a log P of 2.7 and DOAction ) 0.5 |
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Metabolisim of Barbs is done by________, a member of the CYP450 fam. It makes molecules more polar by hydroxylation. It adds OH. Increases Oxygen presence or bonds to oxygen. It can also be ___________ but it takes longer. |
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Branched chained Barbs take longer to because they are more polar so the OH binds to it easier. This goes through ______ ,metabolism.
Or it can be hydroxylated THEN _______ via Phase _____ |
-Phase 1 metabolisim. -glucoronidated via phase 2 |
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Barbituruate side effects include |
STEVEN JOHNSON SYNDROM (necrolysis disease)--> RASH -Tolerance, increased amount of drug makes you tolerant -Addiction -Barbiturate "hang over" -Respiratory depression -REM rebound, reduced deep sleep after barbiturate withdrawal. - Enzyme Induction. Some BARBS covalently modify P450
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Barbs final points |
Ultra short is for anesthesia -not used as hypnotics prefer benzodiazapienes. -Pheno barb still used a little GABA A receptor of CL- ION |
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Benzodiazepines MOA Name some parts (2) Location of binding to GABA |
The ring to the right is the "core" -Ring at the bottom is Phenyl ring
Barbs MOA causes Cl- pore to stay open once GABA binds to the receptor- Positive allosteric Modulator.
MOA - enhances receptor affinity for GABA. It increases number of Cl- channel openings.
BINDS to GABA between Alpha and Beta subunits
Potency depend on how tightly it binds, and that depends on LIPOPHILLICITY AND METABOLISIM |
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1. Lipophilicity determines what in benzodiazapines ?
2. Metabolisim determines what in benzodiazipines?
What is the difference between hypnotics and sedatives?
CAVEAT - explain |
1. it determines the onset of action and CNS penetration 2.determines duration of action and potential for "benzo-hangover"
3. Hypnotics causes drowsiness and ENCOURAGES sleep 4. Sedatives calm you without effecting motor or mental function
but depending on dose, all of them have an effect on both hypnotic and sedation. |
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What do you want from a GOOD benzo as a hypnotic? |
You want: -max effect -fast cns levels -rapid absorbtion / high lipophilicity *** The metabolism rate must reduce active metabolite of drug by morning so don't get hangover effect. |
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What do you want from a GOOD benzo as a Anxiolytic? |
DOnt want it TO strong because WE DONT WANT TO SLEEP - Intermediate effect -long Duration of action because we just want to dose once We can achieve this intermediate level by having slower metabolism or active metabolites. -SLOW ABSORPTION -SLOW LIPOPHILICITY |
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Benzo users get tolerant and addicted quick. WHY?
how does a pt get off of this drug? |
-GABA desenitiztion (changes subunit makeup) -Reduction in GABA receptors (Receptor internilazation) -Changes in other neuronal systems (glutamate)
WEAN patients off drug
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What is this a picture off? |
This is a picture of how benzo should be binding to receptor. R part fits into receptor. The molecule prefers to be on its BACK mosts stable. There isn't a lot of room for substituents. |
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What are specific parts that bind in receptor ? |
-aromatic staking -H bond with threonine far right -lipophilic binding far right -pi staking with histidine the far left (N-H ring)
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In detail : |
1- position can't have big groups on it 2-4 position hydrogen bond acceptor required. 2-Electron withdrawing groups. NO sub at 4 3-position no substitution here except OH. THE S ENANTIOMER is potent. Add things to this peri planar ring you encourage twisting. 7/- lipophilic electron withdrawing groups to enhance potency
NO SUBSTITUTION AT 6/8/9
placing an OH here modifies ADME properties like rate of elimination
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Substituent (R) in the bezodiazepine is in what position ? What about the H?
And what does this help it achieve? |
Equitorial/ pointing down H is pointing up. Itr helps it achieve better binding with protein. ( look to far right) |
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difference between class A and class B benzodiazapines is ... |
Class A has 3 rings class B has that 4th ring. That 4th ring is electron rich and is a H-bond accepting ring. CLASS B has better affinity for the bzr receptor. |
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Benzodiazapiene class B.
-Which part can't tolerate a lot of carbons? -Which part behaves like carbonyl on class A? When do you loose activity? -antagonist or partial agonist promotes what? - |
-The R2 can only tolerate small groups -This ring mimics carbonyl on class A (Ring with all the N and Ys). -you loose activity -promotes convulsions |
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pick which ones are class B
Triazolam |
Estazolam and Triazolam
- triazolam has a short half life and lack of active metabolites so its good for acute insomnia jet lag . no active metabolites. not on market tho
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Metabolism of hypnotic benzodiazipines.
Short half life puts pt at risk for?
Long half life puts pt at risk for?
what should be taken into consideration? |
short= loss in sleep maintenance and tolerance long= residual effects (sedative "hangover")
must consider metabolism when used in elderly patients with reduced liver function and reduce the dose. |
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what are two enzymes used for metabolize ? what does each respective enzyme do in Flurazepam / Quazepam and Temazepam/?
class B |
CYP 3A4 and 2C9.
in Flurazepam, 3A4 knocks off -OH and gluccoronidates it to be inactive. This takes a while and causes the "hangover" LONG Metablite
2C9 and 3A4 is Quazepam knocks off Sulfer and oxidizes it to weakly active.
Temazepam gets glucoronidated to become inactive.
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Metabolisim of Estazolam by 3A4 leads to an
Triazolam inactivates via 3A4 by
class B |
- add OH then inactivates it with monster glucoronidation.
- 3A4 adds OH to N structure ring on top (pentamer) then inactivates it with glucoranoidation |
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what do we target in order to reduce side effects of benzos?
What was first targeted benzo drug and what was it for? |
Receptors.
type 1 receptors are (a1B2y2) they mediate hypnotic,amnestic and seizure. (sleep deep sleep and shaking.
Type 2 is (A2B2Y2) and targets anxiety and muscle relaxation. Want more type 1.
Quest to reduce muscle relaxation led to type 1 SELECTIVE drugs. -Quazepam |
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While looking for type 1 selective benzo antagonists they found the ___ drug. -Name them -Are they the same as benzos? how do they work? |
1. z drug. 2. Z drugs 3. .zolpedem .Escopliclone .Zaleplon 4. They are structurally different but bind benzo binding site and binds in different direction/ partial sharing of sites .
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this be |
Quazepam - Z drug |
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this be - what type of drug |
Zaleplon - Z drug |
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Eszopliclone - Z drug |
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Name 3 things about the binding |
At H1 they share intermediate region of binding.
There are three lipophillic regions for binding
2 hydrogen binding effects
Zolpidem uses only 2 of the hydrogen binding regions. |
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For Z drugs
The IC 50 is for
Elimination half life, what do we want for hypnotics?
which has the longest ? and why? |
Affinity. Lower the number the better.
We want a longer elimination half life so it maintains sleep. ONLY Eszoploclone keeps em inna da zone. It has no active metabolites
Best for chronic insomnia |
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Z drugs are also NOn- Benzodiazipine GABAa Agnoists
Why bother ? Whats the warning ? |
less tolerance and dependence -lesss morning hang overs -less rebound insomnia following withdrawls
caution with elderly |
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Z drug major metabolic pathways |
Zolpidem CYP3A4--> adds OH then alcohol dehydrogenase makes carbonyl C=0 or co2h
Zaleplon uses aldehyde oxidase. adds a C=O
Eszoploclone --> uses cyp 3A4 to ADD a ch3 and CYP 1A2 |
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this barb be |
thiopental |
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this barb be |
secobarbital |
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this barb be |
Pento barbital |
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this barb be |
pheno barbital |
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Melatonin works at? How many? |
A hormone thats normally secreted at night. -sleep circadian -made in pineal gland -it is a positive allosteric modulator of GABAa at HIGH concentrations. prob doesn't naturally work at sleep induction. works on 3 receptors
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Melatonin receptors are?
which receptor is preferred ? |
MT1 MT2 MT3.
MT1 and MT2 both have high affinity and are G-coupled receptors.
MT3 has low affinity / binding site on an enzyme (oxio-reductase) - its role in the body are unknown.
MT3 is preferred |
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Melatonin is a sedative or hypnotic ? |
its a hypnotic it induces sleep like the H1 antagonist.
Need high doses for efficacy. High doses can causes side effects. Works less on elderly because you loose receptors.
SE: changes in sleep wake cycle |
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How do we improve that great M1 melatonin receptor? |
We use homology with rhodopsin to design new drugs with improved bioavaialabity and selectivity for MT1.
we want to target sleep induction not disrupt circadian rhythm |
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More room around MT1 binding site than MT2 |
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This is -whats great about it |
Rosarem. It does not have that double bond. ITS MORE SELECTIVE FOR MT1. -orally absorbed gets into brain less SE -gets metabolized extensivly -does not effect sleep maintenance -can interact with enzyme inhibitors
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Metabolic fate of Ramelteon |
-CYP 1A2 makes it active metabolite then inactive The concentrated active metabolite is 20-100 xs higher than ramelteon the drug but less potent. -CYP 3A4 makes makes it inactive inactive. |
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Antihistamines are: |
used as OTC sleep aid except Hydroxyzine. pre anesthetic treats insomnia induced by anxiety. Donoxepin is an anti depressant by virtue of being able to inhibit serotonin reuptake inhibitor and NE a little
H1 antagonist
Lipophilic
causes drowsiness |
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this is |
antihistamine diphendraminine |
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this is |
antihistamine doxylamine |
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This is |
antihistamine thats hydroxyzine (RX ONLY) |
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This is |
Unknown mech Glutethimide . Produces heroine euphoria like . |
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this is |
Methyprylon |
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this is |
antihistamine methqualone also known as quaalude. |
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Drugs of unknown Mech over view |
all have been withdrawn from the market . Some of effects are GABAa like. of course unknown mech drugs still cause tolerance and dependance. |
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Anxiety disorder is a |
COLLECTION of disorders not just one |
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For Benzodiazapines that treat anxiety what do you want? -how do you get this? |
we don't want a sudden rush of it to your brain that will put you to sleep (hypnotic). you want a controlled release so you get sedation. -want long duration of action so you can use it once a day. ----- Get by doing (opposite of hypnotics) THEY ARE MORE POLAR ALSOwhich slows absorption and penetration into cns -slower absorption -lower lipophillicty -slower metabolism or active metabolites |
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Common anxiolytics |
Oxazepam . |
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Alpazolam |
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The log P smaller in Anxio why is in important in Anxiolytics compared to hypnotics why |
because it determines how the drug will work. we don't want anxiolytics to go into the brain fast. With lower log Ps they go in slow we. In Oxazepam the missing methyl group doesn't lowers the log P
- In Alprazolam (xanax) the log P is lowered by taking the Cl- off. |
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We want anxiolytic benzodiazepines to be metabolized faster or slower? Which one is known having active metabolites which increases the half life and DOA |
SLOWER. Chlordiazepoxide has a lot of metabolites so it has a longer half life. Its A pro drug so its metabolites are active and working
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This anxiolytic benzo is |
Lorazepam (atavan) |
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This anzio benzo |
Flurazepam its metabolite is |
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This anxio benzo is |
Alprazolam its acetic metabolite is |
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Serotonin and anxiety
what are successful anxiolytics |
Its related because when there isn't enough serotenergic tone. There is less tone in the 5-HT receptors.
how to fix? Increase 5HT activity. , 5-HT1A partial agonists and 5-HT reuptake inhibitors SSRI.
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Serotonin in general |
- There are 11 known 5-HT receptors. -All are GPCR except 5HT3 receptor. INHIBITORY !! |
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If we target the presynaptic 5HT1A receptor we are targeting the
If we target the postsynaptric auto receptor we are targeting the
what do you avoid |
-autoreceptor -inhibitory receptor
*need to balance partial agonism. Avoid 5HT1 agonisim cause cvd effects and serotonin syndrome** We want to avoid stimulating pre synaptic and focus on post synaptic recptor stimulation. |
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Buspirone is part of |
a member of a general class of 5HT modulators called ARYLPIPERZINES |
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5-HT1A partial agonist - |
Buspirone. Has a spirono group!! Which has a H bond donor. The H bond acceptor on binding site interacts here. This is lipophilic binding region -the 4c spacer here GUARAENTES agonist activity. serrotonin binding site -The arylpiperzine ring mimics the natural NT. The two basic amines over lap with each other. - |
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Aryl ring geometry . Agonost vs antagonist |
-If the compound is planar without substituents it has agonist activity. The nitrogen lone pairs promote this. -Having the aryl rings perpendicular to nitrogen lone pair promotes ANTAGONIST activity . NO LONGER PLANAR WITH SUBSTITENTS IT TWISTS
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this be |
Buspirone 5HT1A partial agonist -no gabanergic side effects -has anti-dopaminergic actvity -used for mild anxiety -less risk of tolerance -not a successful because ppl were like I CANT FEEL IT WORKING" |
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Inhibitors at 5-HT- |
prevent reuptake of serrotonin -Depressed anxious pts
In the short term, the inhibitor prevents the re-uptake of 5-HT into the neuron which increases the amount of 5HT.
In the long term, the inhibitor of 5HT down regulates the 5HT NT |
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Anxiolytics as SSRI |
Need to enhance the 5HT activity. anxiolytic activity form drug may involve another MOA |
