MED.CHEM EXAM IV PACKET 3

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88 terms · Sedatives, Hypnotics, and Anxiolytics

Therapeutic effect of Sedative Drugs?

Sedatives induce calm, without producing sleep

Therapeutic effects of hypnotic drugs?

Hypnotics induce sleep

What are Anxiolytic Drugs used for?

are used to treat symptoms of anxiety

define anxiety

anxiety is an unpleasent state of tension, apprehension, or uneasiness that seems to arise from an unknown source.

Symptoms of anxiety is said to be similar to those of what?

fear

Muscle relaxants are also known as?

-Neuromuscular blocking drugs
-Spasmolytics

What are Muscle relaxants drugs?

muscle relaxants are drugs which affect skeletal muscle function and decrease muscle tone.

What are your anticonvulsant?

Diverse group of pharmaceutical used in treatment of epileptic seizures. Anticonvulsants are also increasingly being used in treatment of bipolar disorder.

Why are anticonvulsants used to treat bipolar disorders?

anticonvulsants used to treat bipolar disorders because they act as mood stabilizers

What are anesthetics?

Anesthetics are drugs that cause anesthesia

What is anesthesia?

Reversible loss of sensation.

What's the difference between the older Sedatives, Hypnotics, and Anxiolytics as compared to the newer ones

To get to a level of anesthesia with the older drugs you risked death but with newer ones you can increase the dose and never get too deep of an anesthetic effect that may risk coma or death.

What are the two classes for Sedative-Hypnotic Drugs?

1. Barbiturates
2. Non-Barbiturates

Non=barbiturates class can be broken down into 5 more categories what are they

1. Aldehydes and aldehyde derivatives
2. Piperidine derivatives
3. Quinazoline derivatives
4. Alcohols and their carbamate derivatives
5. Benzodiazepine derivatives

studies show that, the neuronal effects associated with anxiolytics, sedatives, and hypnotics effects, especially positive modulation of GABAa receptors also relate to what other effects?

anticonvulsant effects

What are the GABA receptors?

A class of receptors that respond to the neurotransmitter GABA

what is GABA?

GABA is a neurotransmittor also known as y-aminobutyric acid and is the cheif inhibitory of the CNS

What are the two classes of GABA

GABAa and GABAb

which class of GABA receptors are ligand gated chloride ion-channels

GABAa

which class of GABA receptors are protein-coupled receptors?

GABAb

6 locations in the brain where you can find GABA receptors

1. cerebral cortex
2. hippocampus
3. basal ganglia
4. thalamus
5. cerebellum
6. brainstem

most of the GABAa receptors consist of what comboniation of subunits? which are most common?

Alpha, Beta, and Gamma
most common will be alpha-1, beta-2, gamma-2

the active site of GABAa receptors are also the binding site of what three common drugs?

-Gaboxadol
-Bicuculline
-Muscimol

This drug is a selective agoniist of the GABAa receptor, major psychoalkaloid present in many mushrooms

Muscimol

This drug is an experimental sleep aid drug

Gaboxadol

This drug is light-sensitive competitive antagonist of GABAa receptors.

Bicuculline

This drug blocks the action the inhibitiory action of GABAa receptors

bicuculline

the action bicuculline mimics what condition?

epilepsy

this drug acts like a non-competitive antagonists for the GABAa receptor chloride ion channels

Picrotoxin

Picrotoxin is a channel blocker or a recptor antagonist?

channel blocker

infusion of picrotoxin has what type of effects?

1. stimulant
2. convulsant.

the binding sites of GABAa receptor are also called?

Allosteric binding sites

What are barbiturates?

CNS depressants

What effects do barbiturates produce? and what exactly are they used for?

Barbiturates produce a wide spectrum of effects from mild sedative to coma. Barbiturates are used as sedatives, hypnotics, anesthetics, and anticonvulsants

Whats the issue with barbiturates?

they can e addictive and abused. Excessive use of barbiturates can caused depression, slurred speech, slowed reflexes and confusion.

bariturates can undergo what type of tautomerism?

keto-enol tautomerism

What's the benefits of Keto-enol tautomerism of barbituric

it allows the formation of water-soluble salts with a strong base since barbiturates are not readily dissolved in water

What two compounds help maintain the pH of barbiturates between 10 and 11?

Na2CO3 & CO2

barbiturates should not be placed in acidic solutions or mixed with acidic solutions why?

because the barbiturates may percipatate as free acids

Barbiturates binds where to exer their characterstic CNS effects?

allosteric binding sites on GABAa receptors

Whats the effect of having barbiturates bind to allosteric binding site GABAa receptors?

1. they can positively modulate the effects of the GABAa - GABA combinations

2. Can increase chloride ion influx by without GABA attaching to its receptor site on GABAa

What is the term associated with the effects barbiturates produce after binding to GABA receptors?

GABA mimetic effects

Barbiturates also block what receptors besides GABA?

AMPA

what is the principal excitatory neurotransmitter in the mammalian CNS?

Glutamate

what is AMPA receptor? where is its name derived from?

alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor -

is a non-NMD-type ionotropic transmembrane receptor for glutamate.

name derived from its ability to be activated by the artificial glutamte analog AMPA

SAR of barbiturate: Hypnotic activity

-side chains at position 5
-both hydrogens at position 5 must be replaced

SAR of barbiturate: Potency and DOA

Length of the side chain at position 5 influences potency and DOA. the bigger the side chain the more potent.

SAR of barbiturate: rapid onset /shorter DOA

sulfur instead of oxygen at position 2 has has more rapid onset of action but shorter DOA

SAR of barbiturate: increase in potency, rate of onset, and short action

-increase in lipophilicity
-branched/cyclic/unsaturated side chain will decrease DOA

reviewing the hypnotic activity of barbiturates what if we failed to replace one of the hydrogen at position 5 of the barbiturate?

the barbiturate may succeptible to tautomerization to a highly acidic compound triihydroxypyrimidine

reviewing the SAR of barbiturates what simple factor will cause the barbiturate to become more hydrophilic?

by adding the polar groups to the alkyl sidechain at position 5 on the barbiturate structure

SAR of barbiturate: substitution on nitrogen

-substitution of one of the hydrogens on the imidie in the barbiturate by alkyl groups increases lipid solubility.

-as the size of the N-alkyl group increases so does lipophilicity

reviewing the SAR of barbituates and the effects that can be produced after substituting one the hydrogens on the imide what can impart convulsant like properties to the barbituate?

-The attachment of large alkyl groups

SAR of barbiturate: moodifications what position(s) are of primary importance in the barbituates used as anticonvulsants and anesthetics?

N1 and N3

What are 4 classes to classify barbituates?

1. Ultra-short
2. Short-acting barbituates
3. intermediate acting barbituates
4. long-acting barbituates

what class of barbituates produce anesthesia within 1min after IV administration

ultra short acting barbituates

what class of barbituates produce action with half-hr and last about 4hrs

short-acting barbituates

what class of barbituates produce action within half-hr and lasts for about 6hrs

intermediate acting barbituates

what class of barbituates produce action within half-hr and lasts for 8hrs

long acting barbituates

what class of barbituates are used for daytime sedation and the treatment of seizure disorders and mild anxiety

long acting barbituates

name the three important long acting barbituate drugs

1. barbital
2. phenobarbital
3. mephobarbital

which of the three important long acting barbituate drugs is unique due to its low lipid/water partition coefficient?

barbital

which of the three important long acting barbituate drugs is a long-actig sedative and hypnotic but also a valuble anticonvulsant?

phenobarbital

which of the three important long acting barbituate drugs is used primarily for anticonvulsants and is considered a N-dealkylated phenobarbital?

mephobarbital

which class of barbituates are used primarily as sedative-hypnotics

Intermediate Duration of Action

the two barbituate drugs you must remember for intermediate DOA

1. amobarbital
2. butabarbital

the barbituates that have substituents in the 5 position proomoting more rapid metabolsim than the intermediate barbituates are known as

barbituates with a sort duration of action

the two important barbituate drugs with a sort duration of action are?

-secobarbital
-pentobarbital

one of the most active non-barbituate hypnotics that structurally stucturally similar and has the same toxic effects as barbituates.

-Glutethimide (Doriden)

Alcohols can also be used as a sedative and hypnotic. The order of potency of the alchols is the same as...

marchovnikof rule:
3>2>1

what happens when you replace the hydrogen atom in the alkyl group with an halogen of alcohols with barbituate activitiy

will increase potency

carbabmylation of alcohols generally produce what effect

generally increases the depressants potency

what is the Ethchlorvynol (Placidyl) ?

mild sedative-hypnotic with quick onset and short DOA

whats the Generic and brand of the drug that's officialy indicated as an antianxiety agent and also a sedative-hypnotic agent?

meprobamate

benzodiazepines binds to the interface of what subunits of the GABAa receptor ?

alpha and gamma subunits

which subunits are required for sedative and hypnotic effects and anticonvulsant effects of benzodiazepines?

alpha-1 subunits

which subunits are required for anxiolytic effects of benzodiazepines?

alpha-2 subunits

which subunits are involved in other miscellaneous actions of benzodiazepines?

alpha-3 and alpha-5

which subunit is required for most positive allosteric effects?

gamma-2 subunit

most classical benzodiazepines are what type of modulators?

positve modulators

whats another name for the benzodiazepine recognition site?

allosteric site

what are known to be negative modulators at benzodiazepine modulatory site?

beta carbolines

antagonist, zero modulators, and neutralizing allosteric modulators are all defined as

compounds that can occupy benzodiazepine modulatory sites and have no effect on chloride flux themselves and can block positve as well as negative modulators.

SAR of Benzodiazepines: what is required for activity that may participate in pi-pi stacking with amino acid residues on the receptor

Aromatic or heteroaroomatic ring

SAR of Benzodiazepines: what is required for general activity and how can you increase the activity of benzodiazepines

-an electornegative substituent at position 7 is required for general activity
- position 6 8 9 must be vacant
-the more electronegative the substituent is at position 7 the higher the activity

SAR of Benzodiazepines: phenyl ring at position 5 promotes activity but how can u increase this activity?

if this pheny roup is positioned ortho (2) or diortho (2,6) substituted with EWG activity is increased.

SAR of Benzodiazepines: what is the importance of 2-carbonyl function and the nitrogen atom at positon 1

important for benzodiazepine activity

5 therapeutic uses of benzodiazepines

Panic disorders
Generalized anxiety disorders
insomnia
seizures
alcohol withdrawl

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