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MED.CHEM EXAM IV PACKET 3

Sedatives, Hypnotics, and Anxiolytics
STUDY
PLAY
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