Central Nervous System Drugs - Detailed Notesشكرا

CNS Depressants

• Drugs that act on the central nervous system to cause a depressive or inhibitory effect.

• Categories:

  • Sedative-hypnotics, Anxiolytics

  • Antipsychotics

  • Anticonvulsants

  • Central muscle relaxants

Central Nervous System (CNS)

• Largest part of the nervous system.

• Includes the brain and spinal cord.

• Fundamental role in controlling behavior, along with the peripheral nervous system.

Immediate Effects of Depressants

• Euphoria.

• Muscle relaxation.

• Drowsiness.

• Loss of motor control.

• Impaired judgment.

Long-Term Physiological Effects of Depressants

• Respiratory and circulation depression.

• Hangover.

• Coma.

• Seizures.

• Death.

Long-Term Psychological Effects of Depressant Use

• Depression.

• Paranoia.

• Hallucinations.

• Delusions.

Sedative-Hypnotic and Anxiolytic Drugs

• Also known as minor tranquilizers.

• Focus areas for study:

  • Drug name and structure.

  • Chemical synthesis.

  • Structure-activity relationship (SAR).

  • Use and metabolism.

Ideal Anxiolytic

• Calms the patient without excessive daytime sedation or drowsiness.

• Does not produce dependence.

Ideal Hypnotic

• Helps the patient fall asleep quickly.

• Maintains sleep of sufficient quality and duration.

• Allows the patient to wake up refreshed without a “hangover” effect.

Definitions

• Anxiolytics: Drugs for treating anxiety symptoms, e.g., benzodiazepines.

• Sedatives: Drugs that cause calmness, relaxation, and anxiety reduction without inducing sleep. Referred to as tranquilizers, depressants, or downers; includes barbiturates, benzodiazepines, and zolpidem.

• Hypnotics: Drugs that induce sleep, used for severe insomnia; includes barbiturates, benzodiazepines, and zolpidem.

Pharmacokinetic Profile of Sedatives and Hypnotics

• Generally nonionized at physiological pH with high lipophilicity.

  • More lipophilic compounds distribute more readily to the brain and are well-absorbed from the GI tract, leading to rapid CNS effects (e.g., triazolam, thiopental).

  • Polar compounds absorb more slowly.

• Many cross the placental barrier and are detectable in breast milk.

• Highly lipophilic drugs may have a short duration of action.

• Most are highly protein-bound; greater lipophilicity means greater binding.

• Metabolism to water-soluble metabolites is necessary for clearance.

Mechanism of Action

• Ligand-gated ion channels:

  • Transmembrane ion channels opened by chemical messenger binding.

  • Regulated by neurotransmitter ligands.

  • Selective to ions like $Na^+, K^+, Ca^{2+}, Cl^-$.

  • Examples: GABA, acetylcholine, glycine, and serotonin receptors.

GABA Site

• GABA Site:

  • Agonists

  • Antagonists

• Barbiturate site:

  • Depressants (also ethanol?)

  • Excitants?

• Benzodiazepine site:

  • Agonists (depressants)

  • Antagonists

  • Inverse agonists

• Steroid site:

  • Anesthetics

  • Excitants?

• Picrotoxin site:

  • Convulsants

• Chloride channel:

  • Depressants?

GABAA Site Action

• Binding to GABAA receptors facilitates GABA-induced neurotransmission.

• Channel opens, allowing influx of $Cl^-$ ions, causing hyperpolarization.

• This mechanism is responsible for the sedative-hypnotic and anesthetic effects of barbiturates, benzodiazepines, anesthetics, and other “depressants.”

GABA Agonists

• Benzodiazepines increase pore opening frequency.

• Barbiturates increase pore opening duration.

Benzodiazepines

• Introduced in the 1960s.

• Still widely used (1 in 5 prescriptions).

• Properties: anxiolytic, sedative, anticonvulsant, relaxant.

Effects of Benzodiazepines

• Safer than barbiturates.

• Much less respiratory depression.

• Large doses rarely fatal (except with alcohol).

• CNS toxicity in chronic use/high doses.

Mechanism of Action of Benzodiazepines

• Increase affinity of GABA for GABAA receptors.

• Increase the frequency of $Cl^-$ channel opening, leading to hyperpolarization and postsynaptic inhibition, decreasing transmission.

Adverse Effects of Benzodiazepines

• CNS depression, tolerance.

• Blurring of vision.

• Hallucinations.

• Additive effects with other depressants.

• Overdose treatment: Flumazenil.

General Structure and SAR of Benzodiazepines

• 1-NR group is optimal for activity.

• Effects of Ring A:

  • Aromatic ring > heteroaromatic ring.

  • 7-EWG (electron-withdrawing group) required; ↑ electronegativity → ↑ activity.

  • H-accepting group ↑ activity.

• 2-C=O group is important for activity.

• 1,2-fused triazole or imidazole ring ↑ activity.

• Substitution with a 3-OH group ↑ activity.

  • With 3-OH group: polar, readily converted to the excreted glucuronide.

  • Without 3-OH group: nonpolar, undergo hepatic oxidation & active metabolite.

• 5-phenyl group ↑ activity.

• 2' or 2', 6' substituted with EWG activity.

• 4' substitution decreases activity.

SAR Details

• Aromatic or heteroaromatic ring A is required, participates in $π-π$ stacking with aromatic amino acid residues of the receptor.

• Electronegative substituent at position 7 is required; higher electronegativity increases activity.

• Positions 6, 8, and 9 should not be substituted.

• Phenyl ring C at position 5 promotes activity; ortho or di-ortho substitution with electron-withdrawing groups increases activity, while para substitution decreases activity.

• Saturation of the 4,5-double bond in diazepine ring B or shifting it to the 3,4-position decreases activity.

• Alkyl substitution at the 3-position decreases activity; substitution with a 3-hydroxyl does not.

• The 2-carbonyl function is important, as is the nitrogen atom at position 1.

• N1-alkyl side chains are tolerated.

• A proton-accepting group at C2 is required, may interact with histidine residue in the benzodiazepine binding site of the GABAA receptor; triazole or imidazole rings fused on positions 1 and 2 increase activity.

• Compounds with a fused triazolo ring (e.g., triazolam and alprazolam) or imidazolo ring (e.g., midazolam) are short-acting due to rapid metabolism by α-hydroxylation of the methyl substituent, followed by glucuronidation. Also metabolized by 3-hydroxylation of the benzodiazepine ring.

Chlordiazepoxide (Librium)

• First benzodiazepine synthesized.

• 7-chloro-2-(methylamino)-5-phenyl-3H-1,4-benzodiazepine 4-oxide monohydrochloride.

Synthesis of Chlordiazepoxide

• 4-chloroaniline + benzoyl chloride → intermediate product of complex structure

• Key intermediate for preparation of all benzodiazepines

• Treatment of 2 chloro methyl, 4 phenyl 6 chloro quinazoline, 3 oxide with methyl amine produced benzodiazepine (chlorodiazepoxide).

SAR of Chlordiazepoxide

• Treatment of 2-chloro methyl, 4 phenyl 6 chloro quinazoline, 3 oxide with methyl amine, unexpected ring enlargement produced benzodiazepine (chlorodiazepoxide).

• Used for relief of anxiety, tension, and related neurosis, agitations during alcohol withdrawal.

• N-O was found not essential for activity.

• N-demethylation produces demoxepam as a major metabolite, which is converted to nordazepam, and then to oxazepam.

Diazepam (Valium)

• 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one.

• Log P = 3.86, t1/2 = ~46 h

• Long-acting, Protein binding = 99%

Synthesis of Diazepam

• Starting from 4-Chloroaniline and Benzoyl chloride.

• Friedel-Crafts acylation.

• Reaction and cyclization to form Diazepam.

Properties of Diazepam

• Prototypical and first member of the benzodiazepine-2-one group.

• Very lipophilic, rapidly and completely absorbed after oral administration.

• Maximum peak blood concentration occurs in 2 hours, elimination is slow with a half-life of about 46 hours.

• Used for anxiety states, anticonvulsant, premedication in anesthesiology, and in various spastic disorders.

Hydrolysis of Diazepam

• At 37°C and acidic conditions, the imine bond is hydrolyzed.

• At neutral pH or basic condition, it is rapidly cyclized.

• Under the interaction of gastric acid, ring opens between site 4 and 5.

• When the compound gets into the basic atmosphere of small intestinal, it is cyclized again.

• The ring opening does not affect its bioavailablity.

Prazepam (Verstran)

• 7-chloro-1-(cyclopropylmethyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one.

• Long overall half-life.

• Extensive N-dealkylation occurs to yield active nordazepam, 3-Hydroxylation of both prazepam and nordazepam occurs.

Halazepam (Paxipam)

• 7-chloro-1,3-dihydro-5-phenyl-1(trifluoroethyl)-3H-1,4-benzodiazepine-2-one.

• Active and present in plasma, activity is caused by major active metabolites nordazepam and oxazepam.

Clorazepate Dipotassium (Tranxene)

• 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid dipotassium salt monohydrate.

• Prodrug; inactive itself, undergoes rapid decarboxylation in the stomach to nordazepam, which has a long half-life and converts to active oxazepam.

Synthesis of Clorazepate Dipotassium

• Synthesized starting from 2-amino-5-chlorobenzonitrile, which upon reaction with phenylmagnesium bromide is transformed into 2-amino-5-chlorbenzophenone imine.

Oxazepam (Serax)

• 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazpin-2-one.

• Active metabolite of chlordiazepoxide and diazepam, prototype for 3-hydroxy benzodiazepines.

• More polar than diazepam; rapidly inactivated to glucuronidated metabolites excreted in the urine; half-life of 4 to 8 hours.

• Marketed as a short-acting anxiolytic; less cumulative effects with chronic therapy.

Lorazepam (Ativan)

• 7-chloro-5-(2-chlorophenyl)-3-dihydro-3-hydroxy-2H-1,4benzodiazepine-2-one.

• 2'-chloro derivative of oxazepam; the 2'-chloro substituent increases activity.

• Metabolism is relatively rapid and uncomplicated due to the 3-hydroxyl group; short half-life (2–6 hours).

Flurazepam Hydrochloride (Dalmane)

• 7-chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one dihydrochloride.

• Extensive metabolism of the dialkylaminoalkyl side chain.

• Major metabolite is N1-dealkyl flurazepam, which has a very long half-life, producing cumulative clinical and side effects even after discontinuation.

Flurazepam Synthesis

• Multistep synthesis starting from (2-amino-5-chlorophenyl)(2-fluorophenyl)methanone.

Triazolo Benzodiazepines

• The triazo moiety increases the drug’s binding affinity and stability, greatly increasing potency.

Alprazolam (Xanax)

• 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

• Rapidly absorbed from the GI tract; protein binding is lower (70%).

• Hydroxylation of the methyl group followed by conjugation is rapid, resulting in a short duration of action. Hydroxylation of the methyl group to the methyl alcohol followed by conjugation is rapid.

Triazolam (Halcion)

• 8-chloro-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

• Ultra–short-acting hypnotic; rapidly hydroxylated to the 1-methyl alcohol, which is then rapidly conjugated and excreted.

• Gained popularity as sleep inducers, especially in elderly patients.

• Coadministration with grapefruit juice increases its peak plasma concentration by 30%, leading to increased drowsiness.

Biotransformation of Benzodiazepines

• Complex metabolic pathways involving desmethylation, hydroxylation, and conjugation.

• Metabolites can be active or inactive, affecting the duration of action.

Metabolism of Benzodiazepines

• Multiple pathways including N-demethylation, hydroxylation, and glucuronidation.

• Differing half-lives of parent drugs and metabolites contribute to varying durations of action.

Barbiturates

• CNS depressants producing a wide spectrum of effects from mild sedation to anesthesia.

• Some used as anticonvulsants; GABA agonists acting on the GABAA receptor.

• Derivatives of barbituric acid.

SAR of Barbiturates

1. For optimal activity at carbon 5, the sum of carbon atoms of both substituents should be between 6 & 10.

2. Within the same series, the branched series has greater activity and shorter duration.

3. Within the same series the unsaturated allyl, alkenyl have greater potency than the saturated analuoges.

4. Aromatic substituents impart greater activity than the aliphatic analuoges.

5. Introduction of a halogen atom into the 5- alkyl substituents increases potency.

6. Introduction of a polar group into the 5 alkyl subsituent destroys potency.

7. Replacement of sulfur for the carbonyl oxygen results in thiobarbiturates with quick onset & short duration.

8. Introduction of more sulfur atoms ( 2,4 dithio ) decreases potency.

9. $R<em>2=CH</em>3$ =Fast action

Tautomeric Forms of Barbituric Acid

Metabolism of Barbiturates

• Takes place mainly in the liver.

• Lipophilic character decreases with corresponding loss of depressant activity.

  1. Oxidation of substituents at carbon 5 results in alcohols, phenols, ketones which because of their hydrophilic character are insoluble in all lipids.

  2. Cleavage of the barituric ring leads to formation of acetamide and acetylurea derivatives ( lipophobic )

  3. Desulfuration of 2- thiobarbiturates takes place readily to yield the more hydrophilic barbiturates

  4. Dealkylation at the nitrogen decreases lipophilic character.

Classification of Barbiturates

• According to duration of action:

  • Long-term

  • Mid-term

  • Short-term

  • Super short-term

Long-Term Relief Barbiturates

• Barbital

• Phenobarbital

Mid-Term Relief Barbiturates

• Amobarbital

• Cyclobarbital

Short-Term Relief Barbiturates

• Secobarbital

• Pentobarbital

Super Short-Term Relief Barbiturates

• Hexobarbital

• Thiopental sodium

Chemical Synthesis of Amobarbital

• From Diethyl malonate

Metabolism of Amobarbital

• It metabolizes in the liver and it under goes C-Gluc conjugation.

Antiepileptic Drugs (Anticonvulsants)

• Used in prevention of epileptic seizures.

• Goal: suppress the rapid and excessive firing of neurons that start a seizure.

• Decrease the frequency and/or severity of seizures in people with epilepsy.

• Treat the symptom of seizures, not the underlying epileptic condition.

What are Seizures?

• Episodes of neurologic dysfunction arising from abnormal activity of neurons.

• Epilepsy: a disease characterized by spontaneous recurrent seizures.

• Affecting about 1% of the population.

Causes of Seizures

• Genetic.

• Congenital defects.

• Severe head trauma.

• Tumor.

• Drug abuse.

• Infection.

• Unknown.

Nerve Cell Communication

• Neurons communicate using neurotransmitters.

• Neurotransmitters modulate and regulate the electrical activity of a given neuron.

  • Glutamate = excitatory (tells the neuron to fire).

  • GABA = inhibitory (dampens the neuron firing rate).

• The action potential is an electrical signal that travels down the axon, created using sodium ions influx ($Na^+$), and inhibited by potassium ions efflux ($K^+$).

• When dysfunctional, abnormal electrical activity occurs, it can produce seizures.

Diagram of Nerve Cell Communication

• Illustrates neurotransmitters, receptor molecules, sodium and potassium ions/channels, and action potential.

Antiepileptic Members

• Overview of various antiepileptic drugs and their mechanisms of action.

Excitatory and Inhibitory Synapses

• Detailed diagram of excitatory and inhibitory synapses showing different drugs and their mechanisms of action (e.g., lacosamide, gabapentin, pregabalin, phenytoin, carbamazepine, oxcarbazepine, lamotrigine, vigabatrin, levetiracetam, perampanel, valproate, topiramate, ethosuximide, benzodiazepines, phenobarbital).

Mechanisms of Action of Anticonvulsants

1. Modulation of voltage-gated ion channels ($Na, Ca, K$).
   *Inhibition of voltage-gated $Na^+$ channels to slow neuron firing (phyentoin-carbamazepine)
   *Inhibition of T-type $Ca^{2+}$ Channel (Oxazolidinediones, ethosuximide)

2. Enhancement of -aminobutyric acid (GABA)-mediated inhibitory neurotransmission: barbiturate

3. Attenuation of excitatory (particularly glutamate-mediated) neurotransmission in the brain.

Barbiturates as Anticonvulsants

• Commonly display anticonvulsant properties.

• Phenobarbital and mephobarbital display adequate anticonvulsant selectivity for use as antiepileptic.

• Mechanism of anticonvulsant action: Decrease electrical excitability at the site or at adjacent of recruited neurons.

• Enhancement of GABA transmission.

Hydantoins

• Cyclic monoacylureas, all the clinically useful compounds posses an aryl substituents on the 5- position.

Oxazolidinediones

• Dermatological and hematologic toxicities limit their use although paradione is safer , its N – demethyl metabolite is excreted rather slowly.

Succinimides

• Safer and more active than oxazolidinediones.

• Metabolism by demethylation then inactivation by p-hydroxylation and conjugation , for ethosuximide the metabolism by oxidation of the ethyl group .

• Examples: Phensuximide, Methsuximide, Ethosuximide.

Valproic Acid

• 2-propylpentanoic acid (Depakene).

• Has good potency, metabolism is through conjugation of the carboxylic acid and oxidation of one of the hydrocarbon chains.

• Prolongs $Na^+$ channel inactivation

• Inhibation of

• Facilitation of GABA action

Dantrolene Sodium (Dantrium)

• Decreases the release of calcium ion thereby blocks contractions of skeletal muscle.

• Acts peripherally.

• Its most common side effect is muscle weakness also hepatic toxicity.

Other Antiepileptic Drugs

• Carbamazepine: binds to voltage-gated sodium channels in their inactive conformation, preventing repetitive and sustained firing of an action potential.

• Lamotrigine: Belong to the phenyltriazine class selectively binds and inhibits voltage-gated sodium channels, stabilizing presynaptic neuronal membranes and inhibiting presynaptic glutamate release

• Topiramate: a sulfamate modified sugar Topiramate has frequency-dependent blockade of voltage-gated $Na^+$ channels, activation of a hyperpolarizing $K^+$ current, benzodiazepine-like potentiation of postsynaptic GABAA receptors, inhibition of the AMPA receptors of glutamate

SKELETAL MUSCLE RELAXANT

• Skeletal muscle relaxants are drugs that act peripherally at neuromuscular junction/ muscle fibre itself or centrally in the cerebrospinal axis to reduce muscle tone and/or cause paralysis.

• A muscle relaxants is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to improve symptoms such as muscle spasms, pain, and hyperreflexia.

Skeletal Muscle Relaxants members

1. 1- aryl glyceryl ether 1st derivative in this field: 3- (ortho toloxy) 1- 2 propane diol (Mephenezine).

2. * SAR of Mephenizine -Structural modification among the aryl moiety demonstrates that the benzene ring is not required for muscle relaxant properties.

3. Rapidly absorbed from the G I T.

4. Has very short duration of action (rapidly absorbed and rapidly degraded) due to metabolic oxidation of terminal alcoholic function into inactive carboxylic acid.

• Mephenezine undergoes hydroxylation at p position of the aromatic ring to the much less active hydroxyl – derivative (lipid solubility decreases , partition – coefficient decreases so the activity decreases)

Mephenizine and its Derivatives

• Carbamate ester has a longer duration of action as it is not absorbed quickly

• Chlorphenizine has a longer duration than the parent compound

• Chlorphenizine carbamate , has the longest duration of action.

• Methocarbamol : 3.[methoxy– phenoxy] 1-2 propane diol its main use is to relieve skeletal muscle spasms .

SAR of Meprobomate and Carisoprodol

• From the SAR benzene ring is not important for activity so it is replaced by aliphatic structure.

Other Muscle Relaxants

• Chloroxazone: 5-chloro-2-benzoxadinone : It is a centrally acting muscle relaxant. it inhibits multi synaptic reflex involved in producing and maintaining skeletal muscle spasms of varied etiology. Adverse reactions include drowsiness, dizziness and light headness.

• Orphenadrine( O-Methyldiphenhydramine ) Muscarinic antagonist with muscle relaxant properties