CNS Drugs: Synaptic Effects & Neurotransmission

Drugs Affecting the CNS

• Drugs mainly affect synapses, leading to selective effects via synaptic mechanisms.
• Effects in synapses include impulse overload and modulation which changes synaptic activity.

Importance of CNS Drugs

• They have specific physiological and psychological effects.
• General anesthesia makes surgery possible.
• Relieving pain, reducing fever, eliminating movement disorders, regulating sleep-wake, appetite suppression, and preventing vomiting are all effects.
• Used to treat anxiety, depression, mania, and schizophrenia without disrupting consciousness.
• There is widespread nonmedical self-administration, leading to uncontrolled use of anxiolytic and stimulant drugs.

Neurohumoral Transmission

• Communication between neurons is neurohumoral transmission.
• Communication tools include neurotransmitters, neuromodulators, and neurohormones, collectively known as neuromediators or neuroregulators.

Postsynaptic Membrane

• Neuromediators are removed via enzymatic degradation, re-uptake, and diffusion.

Neuromediators Chemical Structures

• Amine structured examples include Dopamine (DA), Noradrenaline (NA), Adrenaline (A), Serotonin (5-HT), Acetylcholine (ACh), and Histamine.
• AA structured examples include GABA, Glycine, and glutamic acid.
• Peptide structured examples include substance P and endogenous opioid peptides.

Amine-Structured Neuromediators

• Dopamine receptors are D1-5.
• Dopamine affects processes like anterior pituitary secretory function, stimulating prolactin secretion, and locomotor function.

Dopamine Overactivity and Deficiency

• Dopaminergic overactivity relates to schizophrenia and is treated with neuroleptic drugs, also known as antipsychotics.
• Decreased dopaminergic activity relates to Parkinson's disease, treated with antiparkinson drugs such as L-DOPA.

Noradrenaline

• Noradrenaline receptors are alpha and beta.
• Noradrenaline contributes to distraction, fear, and alarm states.
• It causes anxiety, panic reactions, tremor, and sympathetic hyperactivation in the periphery.
• It is hypoactive in cases of major depression.

Adrenaline

• It has a small number with roles in mood and behavior that are controversial.

Serotonin

• Serotonin receptors are 5-HT1 and 5-HT7.
• Serotonin impacts depression, schizophrenia, anxiety, panic disorders, feeding behavior, sleep physiology, and endocrine functions.

Serotonergic System

• Hypoactivity in depression is treated with selective serotonin re-uptake inhibitorsFluoxetine, paroxetine, and sertraline.
• Serotonin 5-HT1 receptor agonists have anxiolytic and antiaggressive effects.
• Excessive activity in schizophrenia is treated with atypical neuroleptics like Clozapine and risperidone, which antagonize 5-HT1C, 5-HT2, and 5-HT3 receptors.
• Sibutramine, a serotonin re-uptake inhibitor is used for obesity treatment.

Acetylcholine

• Acetylcholine receptors are muscarinic (M1-5) and nicotinic.
• It regulates posture, locomotor activity, learning, memory, and anteroposterior pituitary endocrine function.
• Alzheimer-type senile dementia is treated with acetylcholinesterase inhibitors like Donepezil and memantine.

AA Structure Neuromediators

• GABA is the main inhibitory neuromediator in the brain, acting on GABAA and GABAB receptors.
• Drugs that increase GABA activity are used as sedatives, anxiolytics, and anticonvulsants.

Glutamic Acid

• It is the major excitatory neuromediator.
• Released from nerve endings, glutaminergic affects NMDA (N-methyl-D-aspartate) receptors.
• It is important in epilepsy, increasing seizures in epileptics, and learning and memory, producing beneficial effects.

Peptide-Structured Neuromediators

• Endogenous opioid peptides such as endorphins act on Mü (μ), Delta (Δ), and kappa (δ) receptors.
• Functions include stress analgesia and spinal analgesia.

CNS Drugs mechanisms

• Many drugs act on the central nervous system by changing ion flow through nerve cell membrane channels.
• There are two types of ion channels in the nerve cell membrane, including Voltage-dependent and receptor-activated. EPSP, IPSP

Ion Flows

• Excitatory postsynaptic potential (EPSP) involves opening Na+ and Ca++ channels and closing K+ channels.
• Inhibitory postsynaptic potential (IPSP) is formed by opening K+ or Cl+ channels.

Neurotransmitter Release

• Action potential in presynaptic region activates N-type voltage-dependent Ca++ channels to allow release of neurotransmitters from vesicles.
• These channels are not blocked by some toxins.

Ion Channels

• Voltage-gated Na channels are blocked by Tetrodotoxin.
• Voltage-gated potassium channels are blocked by Apamin.
• Voltage-gated N-type Ca channels are blocked by Omega conotoxin.
• Nicotinic Ach receptors are blocked by α-bungaratoxin.
• GABAA receptors are blocked by Picrotoxin.
• Glycine receptors are blocked by Strychnine.

Synaptic Potentials

• Excitatory stimulus causes a small depolarization or excitatory postsynaptic potential (EPSP), activating ion channels and stimulating entry of sodium and potassium.
• Inhibitory stimulus opens Cl channels in the postsynaptic membrane causing hyperpolarization and an inhibitory postsynaptic potential (IPSP).

Drug Action

• Drugs can directly interact with ion channels to affect axon, synthesis, storage, secretion, reuptake, and metabolism of neurotransmitters.
• Drugs can activate or block receptors on presynaptic or postsynaptic membranes.
• They can block the influence of second messengers.

Hypnosedative Drugs

• They depress the CNS in a dose-dependent and wide-ranging manner.
• Doses can lead to drowsiness, sedation, hypnosis, anesthesia, or coma.
• Other effects include anxiolytic, anticonvulsant, and central muscle relaxant effects.
• Examples are Benzodiazepines (BDZ) and Barbiturates (BRBT).

Dosing for Hypnosedatives

• Dose of hypnosedatives determines sedation, sleep, general anesthesia, or coma.
• Sufficient doses induce sleep in normal people.
• They are not used as general anesthetics, except short-acting barbiturates and midazolam due to low security indexes.
• Acute poisoning causes respiratory depression, neurological and CV disorders, or coma,
• Benzodiazepines have a high therapeutic index, and at high doses, CNS depression is lower with less lethality.

Anxiety & Hypnosedative Drugs

• Anxiety involves emotional and somatic psychoneurotic disorders developing in response to distressing situations.
• Good anxiolytic drugs eliminate anxiety without causing sedation, as well as sedation with Anxiolytic and anticonvulsant effects, decreased striated muscle tone, and cross tolerance and dependency.

Sedative Drug

• Ideal sedative medications do not disrupt daily work, impair mental and sensory perception, are not addictive, and tolerance doesn't develop to its effects.

Hypnotic Drug

• Ideal hypnotic medications begin working quickly, create sleep similar to natural sleep, don't create residual effects, are not addictive, resistance should not develop, and have a wide treatment index.

Mechanisms of Effect by Hypnosedative Drugs

• It involves cytoplasmic membrane of the target neuron, GABA-A receptor-chloride channel complex.
• Facilitates chloride channel opening of GABA, the most common inhibitory neuromediator and increasing the binding.

Addiction and Tolerance

• Hypnosedatives have psychic and physical addiction potential.
• BZ addiction potential and abuse are less than barbiturates.
• Tolerance develops during hypnotic use and physical dependence are proportional.
• Withdrawal syndrome occurs when barbiturates are stopped suddenly.

Classification of Hypnosedatives

• Benzodiazepines treat Anxiolytic such as alprazolam, chlordiazepoxide, and clonazepam, diazepam, lorazepam with Hypnotic such as Quazepam, midazolam, florazepam, and triazolam.
• Flumazenil is a BZ-receptor antagonist used in BZ toxicity.
• Barbiturates consist of Amobarbital, pentobarbital, secobarbital, and thiopental.
• Non-barbiturate sedatives include Antihistamines, chloral hydrate, and ethanol.
• Additional sedatives include Buspirone and zolpidem.

Pharmacokinetics

• Usually administered orally, because liposoluble, GI absorption is fast which means the hypnotic effect begins quickly.
• The hungry abs includes Acid or basic salts of insufficiently soluble substances.
• Since they're liposoluble, the virtual distribution volume is high and passage to the brain is high.
• Duration ends elimination as rapid redistribution.

Pharmacokinetic

• Metabolized in the liver and excreted as inactive metabolites.
• Flurazepam, diazepam, and some BZs return to active metabolite in the liver which is a Residual Effect.
• Accumulates taken once a day Residual impact intensity .
• Passes into Fetal Circulation because its Lipophilic and into breath milk for a breastfeeding woman.

Hypnosedative Drugs - CNS

• Higher therapeutic index with a flatter CNS related dose response curve with BDZs.
• BRBTs a steep CNS (low therapeutic index)

Benzodiazepines Advantages

• There are therapeutic indexes.
• They do not cause death for acute poisoning.
• They are lower for causing in liver, drug interaction.
• They have effects seen w/significant sedation.
• There's low potential with psychic addiction.

Benzodiazepines Duration of Effect

• Long-acting (2-4 days) Anxiolytic: Diazepam, chlordiazepoxide with Hypnotics: Quazepam, florazepam.
• Medium (10-20 hours) Anxiolytic: Oxazepam, alprozolam with Hypnotics: Lorazepam, nitrazepam.
• Short (3-8 hours) Medication includes Midazolam and triazolam.

Affecting BZ-receptors

• BZs agonist, Anxiolytic with zopiclone (not BZ)
• Inverse activation prevents GABA from opening chloride channels and convulsant.
• BZ antagonist, Flumazenil, agonist reverses.

Mechanism of Action of Benzodiazepines

• Opening Cl channels binding GABA.
• Hyperpolarization and Cl conductance.
• Firing with anxiety, hypnotic with anticonvulsant.

Therapeutic Use of Benzodiazepines

• Anxiety with depression.
• As a Muscle Relaxant (Diazepam; Spasticity)
• Seizures (Diazepam, Lorazepam)
• Clonazepam (Absence seizure).
• Sleep disorders and syndromes.

Side Effects of Benzodiazepines

• Linger hangry .
• Insomnia / addiction.
• Elderly dizziness from CNS depression.

Barbiturates Mechanisms

• Bind to the complex to cause inhibitory of the transmitters.
• Block transmitters.

Barbiturates (classifying)

• Effect by Thiopental for anesthesia from the IV.
• Purposes Pentobarbital and Amobarbital with Secobarbital for hypnotic for uses.
• Effect, Phenobarbital for epilepsy.

Properties of Barbiturates

• Taken with oral.
• Rectal absorption.
• Liver elimination with redistribution.

Barbiturates

• Tolerate, Phenobarbital is induce.

Pharmacological——— Effects of Barbiturates

• Can’t analgesic
• Sedative and alcoholic.
• Ataxia

Anticonvulsant

• Loss anticonvulsant used as epileptic.

Anesthesia and Na Barbiturates

• Proportional depth with rate decreasing.

Cardiac Barbiturates

• Blood increase and flow decreases with heart traumas from barbiturate poisoning.
• No muscle dose.
• Effect: Hypothermia, Contraindicated

What is Porphyria

• Disorder causing photosensitivity.
• Causes deformity.

Properties/Effects

• Sedation.
• Anticonvulsant and antiepileptic.
• Causes pressure with jauncie.

Barbiturates Side

• Allergic.
• Depressions depend on pain.

Sedatives

• Has Melatonin with agonist, partial with metabolite effect’s.

Effect of Sleep

• Obtained from EEG.
• Sleep.

Rapid Eye

• Alpha rates with motor movements.

Properties of nonrem

• Slow activity EEG.
• Is a deep time sleep.
• Wave.