Central Nervous System Pharmacology; all lectures

• Centrally acting drugs are the most commonly used pharmacological agents, primarily affecting synaptic transmission, though their therapeutic mechanisms aren't always well understood.

Organization of the Central Nervous System

• Cortex: Responsible for sensory, motor, and thought processes.
• Limbic System: Governs emotion and memory.
• Diencephalon: Manages endocrine and autonomic functions.
• Cerebellum: Coordinates sensory and motor activities.
• Midbrain/Brain Stem: Involved in reflex pathways, information relay, awareness, and arousal.
• Spinal Cord: Handles sensory, motor, and autonomic functions.

Neural Communication

• Neurons are the primary communicating cells within the CNS.
• Interneurons facilitate communication within the same brain region.
• Projection neurons send axons from one brain region to another.
• Communication is primarily mediated through neurotransmitters.
• Neurodegenerative diseases and CNS disorders often stem from neurotransmission imbalances, which drugs aim to correct.
• Drugs of abuse cause neurotransmission imbalances, leading to behavioral changes.

Classification of CNS Transmitters

• Amino acids, acetylcholine, monoamines, and peptides are key CNS transmitters.

Amino Acids

• Glutamate: An excitatory neurotransmitter that acts as an agonist of NMDA and non-NMDA receptors, which increase Ca2+, Na+, and K+ ion flow, relaying neurons throughout the CNS.
• GABA: An inhibitory neurotransmitter that is an agonist of GABA receptors found throughout the CNS, influencing behavior. GABAa receptors increase Cl- ion flow, while GABAb receptors, linked to G proteins, increase K+ ion flow.

Acetylcholine

• It is found in interneurons associated with motor control and projection neurons linked to learning, memory, and cognition, the latter of which is often lost in Alzheimer's disease.
• Works as an agonist of various muscarinic and nicotinic receptor subtypes.

Monoamines

• Dopamine: Associated with motivation, emotion in the cortex, mood/behavior in the limbic system (linked to drug-seeking behavior and psychosis), and motor control in the midbrain. Loss of dopaminergic neurons in the nigrostriatal pathway leads to Parkinson's disease.
  • There are five subtypes of dopamine receptors (D1-D5), linked to the G-protein second messenger system. D1 receptors increase cAMP, while D2 receptors decrease cAMP and are found both pre- and postsynaptically.
• Norepinephrine: Throughout the CNS, it is important in awareness, arousal, and autonomic control; some antidepressants increase NE levels and act as agonists of α1, α2, and β1 receptors.
• Serotonin (5-HT): Projects from the midbrain and brain stem throughout the brain, impacting behavior and sleep control, and acts on at least 15 subtypes of 5-HT receptors (both excitatory and inhibitory, pre- and postsynaptic). Most 5-HT receptors are linked to G-proteins, except for 5-HT3, which is an ion channel.
  • 5-HT1A receptors are inhibitory and decrease cAMP, while 5-HT2A receptors are excitatory and increase DAG and IP3, and some antidepressants increase 5-HT levels.
  • 5-HT2A receptors are targeted by some hallucinogens (e.g., LSD) as agonists and some antipsychotics as antagonists.

Access of Drugs to the CNS

• The blood-brain barrier (BBB), formed by endothelial cells and astrocytes, restricts drug access to the CNS, and astrocytes are support cells in the CNS.
• Endothelial cells in blood vessels supplying CNS differ from those in other organs.
• Transport mainly occurs via passive diffusion, depending on a drug's lipid solubility and pKa.

Neurodegenerative Disorders

• Neurodegenerative disorders involve the progressive loss of specific neuron populations, leading to symptoms.
• Treatments aim to alleviate symptoms since no cures are available.
• Drug efficacy decreases as neuron loss becomes severe.

Alzheimer's Disease

• It is the most common neurodegenerative disease, affecting 1 in 13 people over 65 and 1 in 4 over 85 in Canada.
• Symptoms: Progressive and irreversible memory loss and cognitive impairment resulting from degeneration of basal forebrain cholinergic input to the hippocampus (memory) and cortex (cognition).

Pathological Changes in Alzheimer's Disease

• Pathological signs: Neurofibrillary tangles (intracellular accumulation of twisted fibers of phosphorylated tau proteins) and amyloid plaques (extracellular deposits of beta-amyloid protein) in the hippocampus and cortex.

Treatment of Alzheimer's Disease

• Approved treatments do not prevent or reverse plaque and tangle formation but aim to restore neuron communication and improve symptoms.
• AChE inhibitors (e.g., donepezil) easily enter the CNS, inhibiting ACh breakdown and are effective in mild-moderate AD cases.
• Side effects: Primarily autonomic, similar to peripheral-acting AChE inhibitors.

Parkinsonism

• Naturally occurring Parkinsonism has an uncertain etiology, increasing in frequency in the 5th or 6th decade of life, whereas drug-induced Parkinsonism can be reversible with antipsychotic drugs that block dopamine receptors.
• Irreversible Parkinsonism can result from MPTP, destroying dopaminergic neurons in the substantia nigra.

Therapeutic Strategies for Parkinson's Disease

• Dopaminergic neuron degeneration cannot be reversed; drugs correct the imbalance between dopamine and ACh activity in the basal ganglia by increasing dopamine activity or decreasing muscarinic receptor activity.

Drugs Used in Parkinsonism

• Dopamine agonists: Levodopa and ropinirole.
• MAO inhibitors: Selegiline (deprenyl).
• Antimuscarinic drugs: Benztropine.

Key Facts about Parkinson's

• Exposure to environmental factors, such as chemicals is related to the cause.
• MPTP exposure can cause Parkinson's.
• L-dopa is not a final solution for Parkinson's.

Symptoms of Parkinson's Disease

• Brain disease leading to impaired speech and movement.
• It is an age-related disease with a loss of voluntary movement control.

Substantia Nigra in Parkinson's Disease

• The substantia nigra loses its black pigment, leading to decreased dopamine signals and cell death.

Mechanism of MPTP Toxicity

• MPTP, a side product of MPPP, is converted by an enzyme (MAO) in the brain into MPP+, which is toxic and leads to Parkinson's, exposure can cause Parkinson's, and higher doses can be fatal.

Role of L-dopa in Parkinson's Treatment

• L-dopa replaces dopamine, restoring voluntary control of movement.

Major Side Effects of L-dopa

• Hallucinations can result from the use of L-dopa.

Psychosis

• Psychosis is a severe disturbance in brain function that disrupts normal perceptions of the environment, leading to a dissociation from reality, along with auditory/visual hallucinations, delusions, suspicion, paranoia, disorganized behavior, and difficulties with social interactions.

Schizophrenia

• Schizophrenia involves a split mind from reality with continuous or relapsing episodes of psychosis; positive symptoms (hallucinations, paranoia, delusions) are often treatable with antipsychotic drugs, while negative symptoms (apathy, social withdrawal, inattentiveness) are not easily treatable.

Drug-Induced Psychosis

• Cocaine or amphetamine use (increased dopamine neurotransmission) cause schizophrenia-like symptoms.
• Hallucinogens like PCP (NMDA receptor antagonists) and LSD (5-HT2A agonist) support the roles of glutamine and serotonin imbalance in psychosis. Glutamate and serotonin are also linked with dopamine neurotransmission in the cortex and limbic system.

Dopamine Hypothesis of Psychosis

• Enhanced dopamine neurons in specific brain areas are associated with the development of psychosis.
• Drugs that increase dopamine activity aggravate or produce psychosis.
• Dopamine receptor density increase in those diagnosed with schizophrenia.
• Antipsychotics block D2 receptors.
• Dopamine metabolites decrease in successfully treated patients with schizophrenia.

Dopamine Pathways

• The three main DA pathways: nigrostriatal (movement), mesocortical and mesolimbic (behavior).

Antipsychotic Drugs

• Believed to decrease psychotic symptoms by decreasing dopamine synaptic activity in the limbic pathway.
• The binding affinity of drugs with D2 receptors correlates with clinical potency as an antipsychotic, and blockade of D2 receptors in the cortex could enhance negative symptoms.
• Newer drugs have a higher affinity for 5-HT2A than D2 receptors and normalize DA transmission in the limbic system and cortex.

Classification

• Antipsychotics: Phenothiazine derivatives, thioxanthene, butyrophenone derivatives (haloperidol), and atypical (Olanzapine)
• Haloperidol: a receptor antagonist of D2>α1>D4>5HT-2A>D1>H1
• Olanzapine: a receptor antagonist of 5HT-2A>H1>D4>D2>α1>D1

Clinical Effectiveness of Antipsychotics

• There may be a delay in clinical effects or treatment ineffectiveness in some schizophrenic individuals.
• Negative symptoms are not effectively treated with classical antipsychotics but are known side effects.
• Hypothesis: Negative symptoms are associated with dopamine hypofunction in the cortex and newer drugs may be more effective due to differences in pharmacodynamic profiles and the interaction between dopamine and serotonin in the CNS.
• Haloperidol blocks D2>5HT-2A, while olanzapine blocks 5HT-2A> D2, decreasing DA release in the limbic system and increasing DA release in the cortex.

Adverse Effects of Antipsychotics

• CNS: Parkinson-like symptoms (D2 antagonism in the striatum), hormonal/metabolic dysregulation and weight gain (D2 antagonism in the diencephalon), and sedation (H1 and α1 antagonism).
• Autonomic: Hypotension (α1 receptor blockage) and atropine-like side effects (e.g., dry mouth, blurred vision, constipation) due to muscarinic receptor antagonism.

Bipolar Disorders

• Mood swings are not always correlated to external environment, most commonly involving episodes of mania/hypomania alternating with episodes of depression, which can occur simultaneously.

Monoamine Theory of Bipolar Disorder

• Decreased monoamine transmission leads to depression, while increased monoamine transmission increases mood, potentially leading to over-activation, linked to mania/psychosis.

Treatment for Bipolar Disorder

• It involves the management of the long-term course of the illness, treating emergent symptoms when necessary.
• Single drug treatment: Mood stabilizer (e.g., lithium) or antipsychotic.
• Multiple medications: Antipsychotic with antidepressant or lithium with antipsychotic, or lithium with antidepressants.

Lithium

• Lithium is a small monovalent cation with a narrow therapeutic index.
• It is more effective against the manic phase of bipolar disorder than the depressive phase.
• Its mood-stabilizing mechanism is not fully known, though some studies report increased serotonin and GABA, decreased NE and DA, and glutamate neurotransmission.
• Best characterized mechanism: Action on second messenger systems, such as a decrease in precursors for IP3 and DAG synthesis, therefore decreasing IP3 and DAG when receptors linked to second messengers are activated.

Therapy for Depression

• Includes psychotherapy and medication and drugs used to treat depression acting on one or more of the monoamine systems.

Tricyclic Antidepressants (TCAs)

• TCAs prevent the reuptake of NE and serotonin and are effective in about 70% of patients.
• Not used as a first-line treatment due to side effects and drug-drug interactions.
• Adverse events: Block cardiac sodium channels (like quinidine) and act as antagonists at muscarinic, H1, and alpha 1 receptors (sleepiness and sedation).

Selective Serotonin Re-Uptake Inhibitors (SSRIs)

• Fluoxetine (PROZAC) also used for panic disorder, anxiety, obsessive-compulsive disorder, and bulimia.
• Common side effects include insomnia and sexual dysfunction. There are reports of increased suicide rates in children and adolescents.
• Drug interactions: SSRIs inhibit CYP2D6.
• Overdose usually not dangerous unless combined with other antidepressants.

Newer Classes of Antidepressants

• Include serotonin and NE reuptake inhibitors (NRIs), 5-HT receptor agonists or antagonists, and atypical agents.

Bupropion

• Bupropion and its metabolites inhibit the re-uptake of DA and NE.
• Fewer side effects than TCAs, with much weaker affinity for H1 or α1 receptors (no sleepiness and sedation), but it does have anti-muscarinic and anti-nicotinic effects.
• Drug interactions: Inhibits CYP2D6, altering the metabolism of multiple drugs.

Monoamine Oxidase (MAO) Inhibitors

• Not selective for MAO-A (metabolizes NE, serotonin, dopamine, and tyramine) or MAO-B (metabolizes dopamine), therefore NE, serotonin, and dopamine pathways are all affected.
• Only used if tricyclic antidepressants are not effective.

Toxicity of MAO Inhibitors

• Few significant side effects on their own.
• A hypertensive crisis can occur if tyramine-containing foods are ingested or if taking CNS stimulants (e.g., cocaine and amphetamine).
• Sympathomimetics are contraindicated in individuals taking MAO inhibitors.
• MAO inhibitors should not be taken with serotonergic agents (i.e., SSRIs, SNRIs, tricyclic antidepressants) because the combination can cause serotonin syndrome.

Clinical Effectiveness of Antidepressants

• SSRIs are usually prescribed first due to fewer side effects and safer overdose profiles; therapy is often started at a low dose, which can take 3-8 weeks for a therapeutic effect.
• Dosage of antidepressants should balance between clinical effectiveness and potential side effects.
• Patients vary in individual responsiveness to different antidepressants (reason unknown).
• If a patient does not respond to one or two SSRIs, they are switched to a drug of a different class.
• Monoamine levels change after a single dose, but antidepressant action is not observed for weeks.

Anxiety

• Feeling of apprehension, tension, uncertainty, dissatisfaction, and fear.
• Anxiety secondary to other disorders is best treated by controlling the primary illness.

Drugs Used to Treat Anxiety

• Sedative-hypnotics (calming activity): Benzodiazepines (used most often) and barbiturates.
• As the dose increases, it slows down the effects of the CNS.
• Anxiolytic sedative: Drug producing a calming effect relieving anxiety with little or no effect on motor or mental function.
• Hypnotic: Drug that produces drowsiness that induces sleep.

Benzodiazepines

• Diazepam (valium)
  • Pharmacokinetics: Phase I oxidation by cytochrome P450, producing active metabolites, and Phase II oxazepam conjugation with glucuronide.
  • Many benzodiazepines undergo first-pass metabolism via oxidation, resulting in active metabolites.
• Action: Enhances GABA neurotransmission by binding to a subset of GABAa receptors at a site distinct from GABA, increasing the frequency of GABA-mediated opening of the Cl- channel.
• The binding of a drug to the benzodiazepine site does not activate GABAa receptors; GABA is required for the effect.

Barbiturates

• Phenobarbital carries a smaller margin of safety than benzodiazepines.
  • Pharmacokinetics: Phase I oxidation by cytochrome P450 and Phase II conjugation with glucuronide.
  • Metabolites are generally not active, but barbiturates increase the expression of some cytochrome P450 enzymes, altering the expression by increasing P450 enzymes interfering with drugs by increasing metabolites.
• Action: Enhances GABA neurotransmission by binding to a subset of GABAa receptors at a site distinct from GABA and benzodiazepines, increasing the duration of the opening of the GABA-mediated Cl- channel, keeping channels open longer, allowing more Cl- to enter and inhibit the cell.
• At high doses, barbiturates can directly activate GABAa receptors and inhibit glutamate receptors and some sodium and calcium channels, reducing activity of excitation channels.
• They enhance Cl- conductance, increasing the inhibition of many neurons in many brain regions.

Adverse Effects of Barbiturates

• Dose-dependent CNS depression (impaired judgment/motor skills ⇒ amnesia ⇒ coma ⇒ death).
• Additive CNS depression with other drugs (opioids, antihistamines, and alcohol).
• Prolonged use produces withdrawal symptoms when medication is stopped.
• Enhanced toxicity in individuals with impaired liver function.
• Tolerance: Increased drug concentrations are required to achieve desired effects.
• Barbiturates alter the metabolism of self and other drugs (via cytochrome P450 enzymes).

Cannabis

• Targets receptors in the amygdala, linked to anxiety, though chronic use to help treat anxiety can lead to addiction.

Endocannabinoids

• Lipid neuromodulators produced on-demand postsynaptically.
• They are retrograde inhibitors of transmitter release by activating CB1 receptors, travel through the membrane, activate the presynaptic cleft, inhibit Cl- from entering, and reduce the K+ (positive) charge in neurons, making it less likely for the neuron to activate.
• They are rapidly metabolized by fatty acid amide hydrolase (FAAH).

Ethanol

• Acute effects: Dose-dependent CNS depression with decreased membrane excitability plus increased GABAa and decreased NMDA activation, diuresis, and an initial increase then decrease in myocardial contractility, anxiety, slurred speech, and impaired judgment.
• Toxic doses: CNS and respiratory depression.
• Chronic effects: Fatty liver⇒ hepatitis ⇒ cirrhosis ⇒ liver failure and malnutrition.

Methanol

• Same CNS depression mechanisms as ethanol.
• Methanol metabolism to formic acid accumulates in the retina, leading to optic nerve damage and blindness.

Treatment for Methanol Poisoning

• Ethanol: Has a higher affinity for alcohol dehydrogenase, slowing down the metabolism of formic acid.

Abused Substances

• Substances administered repeatedly in a pattern and amount that interferes with healthy and daily functions.

Main Classes of Abused Drugs

• Sedatives, stimulants, opioids, hallucinogens, and cannabinoids.
• Most addictive substances increase dopamine levels in the limbic system.

Tolerance

• Reduced drug effect resulting from repeated use, with behavioral compensation for drug effects, functional changes in drug action, and metabolic increases in drug metabolism.

Dependence

• Psychological: Drug-seeking behavior.
• Physiological: Discontinued drug use produces symptoms opposite to effects sought by the user.

Drug Use in Canada

• Alcohol: 76% consumed in the last year, 44% risk drinkers.
• Cannabis: 21% used in the past year, 45% age 20-24, with people with more education being more likely to do cannabis.
• Opioids: 14% in the past year, 6% for pain relief.

Therapeutic Approach to Drug Abuse

• Treat an acute overdose with symptoms and antagonists.
• Manage withdrawal symptoms by administering a drug to suppress acute withdrawal, followed by gradual dose reduction.
• Long-term rehabilitation.

Sedatives

• Benzodiazepines, barbiturates, and ethanol bind and enhance GABA receptors, suppressing the nervous system in the brain, and combining these can be fatal.
• Dependence leads to symptoms of withdrawal, more common from chronic use of ethanol and barbiturates.
• Clonidine helps with autonomic symptoms of withdrawal and benzodiazepines can be used to treat ethanol withdrawal.
• Tolerance: To sedative but not respiratory depressant effects.

Metabolic Tolerance to Ethanol

• The microsomal ethanol oxidizing system converts ethanol to acetaldehyde, playing a minor role in ethanol metabolism.
• As alcohol intake increases, the minor metabolism increases ethanol consumption.
• The enzyme system is induced in chronic alcoholism, therefore individuals addicted to alcohol need more alcohol to feel effects.

Opioids

• Morphine and heroin come from the opium poppy, seeking an initial rush followed by euphoria, tranquility, and sleepiness.
• Mechanisms of action: Opioid receptors (mu) linked to G-proteins. Presynaptically, it decreases Ca2+, decreasing the release of neurotransmitters, allowing cell activity to decrease, and postsynaptically, it increases K+, inhibiting postsynaptic neurons.
• Tolerance and dependence: Metabolism, transport, and distribution with receptor sensitivity and second messengers
• People receiving opioids for pain usually do not become addicted.
• Heroin: Effects last 3-5 hours; many formulations vary in potency, creating a risk of overdose.
• Acute toxicity: Respiratory depression, coma, death.
• Treatment: Naloxone and detoxification. Methadone is an opioid receptor agonist with a long window, so there is not as much withdrawal, and colindine reduces autonomic symptoms of withdrawal.

Stimulants

• Amphetamine and cocaine: Highly addictive.
• Mechanisms of action: Increase the release or decrease the reuptake of NE (cocaine), dopamine, and serotonin.
• Tolerance and dependence: Changes in the sensitivity of dopamine transporters and receptors.
• Desired effects: Increased energy, alertness, and euphoria.
• Cocaine overdose can cause seizures, heart attack, stroke, and respiratory failure. Amphetamines are less fatal, but their long half-life may be more harmful to the CNS.

Hallucinogens

• LSD and PCP.
• LSD: Agonists at several 5-HT receptors, most being agonists or partial agonists of the 5-HT2A receptor.
• PCP: NMDA receptor antagonist.
• LSD adverse effects increased heart rate, increased blood pressure, dilated pupils, sweating, and tremors. Harmful to pregnancy. PCP overdose can be fatal.

Cannabinoids

• Weed, hash, THC psychoactive component.
• Mechanism of action: Cannabinoid receptors are linked to G-proteins, inhibiting GABA or glutamate release.
• Endocannabinoids: Increase Ca2+ (postsynaptic neuron) ⇒ increase Endocannabinoids ⇒ bind presynaptic CB1⇒ decrease glutamate or GABA release.
• THC: Activates CB1 receptors, decreasing glutamate or GABA release.
• Therapeutic use: Cancer, AIDs, and glaucoma (decrease intraocular pressure).