Principles of Pharmacology - Week 6 Seminar Notes
Topic = Central Nervous System part 1
Regions of the brain and CNS organization
CNS includes the brain and spinal cord; major regions are the cerebrum, diencephalon, brainstem, cerebellum, and spinal cord.
Central nervous system (CNS) is organized into distinct functional units that coordinate sensation, movement, emotion, and cognition.
Understanding these regions helps explain pharmacological targets and disease states in pharmacology.
Cerebrum and cerebral cortex
Cerebrum: largest, uppermost part of the brain; divided into left and right hemispheres connected by the corpus callosum (a thick bridge of axons).
Cerebral cortex: outer grey matter with inner white matter (medulla).
Primary roles: perception and interpretation of sensation, initiation of skeletal muscle movement, communication, intellect, abstract thought.
Cerebral cortex – lobes and functional areas
Four main lobes:
Frontal lobe: muscle movement, motor components of speech, abstract thinking, problem solving.
Parietal lobe: sensory modalities (touch, pressure, pain, temperature, vibration).
Temporal lobe: hearing, learning, memory, language functions.
Occipital lobe: vision.
Neural connections between lobes enable integration, communication, and coordination.
Detailed cortical regions (illustrative schematic from Fig. 8.7)
Central sulcus separates frontal from parietal lobes; precentral gyrus houses Primary Central Motor Cortex; postcentral gyrus houses Somatosensory Cortex.
Premotor cortex, Broca’s area (motor speech), Wernicke’s area (sensory speech) are key functional areas.
Taste cortex, auditory cortex, and visual cortex are located in their respective lobes; gyri and sulci increase cortical surface area.
Cerebral medulla and basal ganglia
Cerebral medulla: inner white matter composed of myelinated axons; conducts signals between cortex and other CNS regions.
Basal ganglia: grey matter structures within white matter; regulate motor activity, initiate and smooth voluntary movement; part of extrapyramidal system (EPS), crucial for gross motor control and muscle tone.
Diencephalon
Includes thalamus and hypothalamus; located at the back of the forebrain, below the cerebral hemispheres and above the brainstem.
Thalamus: relay for sensory and motor impulses; regulates consciousness, sleep, and alertness.
Hypothalamus: regulates appetite, temperature, fluid balance, hormonal control, biological rhythms; integrates autonomic nervous system and endocrine function; closely linked to emotion and survival behaviours.
Brainstem and spinal cord
Brainstem comprises midbrain, pons, and medulla oblongata.
Midbrain: head of the brainstem; contains several reflex centers.
Pons: regulation of respiration and sleep.
Medulla oblongata: autonomic control over cardiac, vasomotor, and respiratory functions; also involved in swallowing, coughing, vomiting, gagging.
Spinal cord: conduit for sensory and motor nerves between brain and body; major conduction pathway for CNS signals.
Cerebellum
Means “little brain”; located behind the brainstem below the cerebrum.
Coordinates voluntary movements: posture, balance, coordination, speech.
Fine-tunes ongoing movements and provides quality control; involved in planning and decision-making related to movement.
Functional components of the brain
Reticular formation: network of nerve fibres extending through brain and spinal cord; connects many brain areas; regulates motor control, cardiovascular control, sleep, wakefulness.
Contains inhibitory and excitatory neurons; Excitatory nerves form the Reticular Activating System (RAS).
Susceptible to modulation by stimulants (e.g., amphetamines) and depressants (e.g., alcohol, barbiturates).
Limbic system: interconnected neural network regulating emotions and behavior; functionally connected rather than strictly anatomically defined.
Key structures: Hippocampus (long-term memory formation) and Amygdala (emotional responses such as fear, anger, anxiety, reward/punishment).
Dysfunctions linked to addictions (drug abuse, smoking) and negative emotional states; anxiolytics and some antidepressants can stabilize limbic activity.
Major brain chemical transmitter systems
Catecholamines: Adrenaline, Noradrenaline, Dopamine.
Indolamines: Serotonin, Melatonin.
Monoamines: Dopamine, Serotonin, Noradrenaline, Adrenaline (noradrenaline and adrenaline are sometimes grouped with catecholamines).
Other key transmitters: GABA (inhibitory), Glutamate (excitatory), Acetylcholine (ACh), Histamine, Endorphins and Enkephalins, Adenosine, Substance P.
Transmitter families are often categorized by receptor families and physiological roles.
CNS neurotransmitters – overview and receptor considerations
Adrenaline and Noradrenaline (catecholamines)
Involved in fight-or-flight, mood regulation, arousal.
Adrenergic receptors: α and β subtypes.
Acetylcholine (ACh)
Pathways controlling voluntary movement, memory, learning, alertness.
Cholinergic receptors: muscarinic and nicotinic.
Dopamine
Predominantly in nigrostriatal pathway (voluntary movement), plus mesolimbic, mesocortical pathways involved in behavior, reward, motivation, addiction, endocrine control via tuberoinfundibular pathway.
Receptors: D1-like (D1, D5) and D2-like (D2, D3, D4).
Serotonin (5-HT)
Wide CNS distribution; regulates mood, arousal, eating, vomiting, cognition, sleep, pain, temperature; can be excitatory or inhibitory depending on receptor subtype.
GABA (γ-aminobutyric acid)
Brain’s major inhibitory neurotransmitter; widespread control of excitability.
Receptors: GABAA (ionotropic) and GABAB (metabotropic).
Glutamate
Brain’s major excitatory transmitter; receptors include NMDA, AMPA, kainate (ionotropic) and mGluRs (metabotropic); essential for learning, memory, and synaptic plasticity.
Histamine
Involved in wakefulness, arousal, and immune responses; receptors H1–H4 with variable excitatory/inhibitory roles.
Endorphins and Enkephalins (opioid system)
Modulate pain and mood via μ, δ, κ opioid receptors; generally inhibitory.
Adenosine
Generally inhibitory; regulates sleep, promotes relaxation, provides neuroprotection; acts via A1, A2A, A2B, A3 receptors.
Substance P
Neurokinin receptors (primarily NK1); excitatory; involved in pain transmission.
CNS neurotransmitter receptor and functional relationships (selected highlights)
Acetylcholine
Receptors: nicotinic (ionotropic) and muscarinic (metabotropic).
Roles: muscle contraction, cognitive function, autonomic regulation.
Dopamine
Receptors: D1-like (D1, D5) and D2-like (D2, D3, D4).
Generally excitatory in CNS; controls mood, reward, motor function, and cognition.
Serotonin (5-HT)
Multiple subtypes (5-HT1 to 5-HT7); can be excitatory or inhibitory depending on receptor.
Noradrenaline/Adrenaline
Adrenergic receptors: α and β; generally excitatory in CNS; involved in arousal and mood.
Glutamate
Receptors: NMDA, AMPA, kainate (ionotropic); mGluRs (metabotropic).
Functions: learning, memory, synaptic plasticity; excitatory transmission.
GABA
GABAA and GABAB receptors; inhibitory control of neuronal excitability.
Brain regions and transmitter associations (Table-style synthesis)
Acetylcholine: Cognition, skeletal muscle movement, memory; associated regions include cerebral cortex, thalamocortical tracts, pyramidal pathways, and the reticular activating system; linked to disorders like Parkinson's disease and dementia when dysregulated.
Dopamine: Behaviors, reward pathways, motor control; associated with extrapyramidal pathways and limbic system; involved in emesis and hormone release via hypothalamus.
Noradrenaline: Arousal, wakefulness, mood, appetite, hormone release; linked to reticular activating system and hypothalamus.
Serotonin: Arousal, sleep, mood, appetite, temperature; widespread in CNS; related to depression, eating disorders, insomnia.
GABA: Broad inhibitory control across CNS; abundant in cortex and basal ganglia.
Glutamate: Learning, memory, consciousness; widespread excitatory transmission; epilepsy and neurodegenerative processes linked to excitotoxicity.
Disease states of the CNS – general concept
CNS disorders often arise from neurotransmitter imbalances:
Hyper-excitable neurons (excess excitation) can trigger seizures.
Excessive neurotransmitter binding to postsynaptic receptors can contribute to psychoses.
Deficits in neurotransmitter levels (e.g., dopamine in Parkinson’s disease) contribute to neurodegenerative processes.
Neurotransmitter balances in CNS disorders (conceptual mappings)
Parkinson's disease: Dopamine deficiency with relative acetylcholine excess; motor symptoms prominent.
Depression: Monoamine (NA, 5-HT, and possibly DA) dysregulation.
Schizophrenia: Dopamine imbalance with hyperactivity in mesolimbic pathways and hypoactivity in mesocortical pathways; dopamine, glutamate and serotonin systems implicated.
Dementia: Acetylcholine deficiency and broader neurotransmitter changes.
Sedative and anxiolytic drugs – overview
Sleep disorders and anxiety are common targets for CNS depressants and anxiolytics.
Short-term hypnotics can improve sleep, but may disrupt normal sleep architecture and carry risks of dependence and tolerance.
Anxiety disorders involve GABA, noradrenaline, serotonin, and dopamine systems; limbic structures (amygdala, hippocampus) are key targets.
Sleep disorders and therapeutic approach
Sleep is essential; sleep disturbances affect daily life.
Initial approach: identify underlying cause, optimize sleep hygiene, review medical/psychiatric history.
Hypnotics may provide temporary relief but can disrupt normal sleep cycles.
Anxiety and pharmacotherapy – distinctions
Anxiolytics vs hypnotics:
Anxiolytics: lower CNS activity to reduce anxiety; lower doses.
Hypnotics: promote sleep with higher sedative effects.
Sedatives may be used for anxiety or insomnia; the dose and duration differ.
Sedative drugs – pharmacology basics
Barbiturates (sedative-hypnotics) and benzodiazepines act to enhance GABAergic inhibition; benzodiazepines mainly act on GABA_A receptors.
Zolpidem and Zopiclone are non-benzodiazepine hypnotics that act on GABA_A receptors but with different specificity.
Buspirone is an anxiolytic with a less sedative profile; mechanism is not fully clear but distinct from benzodiazepines.
Flumazenil reverses benzodiazepine toxicity; short half-life necessitates IV administration.
Other hypnotics include Diphenhydramine, Doxylamine (sedating antihistamines) and Melatonin (circadian rhythm regulation).
Benzodiazepines – clinical features and pharmacokinetics
Examples: diazepam, alprazolam, temazepam.
Mechanism: enhance GABAergic inhibition via GABAA receptors; broad CNS effects due to widespread GABAA presence.
Indications: anxiety, insomnia, panic, seizures, anesthesia adjunct, alcohol withdrawal.
Adverse effects: dependence, altered sleep architecture, daytime drowsiness, cognitive/memory impairment, increased fall risk in older adults.
Pharmacokinetics:
Highly lipophilic: rapid, complete absorption.
Can accumulate in fat stores, especially in older patients.
Large variation in half-lives; long-acting agents may have active metabolites extending action.
Individual responses vary; some benzodiazepines have active metabolites contributing to duration.
Tolerance and withdrawal: risk of dependence; withdrawal symptoms are a concern when stopping.
Benzodiazepines – practical considerations
Different half-lives influence onset/duration, insomnia vs anxiety treatment, risk of dependence, daytime drowsiness.
Tolerability and safety profile are influenced by age, comorbidities, and concomitant medications.
Non-benzodiazepine agents for anxiety and sleep disorders
Barbiturates: act on GABA_A receptors; higher risk profile and dependence potential.
Zolpidem (hypnotic): GABA_A receptor action; risks include tolerance, dependence, withdrawal.
Zopiclone (hypnotic): enhances GABA_A activity; elderly patients are more susceptible to adverse effects.
Buspirone (anxiolytic): mechanism not fully defined; generally well tolerated; limited sedation and motor impairment.
Reversal and other agents
Flumazenil: benzodiazepine antagonist; short half-life; administered IV for acute toxicity reversal.
Other hypnotic drugs
Diphenhydramine and Doxylamine: sedating antihistamines with hypnotic effects.
Melatonin: hormone involved in circadian regulation; used as a sleep aid.
Alcohol – CNS depressant effects and withdrawal
Pharmacological effects: widespread CNS depression; vascular, GI, renal, nutritional effects.
Acute effects: CNS depression; chronic use leads to tolerance and dependence; withdrawal can be debilitating.
Management concept: avoidance therapy (where a conditioning stimulus is paired with adverse effects to discourage drug use).
Disulfiram (antabuse): used in alcohol avoidance therapy; mechanism involves inhibition of acetaldehyde dehydrogenase, leading to acetaldehyde accumulation and a hangover-like reaction when ethanol is consumed.
Mechanism (disulfiram): Ethanol → acetaldehyde (via alcohol dehydrogenase) → acetaldehyde cannot be efficiently converted to acetate due to aldehyde dehydrogenase inhibition by disulfiram, producing adverse effects.
Avoidance therapy – disulfiram example
Mechanism: Disulfiram inhibits aldehyde dehydrogenase; ethanol metabolism accumulates acetaldehyde, causing symptoms such as nausea, vomiting, palpitations, dyspnea, flushing.
Clinical use: adjunct to rehab to create a negative association with drinking.
Antipsychotics – overview and neurobiology of psychosis
Psychosis: loss of contact with reality; symptoms include hallucinations, delusions, emotional blunting, and reduced insight.
Schizophrenia: multifactorial etiology (genetic, neurobiological, environmental); structural brain changes and functional alterations are observed.
Dopamine hypothesis (core): dysregulation of dopamine pathways contributes to schizophrenia; mesolimbic overactivity linked to positive symptoms; mesocortical hypoactivity linked to negative/cognitive symptoms.
Other neurotransmitters (glutamate, serotonin) also implicated through NMDA receptor hypofunction and serotonergic involvement.
Dopaminergic pathways relevant to antipsychotics
Mesolimbic pathway: positive symptoms; blockade reduces these symptoms but may reduce reward pathways.
Mesocortical pathway: negative and cognitive symptoms; blockade may worsen or fail to improve these symptoms.
Nigrostriatal pathway: motor control; blockade produces extrapyramidal symptoms (EPS).
Tuberoinfundibular pathway: dopamine regulation of prolactin; blockade can cause hyperprolactinemia (breast enlargement, galactorrhea, reduced libido).
Antipsychotics – major categories
Typical (first-generation) antipsychotics: Chlorpromazine, Haloperidol, Droperidol; mainly D2 antagonists with narrower receptor profiles.
Atypical (second-generation) antipsychotics: Clozapine, Olanzapine, Risperidone; broader receptor activity including serotonin and histamine receptors; generally lower risk of EPS and hyperprolactinemia, but other side effects exist.
Distinction is not absolute, but typicals are more selective for D2 antagonism; atypicals have broader receptor activity.
Actions and adverse effects of antipsychotics
Therapeutic action: blockade of D2 receptors in the mesolimbic pathway reduces positive symptoms.
Extrapyramidal side effects (EPS): due to D2 blockade in the nigrostriatal pathway; include dystonia, akathisia, parkinsonism, tardive dyskinesia.
Endocrine effects: blockade in tuberoinfundibular pathway increases prolactin release; can cause galactorrhea and other sexual dysfunction.
Antiemetic effects: dopamine blockade in chemoreceptor trigger zone reduces nausea/vomiting.
Antihistamine and antimuscarinic effects: blockade can cause sedation and dry mouth, constipation, blurred vision, tachycardia, urinary retention.
Other receptors: blockade of α-adrenergic receptors can cause orthostatic hypotension and other autonomic effects.
Extrapyramidal side effects and time course
EPS types:
Dystonic reactions (acute muscle spasms), akathisia (restlessness), Parkinsonian symptoms (rigidity, tremor), tardive dyskinesia (late-onset involuntary movements).
Risk increases with longer treatment duration and higher D2 occupancy; some antipsychotics carry different EPS risk profiles.
Antipsychotics – practical safety considerations
Hyperprolactinemia risk contributes to sexual dysfunction and adherence issues.
Sedation and anticholinergic effects can be problematic for elderly patients (falls, cognitive impairment).
Atypicals may offer better tolerability for negative symptoms but require monitoring for metabolic effects (weight gain, dyslipidemia, diabetes risk).
Summary connections to foundational principles and real-world relevance
CNS structure–function relationships underpin pharmacologic targeting: blocking specific neurotransmitter receptors in particular circuits can relieve symptoms but may introduce adverse effects in other circuits.
The balance between dopamine and acetylcholine in motor pathways explains Parkinsonian-like symptoms with some antipsychotics and the rationale for anticholinergic co-therapy in EPS.
Multiple neurotransmitter systems (dopamine, serotonin, glutamate, GABA) contribute to complex psychiatric disorders; this underlies the rationale for atypical antipsychotics with broader receptor activity beyond D2 antagonism.
Quick reference: key numerical/temporal points
Benzodiazepine use should be limited to approximately 14\text{–}21\text{ days} to minimize tolerance and dependence.
Flumazenil is used to reverse benzodiazepine toxicity and has a short half-life, requiring IV administration.
Extrapyramidal symptoms are a major concern with typical antipsychotics due to nigrostriatal D2 blockade.
Connections to assessed topics and exam-style concepts
Distinguish anxiolytics from hypnotics by dose and CNS effects; understand receptor mechanisms (GABA_A for most benzodiazepines).
Recognize the dopamine hypothesis in schizophrenia and how antipsychotics modulate pathways differently, impacting positive vs negative symptoms.
Understand the practical pharmacokinetic implications of benzodiazepines (lipophilicity, fat storage, active metabolites) for onset, duration, and withdrawal risk.
Illustrative concepts and examples (hypothetical scenarios)
If a patient presents with tremor, rigidity, and slowed movement after starting a typical antipsychotic, consider extrapyramidal side effects linked to nigrostriatal D2 blockade and evaluate dose reduction or switch to an atypical agent.
In treating insomnia with a benzodiazepine, anticipate possible daytime sedation or cognitive effects, particularly in older adults; prefer shorter-acting agents when possible and monitor for dependence.
Disulfiram as an avoidance strategy creates a strong negative association with alcohol by producing unpleasant symptoms after alcohol ingestion, leveraging learned conditioning to support abstinence.
Links to foundational pharmacology principles
GABAergic modulation underpins many sedatives and hypnotics, illustrating how enhancing inhibition can reduce CNS excitability across multiple circuits.
Dopaminergic pathways illustrate how regional neurotransmitter activity aligns with symptom clusters (positive vs negative symptoms) in psychiatric disorders.
Receptor diversity (D1/D2, 5-HT subtypes, NMDA/mGluR, GABA_A/B) explains variability in drug effects, side effects, and patient responses.
Table-style quick reference (synthesis of Table 32.1 concepts)
Brain region associations:
Cerebral cortex, thalamocortical tracts, pyramidal pathway, reticular activating system: Acetylcholine; Dopamine involvement in extrapyramidal pathways and the limbic system; Serotonin involvement in arousal and mood.
Hypothalamus: Serotonin and Noradrenaline related in hormone release and autonomic control; Dopamine involvement in prolactin regulation via tuberoinfundibular pathway.
All regions: GABA and Glutamate as fundamental inhibitory/excitatory transmitters across CNS.
Functional roles:
Cognition, movement, memory, consciousness: Acetylcholine and Glutamate.
Motivation, behavior, vomiting, hormone release: Dopamine, Serotonin, Noradrenaline.
Arousal, sleep, mood, appetite, temperature: Serotonin, Noradrenaline, Histamine, Dopamine.