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Introduction to CNS pharmacology Anne McKinney Microanatomy a) Neurons b) Non-neuronal -Microglia -Microglial related macrophages -Cells of the cerebral vasculation -Meninges c) Blood brain barrier Blood brain barrier (BBB) Cortical microvasculature The BBB has several functions • Protects the brain from “foreign substances” in the blood that my injure the brain • Protects the brain from hormones and neurotransmitters in the rest of the body • Maintains a constant environment for the brain General properties • Large molecules do not pass through the BBB easily • Low lipid (fat) soluble molecules do not penetrate into the brain. However lipid soluble molecules e.g. barbiturate drugs rapidly cross through the brain • Molecules that have a high electrical charge are slowed Transport of substances into the brain are dependent on: • • • • • • • • • • • Conc between compartments Size of molecule (MW) Flexibility and conformation of molecules Amino acid composition Lipophilicity Cellular enzymatic stability Cellular sequestration Affinity for efflux mechanisms Hydrogen bonding potentials (charge) Affinity for carrier mechanisms Effects of existing pathological conditions Penetration of drugs across BBB Factors determining the ability of a drug to cross the blood-brain barrier 1. 2. 3. 4. 5. Lipid solubility Ionization Plasma protein binding Molecular mass Transporter Passiv e Active Diffusion of substances in the brain - Paracellular (between cells) (not occur to great extent at the BBB due to tight junctions) - Transcellular (across cells) The higher the lipohilicity of a substance the greater the diffusion in the brain Transport at the BBB 4 basic mechanisms: • Simple diffusion (low to high conc) • Facilitated diffusion: a carrier mediated endocytosis( solute molecules bind to specific membrane protein carrier low to high conc • Simple diffusion through an aqueous channel formed within membrane • Active transport through a protein carrier: specific binding site that undergoes a change in affinity. Active transport requires ATP hydrolysis and conducts movement against the concentration gradient. Circumventricular Organs Several areas were BBB is weak. These areas known as cirumventricular organs Include: • Area postrema: “vomiting center” when a toxic substance enters the bloodstream • Subfornical organ important for regulation of body fluids • Vascular organ of the lamina terminalis: A chemosensory area that detects peptides and other molecules • Median eminence: Regulates anterior posterior through release of neurohormones • Pineal body: Secretes melatonin and neurosctive peptodes, associated with circadian rhythms • Neurophypophysis (posterior pituitary): Releases neurohormones like oxcytocin and vasopressin into the blood. Strategies for drug delivery through the blood-brain barrier 1. Invasive -intracarotid infusion of hypertonic media 2. Pharmacologic -liposomes -lipid-soluble pro-drugs 3. Physiologic -chimeric nutrients -chimeric peptides Communication in CNS 1. Conduction of nerve impulses within a single neuron 2. Communication among neurons Ion Channels in Neuronal Membrane 1. Voltage sensitive 2. Chemically activated (receptor operated) Types of ion channels 2. Communication among neurons 2.1 2.2 2.3 2.4 Chemical synapses Electrotonic junctions Electrical field (ephaptic) interactions Extracellular milieu CNS synapse 1. 2. 3. 4. 5. 6. 7. 8. axonal transport electrically excitable membrane transmitter synthesis, storage and metabolism transmitter uptake transmitter release postsynaptic receptors, cytoplasmic organelles, messengers, etc. presynaptic heteroreceptors presynaptic autoreceptors 2.1 Chemical synapses and other forms of neurohumoral communication 2.1.1 Neurotransmitters 2.1.2 Neuromodulators 2.1.3 Neurohormones Identification of CNS Neurotransmitters - Criteria 1. Localization 2. Release 3. Synaptic mimicry 3.1 Identity of action 3.2 Pharmacologic identity (antagonists) Neurotransmitters in the CNS 2. Catecholamines 2.1 Dopamine Dopamine Neurotransmitters in the CNS 2. Catecholamines 2.2 Noradrenaline Noradrenaline locus coeruleus Neurotransmitters in the CNS 3. 5-hydroxytryptamine, 5-HT, serotonin 5-hydroxytryptamine Neurotransmitters in the CNS 4. Acetylcholine Renshaw cells interneurons in the striatum medial septum n.→ hippocampus n. basalis Meynert → cortex Neurotransmitters in the CNS 5. Peptides Opioid peptides Substance P Somatostatin, etc. 6. Nitric oxide Co-Transmission Transmitter Peptide Location GABA Hippocampal & cortical n. Cortical neurons Parasympathetic & cortical Pontine neurons Sympathetic neurons Sympathetic neurons Medullary & pontine n. Locus coeruleus Ventrotegmental neurons Ventrotegmental neurons Somatostatin Cholecystokinin Acetylcholine VIP Substance P Noradrenaline Somatostatin Enkephalin NPY Neurotensin Dopamine CCK Neurotensin Transmitter Peptide Location Adrenaline Reticular neurons Reticular neurons Medullary raphe Medullary raphe Medullary raphe Serotonin NPY Neurotensin Substance P TRH Enkephalin Peptide Peptide Vasopressin Oxytocin CCK, dynorphin Hypothalamic neurons Enkephalin Hypothalamic neurons Transmitter Transmitter GABA Glycine Spinal cord General Characteristics of CNS Drugs 1. Nonspecific: effect on many different targets cells & results in diverse molecular mechanism (anesthetic gases) 2. Specific: binds to a target cell receptor, intracellular mechanism and imparts a specific therapeutic action. (psychotropic drugs) Classification of drugs acting on CNS 1. Mechanism of action 2. Therapeutic use Sites of drug action