Lecture 1 introduction to the cns and drug action by Marc Imhotep Cray, M.D.

DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN Lecture 1:

Introduction to the CNS and Drug Action Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Goal of Presentation: The goal of this presentation is to provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the neurologic and psychiatric drugs described in subsequent lectures.

o MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders o Companion eNotes: CNS- Central Nervous System Pharmacology o Textbook Reading: Nicoll RA. Ch. 21 Introduction to the Pharmacology of CNS Drugs. In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 359-71 Marc Imhotep Cray, M.D.

Classification Schema: CNS AGENTS Antiepileptics (Anticonvulsants)

Phenytoin Carbamazepine Topiramate Valproic acid Ethosuxmide Gabapentin Tiagabine GABAergic Phenobarbital Thiopental Diazepam Zolpidem Baclofen *General anesthetics are included in CNS, although their MOA is not mediated by neurotransmitters Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

General Anesthetic* Dopamine Agonists & Halothane Antagonists Local Anesthetic Levodopa/carbidopa Procaine Pramipexole Note: A drug may be Glutamate Antagonists Prochlorperazine classified by the Memantine Antipsychotics chemical type of the Riluzole Chlorpromazine active ingredient, its Serotonin Agonists & Haloperidol molecular target or by the way it is used to Antagonists Olanzapine treat a particular Sumatriptan Lithium condition (therapeutic Ergotamine Opioids & Opioid Antagonists indication). Each drug Buspirone Morphine can be classified into one or more drug Ondansetron Codeine classes. Alosetron Pentazocine Antidepressants Diphenoxylate Amitriptyline Methadone Fluoxetine Naloxone Nefazodone 3 See: Most Common Drugs (Classes) with Phonetic Pronunciations Phenelzine

CNS Pharmacology Lecture 1

Major Neuropsychiatric Disorders and Classes of Drugs Used for Treatment (N-methyl-D-aspartate)

Marc Imhotep Cray, M.D.

Modified from Brodyâ&#x20AC;&#x2122;s Human Pharmacology, 2010

CNS Pharmacology Lecture 1

Methods for Study of CNS Pharmacology  Glass microelectrodes permit intracellular neuronal recording  The brain slice technique permitted an analysis of physiology and pharmacology of synapses  Patch clamp technique permits recording of current through single channels  Channels can be expressed in cultured cells and currents evoked by their activation recorded  Histochemical, immunologic, and radioisotopic methods enable mapping of the distribution of specific transmitters, their associated enzyme systems, and their receptors  Molecular cloning has made it possible to determine the precise molecular structure of receptors and their associated channels  Finally, mice with mutated genes for specific receptors or enzymes (knockout mice) can provide important information regarding the physiologic and pharmacologic roles of these components Marc Imhotep Cray, M.D.

Organization of the Nervous System CENTRAL NERVOUS SYSTEM (CNS)

BRAIN & SPINAL CORD The central nervous system (CNS) consists of the brain and spinal cord. The CNS receives and interprets sensory information (via peripheral afferent nerves) and then initiates appropriate motor responses (via peripheral efferent nerves).

AFFERENT

EFFERENT

(Sensory)

(Motor)

NERVES

EXTEROCEPTORS

INTEROCEPTORS

EFFECTOR ORGANS

Marc Imhotep Cray, M.D.

SKELETAL MUSCLES

VOLUNTARY Monosynaptic

CNS Pharmacology Lecture 1

PERIPHERAL NERVOUS SYSTEM (PNS)

SOMATIC

AUTONOMIC

SMOOTH MUSCLE, CARDIAC MUSCLES AND GLANDS

INVOLUNTARY Pre & Post Ganglionic Fiber

CNS Pharmacology Lecture 1

Overview The properties of the CNS, like the properties of peripheral organs (ANS), are mediated by neurochemical transmitters acting at receptor sites Thus, at the molecular level, the fundamental mechanism of action (MOA) of drugs affecting the CNS differ little from MOA of drugs that act on PNS However, although neurotransmission in CNS parallels that in ANS, the CNS utilizes several chemicals (amino acid) and peptides as transmitters in addition to acetylcholine and norepinephrine

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Overview (2) As in the ANS, the CNS consists of opposing neurotransmitter systems  The major excitatory neurotransmitters are the amino acids glutamate (Glu) and aspartate (Asp)

 The major inhibitory neurotransmitters are GABA and glycine (Gly)

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Overview (3) The etiology of CNS functional disorders is often difficult to determine Psychosocial and cultural influences are important in many disorders

Thus, CNS functional disorders are best treated with a combination of pharmacotherapy and psychosocial /cultural interventions

Marc Imhotep Cray, M.D.

Overview (4)

CNS Pharmacology Lecture 1

 Many CNS disorders are not completely understood and thus, they are imperfectly treated with current medications  basic research findings continuously provide promising leads for new drugs  More is also being learned about the disorders themselves For example:  It is now recognized that clinical depression and clinical anxiety are biochemically distinct from normally experienced feelings of sadness or apprehension (respectively)  Schizophrenia is now known to consist of what are known as positive and negative symptoms  Pain is now known to be multifaceted  Neuronal atrophy is implicated in conditions in which it was not previously suspected

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Overview (4) ď ąDrugs targeted to CNS disorders, like drugs used for conditions affecting the PNS but to a much larger extent, are subject to abuse--sometimes by patients but more often by non-patients ď ąSuch abuse can adversely affect the availability of these drugs (such as opioids for relief of severe pain) to patients in need

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Self-directed learning and review Along with the data provided in UNIT 3 of your MedPharm Digital Guidebook (DRUGS USED IN DISORDERS OF THE CNS AND Tx OF PAIN) the following illustration plates in Netter's Illustrated Pharmacology, Updated Edition (2014) * should serve useful to review for this introduction to CNS Pharm presentation:     

Development of the Nervous System (NIP 3-1) Anatomy of the Nervous System (NIP 3-2) Functional Correlations and Visualization of Brain Structures (NIP 3-3) Resting Membrane and Action Potentials (NIP 3-4) Excitatory and Inhibitory Postsynaptic Potentials (NIP 3-5)

Marc Imhotep Cray, M.D.

* Hyperlink offline. Student access (MS1 & MS2 Core Digital Textbooks Thumb Drive)

Cell Types in the CNS: Neurons and Glia

CNS Pharmacology Lecture 1

 The CNS is composed of two predominant cell types, neurons and glia, each of which has many morphologically and functionally diverse subclasses  Glial cells outnumber neurons and contain many neurotransmitter receptors and transporters  There are three types of glial cells: 1. Astrocytes 2. Oligodendrocytes 3. Microglia Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Glia Cells Function, Astrocytes ď ą Astrocytes physically separate neurons and multineuronal pathways, assist in repairing nerve injury, and modulate the metabolic and ionic microenvironment ď ą Astrocytes express ion channels and neurotransmitter transport proteins and play an active role in modulating synapse function

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Glia Cells Function, Oligodendrocytes ď ą Oligodendrocytes form the myelin sheath around axons and play a critical role in maintaining transmission down axons ď ą Polymorphisms (SNP) in the genes encoding several myelin proteins have been identified in tissues from patients with both schizophrenia and bipolar disorder and may contribute to the underlying etiology of these disorders

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Glia Cells Function, Microglia ď ą Microglia proliferate after injury or degeneration, move to sites of injury, and transform into large macrophages (phagocytes) to remove cellular debris

ď ą These antigen presenting cells (APC) with innate immune function also appear to play a role in endocrine development

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Cell Types in the CNS: Neurons

Structural components of nerve cells.

 Neurons are the major cells involved in intercellular communication because of their ability to conduct impulses and transmit information  They are structurally different from other cells, with four distinct features:  Dendrites  A perikaryon (cell body or soma)  An axon  A nerve (or axon) terminal Wecker L, et al. Brody’s human pharmacology : molecular to clinical 5th ed.

Marc Imhotep Cray, M.D.

CNS Neurotransmitters, Receptors, and Drug Targets

CNS Pharmacology Lecture 1

 Many substances within the CNS modulate neurotransmitter (NT) actions  ACh and norepinephrine (NE), predominant in the PNS, also function in CNS  Dopamine and 5-HT (serotonin)-more prominent in the CNS-and peptides such as endorphins are important in CNS function  Transduction mechanisms for NT action are similar to those in the PNS:  Ionotropic types include: voltage-gated ion channels (respond to membrane potential changes) and ligand-gated ion channels (alter membrane ion permeability in response to ligands such as neurotransmitters or drugs)  Metabotropic types include: GPCRs and involve second-messenger pathways (affect ion channels or biochemical reactions)

Marc Imhotep Cray, M.D.

CNS Neurotransmitters, Receptors, and Drug Targets (2)

CNS Pharmacology Lecture 1

Drugs affect various sites along neuronal pathways, including:  neurotransmitter synthesis, storage, and release;  receptor activation and inhibition;  modulation of intrasynaptic neurotransmitter metabolism or reuptake; and  direct second-messenger pathway effects Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Neurotransmitters of the Brain and Disease  Treatable neurotransmission diseases fall into two categories:  those caused by too much neurotransmission and  those caused by too little neurotransmission

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

“Too much” neurotransmission May be due to: A focus of hyperexcitable neurons that fire in the absence of appropriate stimuli (e.g., seizure disorders)  Therapy is directed toward reducing automaticity of these cells Too many neurotransmitter molecules binding to postsynaptic receptors (possible explanation for psychoses)  Therapy includes administration of antagonists which block postsynaptic receptors Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

“Too little” neurotransmission May be due to:  Too few neurotransmitter molecules binding to postsynaptic receptors (e.g., depression, Parkinson's disease)  Several treatment strategies increase neurotransmission, including: 1) drugs that cause release of NT stores from presynaptic terminal, 2) neurotransmitter precursors that are taken-up into presynaptic neurons and metabolized into active neurotransmitter, 3) drugs which inhibit enzymes that degrade neurotransmitters 4) agonists that act at postsynaptic receptors

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

CNS Drugs and Side Effects ď ą Because numerous pathways in brain use the same neurotransmitter, manipulating transmission in a diseased pathway simultaneously affects synapses of normal neurons ď ą For this reason, CNS drugs are notorious for causing a variety of side effects

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Representative Neurotransmitters in the CNS

Marc Imhotep Cray, M.D.

Wecker L, et al. Brodyâ&#x20AC;&#x2122;s human pharmacology : molecular to clinical 5th ed.

Most Well Studied Neurotransmitters of the Brain 1) 2) 3) 4) 5) 6) 7) 8)

CNS Pharmacology Lecture 1

Norepinephrine Dopamine 5-Hydroxytryptamine (5-HT, Serotonin) Acetylcholine Gamma-amino butyric acid (GABA) Excitatory Amino Acids (EAA), Glutamate The Endogenous Opioids Other Neuropeptides

Marc Imhotep Cray, M.D.

1) Norepinephrine

CNS Pharmacology Lecture 1

 As you learned during the study of the PNS, there are four classes of adrenergic receptors: α1, α2, β1, β2  Pathways in the brain that utilize NE have not been as clearly identified as in the PNS  A leading hypothesis suggests depression is caused by impaired monoamine (e.g., norepinephrine, dopamine, serotonin) neurotransmission  Drugs which induce monoamine release are indicated for attention Deficit Hyperactivity disorder (ADHD) and narcolepsy  However, the biochemical disturbance responsible for these two diseases is still not well understood and under ongoing investigation Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

2) Dopamine ď ą Dopamine is synthesized from Dopa, the hydroxylated congener of the amino acid tyrosine ď ą It is degraded by monoamine oxidase A in the brain and monoamine oxidase B and catechol-o-methyl transferase (COMT) outside the CNS

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Dopamine (2) Dopamine (DA) receptors are classified as D1 & D2  Both subtypes reside in numerous regions of the brain No specific D1 agonists have been identified Activation of either subtype inhibits the rate of neuronal firing

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Dopamine (3)  In the CNS, dopamine serves as a neuromodulator  Two groupings can be distinguished:  the family of D1-like receptors (comprising subtypes D1 and D5) and  the family of D2-like receptors (comprising subtypes D2, D3, and D4)  Subtypes differ in their signal transduction pathways  For example, synthesis of cAMP is stimulated by D1-like receptors but inhibited by D2-like receptors  Released DA can be reutilized by neuronal reuptake and restorage in vesicles or can be catabolized like other endogenous catecholamines by the enzymes MAO and COMT Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Dopamine (4) ď ąParticularly important dopaminergic pathways include: 1) the nigrostriatal pathway (from substantia nigra to striatum) 2) neurons of the chemoreceptor trigger zone (CTZ) of the medulla, which controls vomiting, and ď&#x201A;§ E.g., Apomorphine is a D2 agonist=emesis-inducing 3) projections from the hypothalamus to the intermediate lobe of the anterior pituitary, which regulate prolactin release ď&#x201A;§ Marc Imhotep Cray, M.D.

In other words PIF is mediated via DAergic neurons 30

CNS Pharmacology Lecture 1

Dopamine (5)  Antipsychotic drugs inhibit dopamine-stimulated adenylate cyclase (usually associated with D1 receptor activation) and block D2 dopamine receptors  suggest psychoses may result from overstimulation of dopamine receptors  Parkinson's Disease, is caused by too little dopaminergic input from the substantia nigra into the striatum  Loss of the nigrostriatal dopamine neurons results in a relative decrease in dopamine input (inhibitory) compared to acetylcholine input (excitatory)

Marc Imhotep Cray, M.D.

3) 5-Hydroxytryptamine (5-HT, Serotonin)

CNS Pharmacology Lecture 1

 The amino acid tryptophan is hydroxylated and then decarboxylated to form 5-HT  In neurons, 5-HT is stored (in vesicles), released, taken up into presynaptic neurons and either recycled or metabolized  5-HT is released from inhibitory neurons originating in the raphe nuclei of the pons and midbrain  5-HT stimulates either 5-HT1 or 5-HT2 receptors which are distinguished by specific antagonists  methysergide (5-HT1-specific) and  ketanserin (5-HT2-specific) Marc Imhotep Cray, M.D.

Serotonin (2)

CNS Pharmacology Lecture 1

ď ą The hallucinogenic drug, lysergic acid diethylamide (LSD) is a potent agonist at both receptor subtype ď ą In addition to its role as a neurotransmitter, 5-HT increases small intestine motility and modulates vasodilation ď ą Ninety percent of the body's 5-HT is stored in enterochromaffin cells of the small intestine Clinical correlation: Carcinoid Syndrome: An unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not surgically resectable, a serotonin antagonist may constitute a useful treatment. Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Serotonin (3)  Depression, attention deficit disorder and headaches have been attributed to serotonergic imbalances

 Many serotonergic agents have been developed in the last few years for the treatment of these diseases N.B. Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome (previous slide). More on 5-HT in the ”Histamine, Serotonin, & the Ergot Alkaloids” UNIT Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Serotonin (4) Excess 5-HT can result from accidental or intentional overdose of drugs that directly activate serotonin receptors or, more commonly, drugs that indirectly enhance serotonin levels  by inhibiting presynaptic neuronal reuptake of serotonin  by inhibiting serotonin breakdown by monoamine oxidase  E.g., selective serotonin reuptake inhibitors,  nonselective serotonin reuptake inhibitors, and  MAOIs

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

4) Acetylcholine (Ach)  The synthesis, release and degradation of acetylcholine was learned in PNS study  Acetylcholine binds to both muscarinic (AChm ) and nicotinic (AChn ) receptors throughout the brain (Drugs which mimic or modify acetylcholine neurotransmission were also covered in PNS)

 Cholinergic antagonists are used in the treatment of Parkinson's disease to correct the imbalance of ACh and DA neurotransmission created by the degradation of dopaminergic nerves  Cholinergic or anti-cholinergic drugs are not otherwise used to treat CNS disorders

Marc Imhotep Cray, M.D.

5) Gamma-amino butyric acid (GABA)

CNS Pharmacology Lecture 1

GABA is an inhibitory amino acid neurotransmitter of brain interneurons and other cerebral neurons The enzyme glutamic acid decarboxylase catalyzes the synthesis of GABA from glutamate GABA is stored in presynaptic vesicles and binds to either GABA-A or GABA-B receptors upon release

Marc Imhotep Cray, M.D.

γ-aminobutyric acid (GABA) (2)

CNS Pharmacology Lecture 1

 GABA receptors reside on two subunits of a four subunit receptor complex that surrounds and regulates a chloride ion channel  GABA activation of the receptor induces chloride influx into the neuron>>> this hyperpolarizes the neuron, making it more difficult to fire when stimulated by excitatory neurotransmitters  Benzodiazepines (BDZ) enhance the actions of GABA at GABA-A receptors, but not GABA-B receptors  Agents which enhance actions of GABA such as BDZ and barbiturates are used to Tx anxiety & seizures and as sedatives or muscle relaxants Marc Imhotep Cray, M.D.

The GABA-A receptor depicting the membrane-associated protein composed of five subunits, the Cl– channel, and relative location of binding sites for GABA, benzodiazepines, barbiturates, and picrotoxin. From: Brody’s Human Pharmacology, 2010

6) Excitatory Amino Acids (EAA), Glutamate

CNS Pharmacology Lecture 1

 Glutamate or a structurally-similar chemical is an excitatory neurotransmitter in many areas of the brain  Stimulation of EAA receptors increases cation conductance, leading to depolarization, or stimulates phosphatidyl inositol turnover  Glutamate transmission occurs via N-methyl-D-aspartate (NMDA) receptors  Memantine, used in the Tx of Alzheimer’s disease, binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Glutamate (2)  Excitatory amino acids such as glutamate are thought to be important in learning, memory and other brain functions  Glutamate induced excitotoxicity is implicated in the pathogenesis of Alzheimer's Disease, Huntington's Disease, stroke, epilepsy and amyotrophic lateral sclerosis (ALS)  Riluzole protects neurons from glutamate toxicity in animals and minimally slows progression of ALS Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

N-Methyl-D-Aspartate (NMDA)  Glutamate is an excitatory neurotransmitter, and NMDA receptors (NMDAR) are one type of glutamate receptor

 Binding of glutamate to NMDA receptors results in opening of Ca2+ channels, leading to cellular depolarization and increased neuronal activity  Blockade of glutamate at NMDA receptors therefore results in reduced excitation of neurons in the brain

Marc Imhotep Cray, M.D.

7) The Opioids

CNS Pharmacology Lecture 1

 Endorphins, enkephalins and dynorphins are endogenous opiate receptor agonists that are cleaved from a protein called pro-opiomelanocortin  Opiate receptors are located along the periaqueductal gray matter  Morphine and related drugs act at opiate receptors to relieve pain  In times of stress or pain, endogenous peptides act at opiate receptors

Marc Imhotep Cray, M.D.

8) Other Neuropeptides

CNS Pharmacology Lecture 1

 In addition to the endogenous opiate peptides, other peptides function as neurotransmitters e.g.,  Substance P  vasoactive intestinal peptide (VIP)  These agents are generally cleaved from larger peptide precursors  They can assume a variety of three dimensional shapes, making it difficult to assess the chemistry of peptide-receptor interactions 

For this reason, no chemical agonists (other than morphine) or antagonists have been identified for peptide receptors

Marc Imhotep Cray, M.D.

THE END

Marc Imhotep Cray, M.D.

CNS Pharmacology Lecture 1

Further study (SDL): Online resource center: Medical Pharmacology Cloud Folder

Lectures/discussions to follow: 2. 3. 4. 5. 6. 7. 8. 9.

Sedative-Hypnotic and Anxiolytic Drugs Antiepileptic Agents Antidepressants Drugs Affecting Bipolar Disorder Antipsychotic Agents Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders CNS Skeletal Muscle Relaxants Analgesics and Anesthetics

Marc Imhotep Cray, M.D.