Bio 117 - Basic Pharmacology Module 4 PDF

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Central Nervous System MODULE 4  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM Organization of the CNS The CNS is composed of the brain and spinal cord and is responsible...

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Central Nervous System MODULE 4  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM Organization of the CNS The CNS is composed of the brain and spinal cord and is responsible for integrating sensory information and generating motor output and other behaviors needed to successfully interact with the environment and enhance species survival. The human brain contains about 100 billion interconnected neurons surrounded by various supporting glial cells. Throughout the CNS, neurons are either clustered into groups called nuclei or are present in layered structures such as the cerebellum or hippocampus. Connections among neurons both within and between these clusters form the circuitry that regulates information flow through the CNS. Neurons The typical neuron possesses a cell body (or soma) and specialized processes called dendrites and axons (Figure 2.37). Dendrites receive and integrate the input from other neurons and conduct this information to the cell body. The axon carries the output signal of a neuron from the cell body, sometimes over long distances. The axon terminal makes contact with other neurons at specialized junctions called synapses where neurotransmitter chemicals are released that interact with receptors on other neurons. Neuroglia These are a large number of nonneuronal support cells that perform a variety of essential functions in the CNS. Astrocytes are the most abundant cell in the brain and play homeostatic support roles, including providing metabolic nutrients to neurons and maintaining extracellular ion concentrations. In addition, astrocyte processes are closely 2 associated with neuronal synapses where they are involved in the removal and recycling of neurotransmitters after release and play increasingly appreciated roles in regulating neurotransmission (Figure 2.37). Oligodendrocytes are cells that wrap around the axons of projection neurons in the CNS forming the myelin sheath (Figure 2.37). Similar to the Schwann cells in peripheral neurons, the myelin sheath created by the oligodendrocytes insulates the axons and increases the speed of signal propagation. Damage to oligodendrocytes occurs in multiple sclerosis, and thus, they are a target of drug discovery efforts. Microglia are specialized macrophages derived from the bone marrow that settle in the CNS and are the major immune defense system in the brain. The cells are actively involved in neuroinflammatory processes in many pathological states including neurodegenerative diseases. Page 1  Discussion I. INTRODUCTION TO THE CNS Organization of the CNS Blood Brain Barrier This is a protective functional separation of the circulating blood from the ECF of the CNS that limits the penetration of substances, including drugs. This separation is accomplished by the presence of tight junctions between the capillary endothelial cells as well as a surrounding layer of astrocyte end-feet. As such, to enter the CNS, drugs must either be highly hydrophobic or engage specific transport mechanisms. For example, the second-generation antihistamines cause less drowsiness because they were developed to be significantly more polar than older antihistamines, limiting their crossing of the BBB. Many nutrients (i.e., glucose and essential amino acids) have specific transporters that allow them to cross the BBB. L-Dopa, a precursor of the neurotransmitter dopamine, can enter the brain using an amino acid transporter, whereas dopamine cannot cross the BBB. Thus, the orally administered drug L-DOPA, but not dopamine, can be used to boost CNS dopamine levels in the treatment of Parkinson’s disease. Some parts of the brain, the so-called circumventricular organs, lack a normal BBB. 3 Figure 2.15 Neurons and glia in the CNS. A typical neuron has a cell body that receives the synaptic responses from the dendritic tree. These synaptic responses are integrated at the axon initial segment, which has a high concentration of voltage-gated sodium channels. If an action potential is initiated, it propagates down the axon to the synaptic terminals, which contact other neurons. The axon of long- range projection neurons are insulated by a myelin sheath derived from oligodendrocytes. Astrocytes perform supportive roles in the CNS, and their processes are closely associated with neuronal synapses. Source: Katzung BG. 2018. Basic and Clinical Pharmacology. 14th ed. Page 2  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM NEUROTRANSMISSION IN THE CNS In many ways, the basic functioning of neurons in the CNS is similar to that of the ANS. The transmission of information in the CNS and in the periphery both involve the release of neurotransmitters that diffuse across the synaptic space to bind to specific receptors on the postsynaptic neuron. In both systems, the recognition of the neurotransmitter by the membrane receptor of the postsynaptic neuron triggers intracellular changes. However, several major differences exist between neurons in the peripheral ANS and those in the CNS: The circuitry of the CNS is much more complex than that of the ANS, and the number of synapses in the CNS is far greater. The CNS, unlike the peripheral ANS, contains powerful networks of inhibitory neurons that are constantly active in modulating the rate of neuronal transmission. The CNS communicates through the use of more than 10 (and perhaps as many as 50) different neurotransmitters. In contrast, ANS uses only two primary neurotransmitters, acetylcholine and norepinephrine. The table below describes some of the more important neurotransmitters in the CNS. NEUROTRANSMITTER POSTSYNAPTIC EFFECTS Acetylcholine Excitatory: Involved in arousal, short-term memory, and learning BIOGENIC Norepinephrine Excitatory: Involved in arousal, wakefulness, mood and cardiovascular function AMINES 4 Dopamine Excitatory: Involved in emotion and reward systems Serotonin Excitatory: Feeding behavior, control of body temperature, modulation of sensory pathways including nociception (pain), regulation of mood & emotion, and in sleep/wakefulness AMINO GABA Inhibitory: Mediates the majority of inhibitory postsynaptic potentials ACIDS Glycine Inhibitory: Increases Cl- flux into the postsynaptic neuron, resulting in hyperpolarization Glutamate Excitatory: Mediates excitatory Na+ influx into the postsynaptic neuron NEURO- Substance P Excitatory: Mediates nociception (pain) within the spinal cord PEPTIDES Met-enkephalin Generally inhibitory: Mediates analgesia as well as other CNS effects. Page 3  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM ACTION POTENTIAL An action potential is a rapid rise and subsequent fall in voltage or membrane potential across a cellular membrane with a characteristic pattern. Sufficient current is required to initiate a voltage response in a cell membrane; if the current is insufficient to depolarize the membrane to the threshold level, an action potential will not fire. Examples of cells that signal via action potentials are neurons and muscle cells. 1. Stimulus starts the rapid change in voltage or action potential. Sufficient current must be administered to the cell in order to raise the voltage above the threshold voltage to start membrane depolarization. 2. Depolarization is caused by a rapid rise in membrane potential caused by the opening of sodium channels in the cellular membrane, resulting in a large influx of sodium ions. 3. Membrane Repolarization results from rapid sodium channel inactivation as well as a large efflux of potassium ions resulting from activated potassium channels. 4. Hyperpolarization is a lowered membrane potential caused by the efflux of potassium ions and closing of the potassium channels. 5. Resting state is when membrane potential returns to the resting voltage that occurred before the stimulus occurred. 5 Page 4  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM SYNAPTIC POTENTIALS In the CNS, receptors at most synapses are coupled to ion channels; that is, binding of the neurotransmitter to the postsynaptic membrane receptors results in a rapid but transient opening of ion channels. Open channels allow specific ions inside and outside the cell membrane to flow down their concentration gradients. The resulting change in the ionic composition across the membrane of the neuron alters the postsynaptic potential, producing either depolarization or hyperpolarization of the postsynaptic membrane, depending on the specific ions that move and the direction of their movement. Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they elicit. A. Excitatory Pathways Stimulation of excitatory neurons causes a movement of ions that results in a depolarization of the postsynaptic membrane. These excitatory postsynaptic potentials (EPSP) are generated by the following: Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of sodium (Na+) ions. 6 The influx of Na+ causes a weak depolarization or EPSP that moves the postsynaptic potential toward its firing threshold. If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released. This ultimately causes the EPSP depolarization of the postsynaptic cell to pass a threshold, thereby generating an all-or-none action potential. Note: The generation of a nerve impulse typically reflects the activation of synaptic receptors by thousands of excitatory neurotransmitter molecules released from many nerve fibers. See Figure 2.16 for an example of an excitatory pathway. Page 5  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM SYNAPTIC POTENTIALS 7 Figure 2.16 Binding of the excitatory Figure 2.17 Binding of the inhibitory neurotransmitter, Ach, causes depolarization neurotransmitter, GABA, causes of the neuron. hyperpolarization of the neuron. Source: Lippincott’s Illustrated Reviews: Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Pharmacology. 4th ed. Page 6  Discussion I. INTRODUCTION TO THE CENTRAL NERVOUS SYSTEM SYNAPTIC POTENTIALS B. Inhibitory Pathways Stimulation of inhibitory neurons causes movement of ions that results in a hyperpolarization of the postsynaptic membrane. These inhibitory postsynaptic potentials (IPSP) are generated by the following: Stimulation of inhibitory neurons releases neurotransmitter molecules, such as γ- aminobutyric acid (GABA) or glycine, which bind to receptors on the postsynaptic cell membrane. This causes a transient increase in the permeability of specific ions, such as potassium (K+) and chloride (Cl-) ions. The influx of Cl- and efflux of K+ cause a weak hyperpolarization or IPSP that moves the postsynaptic potential away from its firing threshold. This diminishes the generation of action potentials. See Figure 2.17 for an example of an inhibitory pathway. C. Combined effects of the EPSP and IPSP Most neurons in the CNS receive both EPSP and IPSP input. Thus, several different types of neurotransmitters may act on the same neuron, but each binds to its own specific receptor. The overall resultant action is due to the summation of the individual actions of the various neurotransmitters on the neuron. 8 The neurotransmitters are not uniformly distributed in the CNS but are localized in specific clusters of neurons, the axons of which may synapse with specific regions of the brain. Many neuronal tracts thus seem to be chemically coded, and this may offer greater opportunity for selective modulation of certain neuronal pathways. Page 7  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Most drugs that affect the central nervous system (CNS) act by altering some step in the neurotransmission process. Drugs affecting the CNS may act presynaptically by influencing the production, storage, release, or termination of action of neurotransmitters. Other agents may activate or block postsynaptic receptors. A. TREATMENT OF NEURODEGENERATIVE DISEASES Neurodegenerative diseases of the CNS include Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These devastating illnesses are characterized by the progressive loss of selected neurons in discrete brain areas, resulting in characteristic disorders of movement, cognition, or both. For example, Alzheimer's disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Meynert, whereas Parkinson's disease is associated with a loss of dopaminergic neurons in the substantia nigra. The most prevalent of these disorders is Alzheimer's disease, estimated to have affected 5.8 million Americans in 2020. The number of cases is expected to increase as the proportion of elderly in the population increases. 9 Source:https://www.researchgate.net/publication/323264412_M echanisms_of_aSynuclein_Induced_Synaptopathy_in_Parkinso n%27s_Disease/figures?lo=1 Source: https://www.researchgate.net/publication/281621972_Disease- modifying_therapeutic_directions_for_Lewy-Body_dementias/figures?lo=1 Page 8  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Drugs used in Parkinson’s Disease Etiology: Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. Most cases involve people over the age of 65, among whom the incidence is about 1 in 100 individuals. The cause of Parkinson's disease is unknown for most patients. The disease is correlated with destruction of dopaminergic neurons in the substantia nigra with a consequent reduction of dopamine actions in the corpus striatum-parts of the brain's basal ganglia system that are involved in motor control. Levodopa and carbidopa Action: Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. Therapeutic uses: Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson's disease. 10 Levodopa-carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy. Adverse effects: Anorexia, nausea & vomiting, tachycardia, hypotension, depression, mood changes, anxiety, visual & auditory hallucinations. Figure 2.39 Parkinson’s disease symptoms Page 9 Source: https://www.labiotech.eu/trends-news/axovant-parkinsons-disease-gene/  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Drugs used in Alzheimer’s Disease Etiology: Alzheimer's disease is thought to be caused by the abnormal build-up of proteins in and around brain cells. One of the proteins involved is called amyloid, deposits of which form plaques around brain cells. The other protein is called tau, deposits of which form tangles within brain cells. Pharmacologic intervention for Alzheimer's disease is only palliative and provides modest short-term benefit. None of the currently available therapeutic agents have been shown to alter the underlying neurodegenerative process. Dementia of the Alzheimer's type has three distinguishing features: 1) accumulation of senile plaques (β-amyloid accumulations), 2) formation of numerous neurofibrillary tangles, and 3) loss of cortical neurons - particularly cholinergic neurons. Acetylcholinesterase inhibitors Action: It is postulated that inhibition of acetylcholinesterase (AChE) within the CNS will improve cholinergic transmission, at least at those neurons that are still functioning. Currently, four reversible AChE inhibitors are approved for the treatment of mild to moderate Alzheimer's disease. They are 11 donepezil, galantamine, rivastigmine, and tacrine. Except for galantamine, which is competitive, all are noncompetitive inhibitors of AChE and appear to have some selectivity for AChE in the CNS as compared to the periphery. Therapeutic uses: These drugs provide a modest reduction in the rate of loss of cognitive functioning in Alzheimer's patients. Figure 2.39 Alzheimer’s disease Source: Adverse effects: nausea & vomiting, https://medlineplus.gov/ency/article/000760.htm/ diarrhea, anorexia, tremors, bradycardia, Page 10 muscle cramps or muscle pain.  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM B. ANXIOLYTIC AND HYPNOTIC DRUGS Etiology: Anxiety disorders appear to be caused by an interaction of biopsychosocial factors, including genetic vulnerability, which interact with situations, stress, or trauma to produce clinically significant syndromes. Anxiety is an unpleasant state of tension, apprehension, or uneasiness - a fear that seems to arise from a sometimes unknown source. Disorders involving anxiety are the most common mental disturbances. The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Episodes of mild anxiety are common life experiences and do not warrant treatment. However, the symptoms of severe, chronic, debilitating anxiety may be treated with antianxiety drugs (anxiolytic or minor tranquilizers). Many antianxiety drugs cause some sedation and are used as hypnotic (sleep-inducing) agents. ANXIOLYTIC AND HYPNOTIC DRUGS Benzodiazepines Action: The targets for benzodiazepine actions are the GABA receptors, modulating their effects. All benzodiazepines exhibit the following actions to a greater or lesser extent: reduction of anxiety, sedative & hypnotic actions, anterograde amnesia, anticonvulsant, and muscle relaxant. Benzodiazepines include 12 flurazepam, temazepam, triazolam, alprazolam (agent of choice in treating panic disorders) Therapeutic uses: Benzodiazepines are used in the treatment of anxiety disorders, muscular disorders, amnesia, seizures, and sleep disorders. Adverse effects: drowsiness, confusion, ataxia (at high doses). Figure 2.41 Generalized anxiety disorder symptoms Page 11 Sourcehttps://www.verywellmind.com/dsm-5-criteria-for-generalized-anxiety-disorder-1393147  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM C. CNS STIMULANTS Two groups of drugs act primarily to stimulate the CNS: (1) Psychomotor stimulants - cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity; (2) Hallucinogens, or psychotomimetic drugs - produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord. These have the ability to induce altered perceptual states reminiscent of dreams. Many of these altered states are accompanied by bright, colorful changes in the environment and by a plasticity of constantly changing shapes and color. The individual under the influence of these drugs is incapable of normal decision making, because the drug interferes with rational thought. As a group, the CNS stimulants have diverse clinical uses and are important as drugs of abuse CNS STIMULANTS DRUGS ACTION THERAPEUTIC ADVERSE EFFECTS USES PSYCHOMOTOR STIMULANTS Methyl Decreased fatigue Relax smooth muscles Moderate doses: xanthines: of bronchioles insomnia, anxiety, Increased mental alertness agitation theophylline Asthma therapy Increased heart rate (theophylline) At high doses, toxicity Theobromine 13 manifested by emesis caffeine Diuretic and convulsions Stimulate gastric (HCl) secretion At low doses, euphoria, arousal, relaxation Has potential for Nicotine None addiction (tobacco) At high doses, central respiratory paralysis, severe Irritability hypotension, activity of GIT and Tremors bladder muscles stops Intestinal cramps Diarrhea Increased heart rate Increased heart rate and Increased motor activity of blood pressure bowel Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 12  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM CNS STIMULANTS DRUGS ACTION THERAPEUTIC ADVERSE EFFECTS USES PSYCHOMOTOR STIMULANTS increases mental awareness Has potential for and produces a feeling of well- Local anesthetic: eye, addiction being and euphoria ear, nose and throat surgery Anxiety reactions – produce hallucinations and hypertension, delusions of paranoia or tachycardia, sweating, grandiosity paranoia Cocaine increases motor activity Depression at high doses, it causes tremors Heart disease & convulsions, followed by respiratory & vasomotor Death can result, as a depression function of dose and drug-induced Produces “fight or flight” hyperthermia syndrome characteristics: tachycardia, hypertension, mydriasis, peripheral vasoconstriction increases mental awareness Treatment of attention Has potential for and produces a feeling of well- deficit hyperactivity addiction being and euphoria disorder (ADHD) CNS: insomnia, 14 produce hallucinations and Treatment of narcolepsy irritability, weakness, delusions of paranoia or dizziness, tremor, grandiosity hyperactive reflexes Amphetamine Increase alertness CV: palpitations, cardiac arrhythmias, Decreased fatigue hypertension, anginal pain, circulatory collapse Depressed appetite GIT: nausea, vomiting, Insomnia abdominal cramps, diarrhea Page 13 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Figure 2.42 Mechanism of action of cocaine 15 Figure 2.43 Major Figure 2.44 effects of cocaine use Mechanism of action Figure 2.45 Adverse of amphetamine effects of amphetamine Page 14 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM CNS STIMULANTS DRUGS ACTION THERAPEUTIC ADVERSE EFFECTS USES HALLUCINOGENS Mydriasis Tolerance and physical Increased blood pressure dependence Lysergic acid Piloerection diethylamide Increased body temperature hyperreflexia nausea (LSD) At low doses, can induce muscular weakness hallucinations with brilliant colors, mood alterations High doses may produce long-lasting psychotic changes in susceptible individuals euphoria, followed by drowsiness Available as increased heart rate and relaxation. Dronabinol decreased blood pressure Affects short-term memory and indicated for patients mental activity with AIDS who are reddening of the Tetrahydro- losing weight conjunctiva cannabinol decreases muscle strength and (main impairs highly skilled motor Given for severe At high doses, a toxic psychoactive activity, such as that required to emesis caused by psychosis develops alkaloid in drive a car some cancer marijuana) Tolerance and mild appetite stimulation, xerostomia, physical dependence visual hallucinations, delusions, occur with continued, 16 and enhancement of sensory frequent use of the drug activity produces hypersalivation numbness of extremities staggered gait Phencyclidine causes dissociative anesthesia slurred speech (insensitivity to pain, without loss muscular rigidity of consciousness) and analgesia (PCP, “angel Sometimes, hostile and dust”) bizarre behavior occurs increased dosages cause anesthesia, stupor, or coma Page 15 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM D. ANESTHETICS General anesthesia is essential to surgical practice, because it renders patients analgesic, amnesic, and unconscious, and provides muscle relaxation and suppression of undesirable reflexes. No single drug is capable of achieving these effects both rapidly and safely. Rather, several different categories of drugs are utilized to produce optimal anesthesia (Figure 2.46). Preanesthetic medication serves to calm the patient, relieve pain, and protect against undesirable effects of the subsequently administered anesthetic or the surgical procedure. Skeletal muscle relaxants facilitate intubation and suppress muscle tone to the degree required for surgery. Potent general anesthetics are delivered via inhalation or intravenous injection. With the exception of nitrous oxide, modern inhaled 17 anesthetics are all volatile, halogenated hydrocarbons derived from diethyl ether and chloroform. Intravenous general anesthetics consist of a number of chemically unrelated drug types that are commonly used for the rapid induction of anesthesia. Figure 2.46 Summary of anesthetics Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 16  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM D. ANESTHETICS Stages of Anesthesia The depth of anesthesia has been divided into four sequential stages. Each stage is characterized by increased CNS depression, which is caused by accumulation of the anesthetic drug in the brain (Figure 2.46). These stages were discerned and defined with ether, which produces a slow onset of anesthesia. However, with halothane and other commonly used anesthetics, the stages are difficult to characterize clearly because of the rapid onset of anesthesia. Stage 1 - Analgesia Loss of pain sensation results from interference with sensory transmission in the spinothalamic tract. The patient is conscious and conversational. Amnesia and a reduced awareness of pain occur as Stage II is approached. Stage 2 - Excitement The patient experiences delirium and possibly violent, combative behavior. There is a rise and irregularity in blood pressure. The respiratory rate may increase. To avoid this stage of anesthesia, a short-acting barbiturate, such as thiopental, is given intravenously before inhalation anesthesia is administered. Stage 3 – Surgical anesthesia 18 Regular respiration and relaxation of the skeletal muscles occur in this stage. Eye reflexes decrease progressively, until the eye movements cease and the pupil is fixed. Surgery may proceed during this stage. Stage 4 - Medullary paralysis Severe depression of the respiratory and vasomotor centers occur during this stage. Death can rapidly ensue unless measures are taken to maintain circulation and respiration. Figure 2.46 Stages of anesthesia Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 17  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM D. ANESTHETICS Inhalation Anesthetics Inhaled gases are the mainstay of anesthesia and are used primarily for the maintenance of anesthesia after administration of an intravenous agent. No one anesthetic is superior to another under all circumstances. Benefit over IV agents: the depth of anesthesia can be rapidly altered by changing the concentration of the drug. Inhalation anesthetics are also reversible, because most are rapidly eliminated from the body by exhalation. These include halothane, enflurane, isoflurane, desflurane, sevoflurane, and nitrous oxide. Common features of inhalation anesthetics nonflammable, nonexplosive agents that include the gas nitrous oxide as well as a number of volatile, halogenated hydrocarbons; decrease cerebrovascular resistance, resulting in increased perfusion of the brain; cause bronchodilation which allows redirection of pulmonary blood flow to regions that are richer in oxygen content; The movement of these agents from the lungs to the different body compartments depends upon their solubility in blood and tissues as well as on blood flow. These factors play a role not only in induction but also in recovery. 19 Intravenous Anesthetics Intravenous anesthetics are often used for the rapid induction of anesthesia, which is then maintained with an appropriate inhalation agent. They rapidly induce anesthesia and must therefore be injected slowly. Recovery from intravenous anesthetics is due to redistribution from sites in the CNS. These include barbiturates, benzodiazepines, opioids, etomidate, ketamine, and propofol. Page 18  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Figure 2.48 Summary: Drugs used for local anesthesia. 20 Source: Katzung BG. 2017. Basic & Clinical Pharmacology Page 19  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM D. ANESTHETICS Local Anesthetics Local anesthetics are generally applied locally and block nerve conduction of sensory impulses from the periphery to the CNS. Local anesthetics abolish sensation (and, in higher concentrations, motor activity) in a limited area of the body without producing unconsciousness (for example, during spinal anesthesia). The small, unmyelinated nerve fibers that conduct impulses for pain, temperature, and autonomic activity are most sensitive to actions of local anesthetics. The most widely used of these compounds are bupivacaine, lidocaine, mepivacaine, procaine, ropivacaine, and tetracaine. Of these, lidocaine is the most frequently employed. At physiologic pH, these compounds are charged; it is this ionized form that interacts with the protein receptor of the Na+ channel to inhibit its function and, thereby, achieve local anesthesia. By adding the vasoconstrictor epinephrine to the local anesthetic, the rate of anesthetic absorption is decreased. This both minimizes systemic toxicity and increases the duration of action. Adverse effects result from systemic absorption of toxic amounts of the locally applied anesthetic. Seizures and cardiovascular collapse are the most significant of these 21 systemic effects. Bupivacaine is noted for its cardiotoxicity. Mepivacaine should not be used in obstetric anesthesia due to its increased toxicity to the neonate. Allergic reactions may be encountered with procaine, which is metabolized to p-aminobenzoic acid. Page 20  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM E. ANTIDEPRESSANT DRUGS Depression is a serious disorder that afflicts approximately 14 million adults in the United States each year. The symptoms of depression are intense feelings of sadness, hopelessness, and despair, as well as the inability to experience pleasure in usual activities, changes in sleep patterns and appetite, loss of energy, and suicidal thoughts. Mania is characterized by the opposite behavior - that is, enthusiasm, rapid thought and speech patterns, extreme self-confidence, and impaired judgment. Note: Depression and mania are different from schizophrenia, which produces disturbances in thought. Mechanism of Antidepressant Drugs Most clinically useful antidepressant drugs potentiate, either directly or indirectly, the actions of norepinephrine and/or serotonin in the brain. This, along with other evidence, led to the biogenic amine 22 theory, which proposes that depression is due to a deficiency of monoamines, such as norepinephrine and serotonin, at certain key sites in the brain. The theory also envisions that mania is caused by an overproduction of these neurotransmitters. However, the amine theory of depression and mania fails to explain why the pharmacologic effects of any of the antidepressant and antimania drugs on neurotransmission occur immediately, whereas the time course for a therapeutic response occurs over several weeks. Figure 2.49 Summary of antidepressants Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 21  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM ANTIDEPRESSANT DRUGS DRUGS ACTION THERAPEUTIC USES ADVERSE EFFECTS Depression Headache Sweating Selective Obsessive-compulsive anxiety and agitation Serotonin disorder Block re-uptake of GIT effects (nausea, Re-uptake serotonin Panic disorder vomiting, diarrhea) Inhibitors (SSRIs) Generalized anxiety weakness and fatigue sexual dysfunction Premenstrual dysphoric changes in weight disorder sleep disturbances Bulimia nervosa (insomnia and somnolence) Serotonin/ selectively inhibit the effective in treating Norepinephrine re-uptake of both depression in patients in Re-uptake serotonin and whom SSRIs are inhibitors norepinephrine ineffective Atypical mixed group of Depression Antidepressants agents that have actions at several different sites moderate to severe major orthostatic hypotension block norepinephrine depression dizziness Tricyclic and serotonin panic disorder reflex tachycardia 23 Antidepressants reuptake into the Imipramine - control bed- Weight gain (TCA) neuron wetting in children (older Sexual dysfunction than 6 years) migraine headache and chronic pain syndromes Monoamine form stable for depressed patients who headache, stiff neck, Oxidase complexes with are unresponsive or tachycardia, nausea, Inhibitors MAO, causing allergic to TCAs or who hypertension, cardiac (MAOIs) irreversible experience strong anxiety arrhythmias, seizures, inactivation and possibly, stroke Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 22  Discussion II. DRUGS AFFECTING THE CNS E. ANTIDEPRESSANT DRUGS Treatment of Mania and Bipolar Disorder Lithium salts: used prophylactically for treating manic- depressive patients and in the treatment of manic episodes and, thus, is considered a “mood stabilizer”. These are effective in treating 60 to 80 % of patients exhibiting mania and hypomania. Although many cellular processes are altered by treatment with lithium salts, the mode of action is unknown. Lithium is given orally, and the ion is excreted by the kidney. Lithium salts can be toxic. Their safety factor and therapeutic index are extremely low. Common adverse effects: may include headache, dry mouth, polydipsia, polyuria, polyphagia, gastrointestinal distress (give lithium with food), fine hand tremor, dizziness, fatigue, dermatologic reactions, and sedation. At high plasma levels, ataxia, slurred speech, coarse tremors, confusion, and convulsions. Thyroid function may be decreased and should be monitored. Lithium 24 causes no noticeable effect on normal individuals. It is not a sedative, euphoriant, or depressant. Figure 2.50 Side effects of some drugs used to treat depression Page 23 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM F. NEUROLEPTIC DRUGS Other names: antipsychotic drugs, or major tranquilizers Therapeutic uses: treatment of schizophrenia and psychotic states such as manic states with psychotic symptoms such as grandiosity or paranoia and hallucinations, and delirium. All currently available antipsychotic drugs that alleviate symptoms of schizophrenia decrease dopaminergic and/or serotonergic neurotransmission. Schizophrenia This is a particular type of psychosis, a mental disorder caused by some inherent dysfunction of the brain. It is characterized by delusions, hallucinations (often in the form of voices), and thinking or speech disturbances. This mental disorder is a common affliction, occurring among about 1% of the population. The illness often initially affects people during late adolescence or early adulthood and is a chronic and disabling disorder. Schizophrenia has a strong genetic component and 25 probably reflects some fundamental biochemical abnormality, possibly a dysfunction of the mesolimbic or mesocortical dopaminergic neurons. Figure 2.51 Summary of neuroleptic agents Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 24  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM F. NEUROLEPTIC DRUGS Therapeutic uses of neuroleptic drugs 1. Treatment of schizophrenia: The neuroleptics are considered to be the only efficacious treatment for schizophrenia. Not all patients respond, and complete normalization of behavior is seldom achieved. The traditional neuroleptics are most effective in treating positive symptoms of schizophrenia (delusions, hallucinations, thought processing, and agitation). The newer agents with serotonin-blocking activity are effective in many patients who are resistant to the traditional agents, especially in treating the negative symptoms of schizophrenia (social withdrawal, blunted emotions, ambivalence, and reduced ability to relate to people). 2. Prevention of severe nausea and vomiting: The older neuroleptics (most commonly prochlorperazine) are useful in the treatment of drug-induced nausea. Nausea arising from motion should be treated with sedatives, antihistamines, and anticholinergics, however, rather than with the powerful neuroleptic drugs. [Note: Transdermal scopolamine is a drug of choice for treatment of motion sickness.] 26 Figure 2.52 Neuroleptic drugs block at dopaminergic and serotonergic receptors as well as at adrenergic, cholinergic, and histamine-binding receptors Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 25  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM Figure 2.53 Adverse effects commonly observed in individuals treated with neuroleptic drugs. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed 27 Figure 2.54 Some representative antipsychotic drugs Page 26 Source: Katzung BG. 2017. Basic & Clinical Pharmacology  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM G. OPIOID ANALGESICS AND ANTAGONISTS Pain is defined as an unpleasant sensation that can be either acute or chronic and that is a consequence of complex neurochemical processes in the PNS and CNS. Alleviation of pain depends on its type. In many cases, for example, with headaches or mild to moderate arthritic pain, nonsteroidal anti- inflammatory agents are effective. Neurogenic pain responds best to anticonvulsants (for example pregabalin) tricyclic antidepressants (for example, amitriptyline), or serotonin/norepinephrine reuptake inhibitors (for example, duloxetine) rather than NSAIDs or opioids. For severe or chronic malignant pain, opioids are usually the drugs of choice. Opioids are natural or synthetic compounds that produce morphine-like effects. The term “opiate” is reserved for drugs, such as morphine and codeine, obtained from the juice of the opium poppy. All drugs in this category act by binding to specific opioid receptors in the CNS to 28 produce effects that mimic the action of endogenous peptide neurotransmitters (for example, endorphins, enkephalins, and dynorphins). Their primary use is to relieve intense pain and the anxiety that accompanies it, whether that pain is from surgery or a result of injury or disease, such as cancer. However, their widespread availability has led to abuse of those opioids with euphoric properties. Note: Dependence is seldom a problem in patients being treated for severe pain with these agents, as in cancer or acute pain in terminally ill patients. Figure 2.55 Summary of opioid analgesics and antagonists Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 27  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM OPIOID ANALGESICS DRUGS ACTION THERAPEUTIC USES ADVERSE EFFECTS STRONG AGONIST Analgesia Pain reliever Severe respiratory Euphoria Treatment of diarrhea depression Morphine Respiratory depression Relief of cough Death in acute opioid Antitussive properties Treatment of pulmonary poisoning Miosis edema Potential for addiction Vomiting Urinary retention Decrease motility & increases Nausea & vomiting tone of intestinal smooth Constipation muscle Sedation Histamine release Bronchoconstriction MODERATE AGONISTS Depress cough reflex Codeine Analgesia Oral analgesic Sedation Antitussive Euphoria MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS In high doses, respiratory depression Pentazocine mixed agonist-antagonist Relieve moderate pain decrease GIT activity Increase blood pressure Hallucinations 29 Nightmares tachycardia respiratory depression Buprenorphine Partial agonist Opiate detoxification decrease blood pressure Nausea dizziness OTHER ANALGESICS Management of Tramadol moderate to moderately seizure severe pain Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 28  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM OPIOID ANTAGONISTS DRUGS ACTION THERAPEUTIC USES ADVERSE EFFECTS produces no used to reverse the coma and Naloxone pharmacologic effects respiratory depression of opioid(i.e., in normal individuals, heroin) overdose but it precipitates withdrawal symptoms in opioid abusers for rapid opioid detoxification Naltrexone Hepatotoxic may also be beneficial in treating chronic alcoholism by an unknown mechanism 30 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 29  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM H. DRUGS USED TO TREAT EPILEPSY Epilepsy affects approximately 3% of individuals by the time they are 80 years old. About 10% of the population will have at least one seizure in their lifetime. Globally epilepsy is the third most common neurologic disorder after cerebrovascular and Alzheimer's diseases. Epilepsy is not a single entity but, instead, an assortment of different seizure types and syndromes originating from several mechanisms that have in common the sudden, excessive, and synchronous discharge of cerebral neurons. This abnormal electrical activity may result in a variety of events, including loss of consciousness, abnormal movements, atypical or odd behavior, or distorted perceptions that are of limited duration but recur if untreated. The site of origin of the abnormal neuronal firing determines the symptoms that are produced. For example, if the motor cortex is involved, the patient may experience abnormal movements or a generalized convulsion. 31 Seizures originating in the parietal or occipital lobe may include visual, auditory, or olfactory hallucinations. Figure 2.55 Summary of agents used in the treatment of epilepsy Source: Lippincott’s Illustrated Drug or vagal nerve stimulator therapy is the most Reviews: Pharmacology. 4th ed widely effective mode for the treatment of patients with epilepsy. It is expected that seizures can be controlled completely in approximately 70 to 80% of patients with one medication. It is estimated that approximately 10 to 15% of patients will require more than one drug and perhaps 10% may not achieve complete seizure control. Page 30  Discussion II. DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM H. DRUGS USED TO TREAT EPILEPSY Classification of Seizures A. Partial Partial seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The symptoms of each seizure type depend on the site of neuronal discharge and on the extent to which the electrical activity spreads to other neurons in the brain. Consciousness is usually preserved. Partial seizures may progress, becoming generalized tonic-clonic seizures. B. Generalized Generalized seizures may begin locally, producing abnormal electrical discharges throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness. 32 Figure 2.56 Classification of epilepsy Source: https://journals.rcni.com/nursing-children-and-young-people/an-overview-of-epilepsy- Page 31 in-children-and-young-people-ncyp2012.07.24.6.28.c9190  Discussion II. DRUGS AFFECTING THE CNS ANTIEPILEPTIC DRUGS DRUGS THERAPEUTIC USES ADVERSE EFFECTS PRIMARY ANTIEPILEPTIC DRUGS drug-induced toxicity Phenytoin Treatment of partial seizures and generalized nystagmus tonic-clonic seizures and in the treatment of ataxia status epilepticus Gingival hyperplasia peripheral neuropathies osteoporosis treatment of partial seizures and secondarily Hyponatremia Carbamazepine generalized tonic-clonic seizures Nausea & vomiting Drowsiness Treatment of trigeminal neuralgia and in Blurred vision bipolar disease Vertigo Headache For treatment of: Sedation Phenobarbital simple partial seizures Ataxia Recurrent seizures in children Nystagmus Vertigo Acute psychotic reactions Agitation & confusion Divalproex sodium: treatment of partial and Rare hepatic toxicity Valproic acid primary generalized epilepsies Teratogenic Ethosuximide only for primary generalized absence 33 seizures Diazepam, and lorazepam: Benzodiazepines used as an adjunctive therapy for myoclonic as well as for partial and generalized tonic-clonic seizures Gabapentin adjunct therapy for partial seizures for treatment of postherpetic neuralgia Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 32  References Textbooks ▪ Brunton L, Hilal-Dandan R, Knollman BC. 2018. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill-Education, United States of America. ▪ Katzung, Bertram G. 2018. Basic and Clinical Pharmacology. 14th ed. McGraw Hill- Education, United States of America Online References ▪ Autonomic Nervous System at https://courses.lumenlearning.com/epcc-austincc-ap1- 2/chapter/divisions-of-the-autonomic-nervous-system/ YouTube links ▪ Introduction to Autonomic Nervous System at https://www.youtube.com/watch?v=7EkB9obPnM0 ▪ Autonomic Nervous System: Sympathetic vs Parasympathetic, Animation at https://www.youtube.com/watch?v=D96mSg2_h0c ▪ AUTONOMIC NERVOUS SYSTEM at https://www.youtube.com/watch?v=qeXP_ricT4s ▪ Action Potential in the Neuron at https://www.youtube.com/watch?v=oa6rvUJlg7o ▪ Action Potential in Neurons at https://www.youtube.com/watch?v=iBDXOt_uHTQ ▪ Nerve impulse Animation at https://www.youtube.com/watch?v=dSkxlpNs3tU ▪ Chemical Synapse Animation at https://www.youtube.com/watch?v=mItV4rC57kM ▪ Cholinergic Drugs - Pharmacology, Animation at https://www.youtube.com/watch?v=EwsVmTOBZrc ▪ Cholinergic Agonists and Antagonists animation video at https://www.youtube.com/watch?v=TVFQ7YbKZBE 34 ▪ Pharmacology - ADRENERGIC RECEPTORS & AGONISTS at https://www.youtube.com/watch?v=KtmV-yMDYPI ▪ Adrenergic Drugs - Pharmacology, Animation at https://www.youtube.com/watch?v=FCOJq_G-1TE ▪ Adrenergic Synthesis And Metabolism animation at https://www.youtube.com/watch?v=H1qUpuf0ZP4 ▪ Nerve Synapse Animation at https://www.youtube.com/watch?v=ecGEcj1tBBI ▪ central nervous system at https://www.youtube.com/watch?v=0yXMGQaVVXg Page 33  References YouTube links ▪ A Journey Through Your Nervous System at https://www.youtube.com/watch?v=VAEmxt78bBI ▪ The Influence of Drugs on Neurotransmitters at https://www.youtube.com/watch?v=mVJjWYXS4JM ▪ How do drugs affect the brain? at https://www.youtube.com/watch?v=8qK0hxuXOC8 ▪ Drugs and the Nervous System at https://www.youtube.com/watch?v=3LTPX5yZYqk ▪ Understanding Parkinson's disease at https://www.youtube.com/watch?v=ckn9zybpYZ8 ▪ Inside Alzheimer’s disease at https://www.youtube.com/watch?v=zTd0-A5yDZI ▪ Mechanisms and secrets of Alzheimer's disease: exploring the brain at https://www.youtube.com/watch?v=dj3GGDuu15I ▪ Neuroscience Basics: GABA Receptors and GABA Drugs at https://www.youtube.com/watch?v=MRr6Ov2Uyc4 ▪ How do antidepressants work? at https://www.youtube.com/watch?v=ClPVJ25Ka4k ▪ What causes panic attacks, and how can you prevent them? at https://www.youtube.com/watch?v=IzFObkVRSV0 ▪ What is schizophrenia? at https://www.youtube.com/watch?v=K2sc_ck5BZU ▪ OPIOIDS (MADE EASY) at https://www.youtube.com/watch?v=t2tKyjj7u5Y ▪ This Is What Happens to Your Brain on Opioids | Short Film Showcase at https://www.youtube.com/watch?v=NDVV_M__CSI ▪ How Do Pain Relievers Work? at https://www.youtube.com/watch?v=9mcuIc5O-DE ▪ Epilepsy: Types of seizures, Symptoms, Pathophysiology, Causes and Treatments at https://www.youtube.com/watch?v=RxgZJA625QQ 35 ▪ ANTIEPILEPTIC DRUGS (MADE EASY) at https://www.youtube.com/watch?v=xFUHE9gX6W8 Page 34