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Drugs Affecting the Central Nervous System Disease states of Central Nervous System • Typically caused by too much, or too little neurotransmission • Too much – Hyperexcitable neurons fire in absence of stimuli (e.g. seizure disorders) – Too many neurotransmitter molecules binding to post-synapse receptors • psychoses • Too little – Too few neurotransmitters binding to postsynapse receptors Major Parts of the Brain • Cerebrum • Brainstem • Cerebellum Cerebrum • Largest and uppermost part of the brain • Divided into right and left hemispheres • Controls all the higher intellectual and motor functions of the body • Cerebrum composed of an outer cortex and an inner medulla Cerebral Cortex • Contains neuronal cell bodies (gray matter) that control all voluntary activities of the body • Divided up into 4 lobes: frontal, parietal, temporal, and occipital, each controlling specific brain functions • Electroencephalogram (EEG) is a recording of the electrical activity of the cortex Cerebral Medulla • Referred to as the “white matter” and is composed of myelinated nerve axons • Functions to conduct nerve impulses to and from different parts of the nervous system • Basal ganglia are neuronal cell bodies (gray matter) located within the cerebral medulla that function in the regulation of motor activity Brainstem and Spinal Cord • Located below the cerebrum and is continuous with the spinal cord • Brainstem divided into the thalamus, hypothalamus, pons, and medulla oblongata • Spinal cord is a collection of all the sensory and motor nerves going to and from the brain Reticular Formation • A network of nerves and brain areas involved in regulating alertness, wakefulness, and sleep • Composed of both inhibitory and excitatory nerves • Excitatory nerves collectively referred to as the reticular activating system (RAS) • Many stimulants (amphetamines) and depressants (alcohol, barbiturates) affect the RAS Limbic System • Network of nerves and brain areas involved in emotional and behavioral responses • Associated with emotional responses to fear, anger, anxiety, sexual behavior, and reward and punishment • Affected by drugs of abuse and involved in the development of drug dependency Neurotransmitters Norepinephrine • Adrenergic hormone released at the effector organ by sympathetic neurons – Monamine • Depression thought be caused by impaired monoamine transmission • Drugs that stimulate monoamine release are indicated for ADD or narcolepsy Dopamine • Another monoamine derived from the amino acid tyrosine • Binds dopamine receptors (D1 or D2) • Antipsychotics prevent signals activated by dopamine binding • Parkinson’s disease also caused by altered dopamine binding Serotonin (5-HT) • Monoamine hormone derived from the amino acid tryptophan • Typically released by inhibitory neurons • Lysergic acid diethylamide binds to serotonin receptors • Depression, ADD and headaches associated with serotonin imbalance Gamma-amino butyric acid (GABA) • Inhibitory neurotransmitter of the brain and central nervous system • Synthesized from the amino acid glutamate • Cause Ca2+ influx into the neuron resulting in hyperpolarization – More difficult to excite • Benzodiazepines and barbituates enhance GABA effects Excitatory Amino Acids • Amino acid glutamate or structurally related chemicals • Important for learning and memory • Abnormal increased activity will result in toxicity – Alzheimers, ALS, stroke, Huntington’s Antidepressants Mental Depression • Exogenous or reactive depression usually occurs in response to some external factor or adverse life event • Endogenous depression usually originates from within the psyche of the individual and the causes are less well understood • Bipolar mood disorder involves alternating cycles of depression and mania Causes of Mental Depression • Exact causes not well understood • Mental depression appears to involve the development of low levels of the brain monoamine neurotransmitters, serotonin (SER) and norepinephrine (NE) • This explanation is referred to as the “Monoamine Theory of Mental Depression” Treatment of Depression • Treatment involves a combination of psychotherapy and antidepressant drugs • Antidepressant drugs act to increase NE and SER levels in the brain • Tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) are the two most important antidepressant drug classes • Monoamine oxidase inhibitors (MAOI) are less frequently used and require dietary restriction Monoamine Oxidase Inhibitors (MAOI) • Monoamine oxidase is the enzyme that metabolizes the monoamines NE and SER • Inhibition of MAO increases SER and NE levels and functional activity in the brain • Requires 2–4 weeks for maximum effects • Foods containing tyramine must be avoided • Tyramine stimulates the release of NE and may cause a hypertensive crisis • MAOIs are indicated for patients who cannot tolerate TCAs and SSRIs Tricyclic Antidepressants (TCA) • Mechanism of action of TCAs is to block reuptake of NE and SER into nerve endings • Blockage of reuptake increases NE and SER levels and stimulation of NE and SER receptors • Requires 2–4 weeks for maximum effect • TCAs are divided into secondary amines which increase NE more than SER and are less sedating than tertiary amines which increase SER more than NE Autonomic Effects of TCAs • TCAs possess anticholinergic activity which can cause dry mouth, visual disturbances, constipation, and urinary retention • TCAs also possess alpha blocking activity that can lower blood pressure • TCAs can also affect cardiac rhythm and may cause cardiac arrhythmias Selective Serotonin Reuptake Inhibitors (SSRI) • Selectively block the reuptake of SER • Cause little if any anticholinergic and alpha blocking effects • Are generally not sedating, and in some cases cause CNS stimulation • Common adverse effects include nausea, agitation, restlessness, and less frequently seizures Psychomotor Stimulants • Generally referred to as the amphetamines • Produce CNS stimulation more than an antidepressant effect, little used for depression • Act by increasing NE and DA activity • Clinical use for narcolepsy and treatment of hyperkinetic children • Amphetamines have a high abuse potential • Adverse effects due to excessive CNS and autonomic stimulation Lithium • Lithium is an elemental ion similar to sodium • Acts to depress nerve excitability that helps prevent mood swings and manic behavior • Common adverse effects include nausea, diarrhea, tremors, increased thirst, ringing in the ears (tinnitis), and more seriously kidney and heart damage • Periodic blood levels to prevent overdosage Sedatives and Hypnotics • Sedatives are drugs used to induce a mild state of CNS depression characterized by both mental and physical calmness • Hypnotics are drugs used to induce and maintain sleep • The same drugs are used to induce both sedation and hypnosis; however, the dosage for inducing sedation is lower Classification of SedativeHypnotic Drugs • Barbiturates – a drug family of chemically similar drugs with similar actions and features • Benzodiazepines – a drug family of chemically similar drugs with similar actions and features • Miscellaneous nonbarbiturates – a group of drugs with dissimilar chemical structures and pharmacologic features Pharmacology of Barbiturates • Drugs classified as short, intermediate, and long-acting sedative-hypnotics • At low doses they increase the inhibitory effects of GABA • At high doses they act like general anesthetics, and can cause profound CNS depression and death in overdosage • Barbiturates are also anticonvulsants Effects of Barbiturates on the Sleep Cycle • Decrease stage 1, falling asleep • Increase stage 2, a lighter stage of sleep • Decrease stages 3 and 4 referred to as deep sleep or slow-wave sleep • Decrease REM sleep, and may cause REM rebound Adverse Features of Barbiturates • Cause drug tolerance with chronic use and drug dependency with abuse • Can cause a severe type of physical drug addiction when chronically abused • The withdrawal reaction from barbiturates can be serious, resulting in convulsions and death • Drug interactions, induce microsomal enzymes to increase the rate of drug metabolism of all drugs metabolized by the microsomal enzymes Pharmacology of Benzodiazepines • Drugs classified as short, intermediate, and long-acting sedative-hypnotics • Drugs also produce antianxiety, skeletal muscle relaxing, and anticonvulsant effects • Act by increasing the inhibitory effects of GABA • Drugs do not induce the drug metabolizing microsomal enzymes Effect of Benzodiazepines on the Sleep Cycle • • • • • Decrease stage 1, falling asleep Increase stage 2 Decrease stages 3 and 4 Do not significantly decrease REM sleep Benzodiazepines are considered safer drugs than the barbiturates, especially in overdosage Miscellaneous Nonbarbiturates • Zolpidem and zaleplon are short-acting hypnotics that do not disrupt the sleep cycle • These drugs increase the inhibitory effects of GABA but differently than other drugs • Both drugs are considered to be safer than other hypnotics and are at low risk for abuse • Side effects include dizziness, headache, GI disturbances, and mental confusion Alcohol • Classified as a CNS depressant drug • Unlike other drugs, alcohol provides nutritional calories • Like other drugs of abuse, alcohol causes development of drug tolerance, dependency, and withdrawal reactions • Most of the pharmacology of alcohol centers around its chronic use, abuse, and toxicology Disulfiram • Used to treat alcoholism and deter drinking • Disulfiram inhibits metabolism of alcohol, allowing acetaldehyde to accumulate • Increased acetaldehyde produces severe nausea, vomiting, headache, and hypotension • Alcoholics take the drug on a daily basis, knowing that if they drink any alcohol they will become violently ill Parkinson’s Disease • A neurological movement disorder of the brain involving the basal ganglia • Symptoms include tremor, muscular rigidity, and disturbances of movement • Major cause is a deficiency of the inhibitory neurotransmitter dopamine (DA) and the resulting excessive activity of the excitatory neurotransmitter acetylcholine (ACH) Drug Therapy • Primary therapy is the administration of drugs that increase the levels of DA in the basal ganglia • Secondary therapy is the administration of anticholinergic drugs that decrease ACH activity in the basal ganglia • Goal is to restore the balance between DA and ACH activity Drugs that Increase Dopamine • • • • Levodopa Dopamine agonists Amantadine Enzyme inhibiting drugs that slow the metabolic breakdown of dopamine Levodopa • The precursor of DA that is taken orally and converted into DA in the basal ganglia • Administered in combination with carbidopa that increases the amount of DA that enters the brain • Levodopa and carbidopa drug combination known as Sinemet • Levodopa is considered the most effective drug for the treatment of Parkinson’s disease Adverse Effects of Levodopa • Nausea, vomiting, and loss of appetite • Hypotension, and rapid/irregular heart rate • Dystonias, slow or weak movements that usually occur when levels of DA are low • Dyskinesias, uncontrolled or involuntary movements when DA levels are too high • “On-off” phenomenon when drug effects suddenly increase or decrease due to fluctuating levels of DA in the basal ganglia • Behavioral and mental disturbances Dopamine Agonists • Drugs: bromocriptine, pergolide, pramipexole, and ropinirole • Stimulate DA receptors in the basal ganglia • Used alone or in combination with levodopa • Adverse effects similar to levodopa: nausea, hypotension, dyskinesias, and mental disturbances Amantadine (Symmetrel) • An antiviral drug that additionally increases the release of DA in the brain • Used in early stages of treatment and in combination with other drugs • Effectiveness usually decreases in 6–12 months • Adverse effects include nausea, mental disturbances, and occasionally skin discoloration Enzyme Inhibitors • Selegiline (Eldepryl) inhibits MAO-B enzyme that slows metabolism of DA in the brain, increases DA levels; used alone or with levodopa • Tolcapone (Tasmar) and entacapone (Comtan) inhibit another enzyme, COMT, that also slows metabolism of DA; usually used with levodopa Anticholinergic Drugs • Used to decrease the activity of ACH and restore the normal balance between DA and ACH • Benztropine (Cogentin)and trihexyphenidyl (Artane) most widely used drugs • Antihistamine drugs, diphenhydramine (Benadryl), with high anticholinergic activity occasionally used • Used alone early in treatment or in combination with other drugs Central Analgesics Clinical Indication Produce a state of unconsciousness to prevent painful stimulation during surgical and dental procedures Types of anesthetics • Inhalation gases & volatile liquids: chloroform, halothane, nitrous oxide • Injectable: fentanyl, ketamine, midazolam, propofol Signs & Stages of General Anesthetics General anesthetics gradually depress the CNS Stage I Depression of the cerebral cortex produces analgesia euphoria and sleep Stage II Excitement phase with increased sympathetic tone produces increase in blood pressure, heart rate, respiration, and muscle tone Stage III Surgical anesthesia because blood pressure and respiration return to normal, spinal reflexes are inhibited and skeletal muscles relaxed Stage IV Medullary paralysis, paralysis of the diaphragm circulatory collapse leading to death Action of General Anesthetics Induction of anesthesia: time required to bring the patient from consciousness to Stage III Maintainance of anesthesia: ability to keep the patient safely in Stage III Dissociative anesthesia: anesthesia and loss of memory without skeletal muscle relaxation Neuroleptanalgesia: inhibition of pain while conscious from combination of a narcotic and a tranquilizer Other Effects • CNS Depression of voluntary (motor) and involuntary (autonomic) systems. Secretion of antidiuretic hormone causes postop urinary retention • Vascular Decreased sympathetic tone causes vasodilation & hypotension • Cardiac Myocardial depression, ventricular arrhythmias • Salivary and bronchial secretions • Skeletal muscle relaxation • Gastrointestinal Nausea and vomiting during recovery. Decreased intestinal motility causes constipation • Hepatotoxicity Jaundice, elevated serum liver enzymes, necrosis Adjuncts to General Anesthesia Drugs routinely used before and after surgery to reduce anxiety, counteract the side effects of general anesthetics, and improve patient recovery. • Analgesics-relieve pain, produce sedation • Antianxiety drugs-relieve apprehension • Antiarrhythmics-control arrhythmias • Anticholinergics-decrease secretions • Cholinergics-decrease urinary retention • Tranquilizers-control nausea & vomiting Drug Interactions Residual depression of the CNS • narcotic (opiate) analgesics • muscle relaxants • tranquilizers Potentiate skeletal muscle relaxation, weakness and fatigue • antibiotics that promote potassium loss streptomycin, kanamycin, erythromycin The Opioid System Clinical Indication • Prevent or interrupt moderate to severe pain of any origin without a loss of consciousness • Acute pain-during or after surgical procedures • Chronic pain-of any etiology from back pain to cancer pain Source of Opioid Analgesics Opioid analgesics are derivatives of the • naturally occurring plant substance opium OR • synthetic substances that produce the same pharmacologic effects as opium Types of Analgesics Opiates-opium, heroin codeine, morphine, hydromorphone, oxycodone, oxymorphone Opioids-synthetic butorphanol, fentanyl, levorphanol, meperidine, methadone, propoxyphene Central analgesics (nonopioid)-tramadol Drug Schedule Federal Comprehensive Drug Abuse Prevention and Control Act Because of their liability to produce physical dependence, opioid analgesics are included in the class of controlled substances as Schedule II drugs • Restricted to prescription use • No refill without new written prescription • Regulated by the FDA (Food and Drug Administration) and DEA (Drug Enforcement Agency) Sensation of Pain Pain is composed of at least two elements • localized stimulation of peripheral nerves through damage or inflammation • recognition of pain within the CNS that can intensify the reaction to pain Mechanism of Action Opioid analgesics relieve pain by selectively acting on receptors within the CNS (rather than on peripheral nerve endings) to • • • decrease anxiety reduce the reaction to pain interrupt pain signal transmission within the spinal cord Mechanism of Action (continued) Opioid analgesics mimic the action of endorphins produced in the brain and spinal cord by selectively stimulating receptors • mu (µ) receptors mediate analgesia, euphoria, and respiratory depression • kappa (κ) receptors mediate sedation, dysphoria • delta (δ) receptors mediate, hallucinations, and increased respiration and blood pressure Pharmacological Effects CNS • Change in mental alertness, sedation (μ, κ) • Change mood, euphoria (µ) or dysphoria (κ) • Stimulation of chemoreceptor trigger zone initiating nausea and vomiting • Dose dependent depression of the vomiting center • Depression of respiratory centers (µ) • Headache • Cough suppressant (antitussive) • Secretion of antidiuretic hormone Pharmacological Effects (continued) • Tolerance – Decreased response to euphoria, sedation, respiratory depression and analgesia with chronic daily use – Response returns when the dose is increased • Physical dependence – Chronic use establishes an internal expectation within the body of receiving receptor activiation – Withdrawal symptoms (abstinence syndrome) occur when the drug is abruptly discontinued. (This can be minimized by gradual taper down) Pharmacological Effects (continued) Smooth Muscle (μ receptor mediated) • Spasmogenic – Intestine- constipation – Gall bladder common bile duct- increase pressure, pain – Bronchial constriction – Urinary sphincters- oliguria • Histamine release – Bronchial constriction – Vasodilation-orthostatic hypotension Antitussive Activity Natural opiates such as codeine, hydrocodone, and hydromorphone suppress coughs by inhibiting centers in the brain At present, dextromethorphan is the only opioid that is used in commercial over-the-counter cough suppressant products Usually OTC products include additional active ingredients that treat other symptoms of cold & flu Adverse Effects • • • • • • • • • • • Mental confusion Sedation Headache Nausea Vomiting Dry mouth Constipation Urinary retention Itching, rash, anaphylaxis Orthostatic hypotension Physical dependence Acute Opioid Poisoning Accidental ingestion of a large dose by children or attempted suicide may produce » Coma » Decreased respiration » Cyanosis » Hypotension » Drop in body temperature » Death Opioid Antagonists A pure opioid antagonist fits the opiate receptor, cannot stimulate the receptor, and blocks the opioid analgesic from attaching to the receptor. • naloxone, naltrexone A partial antagonist fits the opiate receptor and weakly stimulates the receptor while it blocks the opioid analgesic from attaching to the receptor • butorphanol, nalbufene Cautions and Contraindications Opioid analgesics should not be used in patients with • Bronchial asthma • Heavy pulmonary secretions • Convulsive disorders • Biliary obstruction • Head injuries • A history of allergy or sensitivity to this class Used with caution in • Elderly patients • Pregnant women Drug Interactions Potentiate CNS depression of all Opioids • sedatives, hypnotics, general anesthetics, alcohol Meperidine or dextromethorphan • MAO inhibitors- sweating, hypotension, hypertension Methadone • Reduced plasma levels of methadonerifampin, phenytoin