Pharmacology II Lecture 10 Drugs That Act in the Central Nervous System Dr. Mahmoud H. Taleb

1. Pharmacology II Lecture 10 Drugs That Act in the Central Nervous System Dr. Mahmoud H. Taleb Assistant Professor of Pharmacology and Toxicology Head of Department of Pharmacology and Medical Sciences, Faculty of Pharmacy- Al azhar Universty Dr. Mahmoud H. Taleb

2. Introduction to the Pharmacology of CNS Drugs • First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate • synaptic transmission. A very few agents such as general anesthetics and alcohol may have • nonspecific actions on membranes (although these exceptions are not fully accepted), but even these • non-receptor-mediated actions result in demonstrable alterations in synaptic transmission • Second, drugs are among the most important tools for studying all aspects of CNS physiology, from • the mechanism of convulsions to the laying down of long-term memory. Dr. Mahmoud H. Taleb

3. This chapter provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the drugs described in the following chapters. Dr. Mahmoud H. Taleb

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7. Amino Acids The amino acids of primary interest to the pharmacologist fall into two categories: the neutral amino acids glycine and GABA and the acidic amino acid glutamate. All of these compounds are present in high concentrations in the CNS and are extremely potent modifiers of neuronal excitability. Acetylcholine Dr. Mahmoud H. Taleb

8. Monoamines Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine. Although these compounds are present in very small amounts in the CNS, they can be localized using extremely sensitive histochemical methods. These pathways are the site of action of many drugs; Peptides Nitric Oxide Dr. Mahmoud H. Taleb

9. 1- Local Anesthetics Clinical Pharmacology of Local Anesthetics Local anesthetics can provide highly effective analgesia in well-defined regions of the body. The usual routes of administration include topical application (eg, nasal mucosa, wound margins), injection in the vicinity of peripheral nerve endings and major nerve trunks (infiltration), and injection into the epidural or subarachnoid spaces surrounding the spinal cord . Intravenous regional anesthesia of the arm or leg (Bier block) is used for short surgical procedures (< 45 minutes). This is accomplished by intravenous injection of the anesthetic agent into a dista vein while the circulation of the limb is isolated with a proximally placed tourniquet. Finally, a infiltration block of autonomic sympathetic fibers can be used to evaluate the role of sympathetic tone in patients with peripheral vasospasm. Dr. Mahmoud H. Taleb

10. VI. Local Anesthetics Local anesthetics are generally applied locally and block nerve conduction of sensory impulses from the periphery to the CNS. [Note: Some of these agents do have additional uses—for example, the antiarrhythmic effect of lidocaine—and they are then administered by other routes.] 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. Dr. Mahmoud H. Taleb

11. None of the currently available local anesthetics are ideal, and development of newer agents continues. However, while it is relatively easy to synthesize a chemical with local anesthetic effects,n it is very difficult to reduce the toxicity significantly below that of the current agents. The major reason for this difficulty is the fact that the much of the serious toxicity of local anesthetics represents extensions of the therapeutic effect on the brain and the circulatory system. Dr. Mahmoud H. Taleb

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14. The choice of local anesthetic for a specific procedure is usually based on the duration of action an intermediate duration of action; and tetracaine, bupivacaine, levobupivacaine, etidocaine, and ropivacaine are long-acting drugs. The anesthetic effect of the agents with short and intermediate durations of action can be prolonged by increasing the dose or by adding a vasoconstrictor agent (eg, epinephrine or phenylephrine). The vasoconstrictor retards the removal of drug from the injection site. In addition, it decreases the blood level and hence the probability of central nervous system toxicity. Dr. Mahmoud H. Taleb

15. The onset of local anesthesia can be accelerated by the use of solutions saturated with carbon dioxide ("carbonated"). The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membranes readily), which in turn results in intracellular accumulation of the cationic form of the local anesthetic. Dr. Mahmoud H. Taleb

16. Repeated injection of local anesthetics can result in loss of effectiveness (ie, tachyphylaxis) due to extracellular acidosis. Local anesthetics are commonly marketed as hydrochloride salts (pH 4.0– 6.0). After injection, the salts are buffered in the tissue to physiologic pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the buffering capacity of the local tissues. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid. Dr. Mahmoud H. Taleb

17. Pregnancy appears to increase susceptibility to local anesthetic toxicity in that median doses • required for nerve block or to induce toxicity are reduced. Cardiac arrest leading to death following • the epidural administration of 0.75% bupivacaine to women in labor resulted in the temporary • withdrawal from the market of the high concentration of this long-acting local anesthetic and • subsequent introduction of potentially less cardiotoxic alternatives (ie, ropivacaine and • levobupivacaine) for this high-risk population. It is not clear whether the increased sensitivity • during pregnancy is due to elevated estrogen, elevated progesterone, or some other factor. Dr. Mahmoud H. Taleb

18. Topical local anesthesia is often used for eye, ear, nose, and throat procedures and for cosmetic • surgery. Satisfactory local anesthesia requires an agent capable of rapid penetration of the skin or • mucosa and with limited tendency to diffuse away from the site of application. Cocaine, because of • its excellent penetration and vasoconstrictor effects, has been used extensively for nose and throat • procedures. It is somewhat irritating, however, and is thus much less popular for ophthalmic • procedures. Recent concerns about its potential cardiotoxicity when combined with epinephrine has • led most otolaryngologists and plastic surgeons to switch to a combination containing lidocaine and • epinephrine. Other drugs used for topical anesthesia include lidocaine, tetracaine, pramoxine, • dibucaine, benzocaine, and dyclonine. Dr. Mahmoud H. Taleb

19. Since local anesthetics are membrane-stabilizing drugs, both parenteral (eg, intravenous lidocaine) and oral (eg, mexiletine, tocainide) formulations of these drugs have been used to treat patients with neuropathic pain syndromes. Systemic local anesthetic drugs are commonly used as adjuvants to the combination of a tricyclic antidepressant (eg, amitriptyline) and an anticonvulsant (eg, carbamazepine) in patients who fail to respond to the standard tricyclic plus anticonvulsant combination. One to 3 weeks are required to observe a therapeutic effect after introduction of the local anesthetic in patients with neuropathic pain. Dr. Mahmoud H. Taleb

20. Neurodegenerative Diseases 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. This chapter provides an overview of the CNS, with a focus on those neurotransmitters that are involved in the actions of the clinically useful CNS drugs. These concepts are useful in understanding the etiology and treatment strategies of Parkinson's and Alzheimer's diseases—the two neurodegenerative disorders that respond to drug therapy Dr. Mahmoud H. Taleb

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22. Neurotransmission in the CNS In many ways, the basic functioning of neurons in the CNS is similar to that of the autonomic nervous system described in Chapter 3. For example, transmission of information in the CNS and in the periphery both involve therelease 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 autonomic nervous system and those in the CNS. The circuitry of the CNS is much more complex than that of the autonomic nervous system, and the number of synapses in the CNS is far greater. The CNS, unlike the peripheral autonomic nervous system, contains powerful networks of inhibitory neurons that are constantly active in modulating the rate of neuronal transmission. In addition, the CNS communicates through the use of more than 10 (and perhaps as many as 50) different neurotransmitters. In contrast, the autonomic nervous system uses only two primary neurotransmitters, acetylcholine and norepinephrine. Figure 8.2 describes some of the more important neurotransmitters in the CNS Dr. Mahmoud H. Taleb

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24. 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. Dr. Mahmoud H. Taleb

25. Figure 8.3 Binding of the excitatory neurotransmitter, acetylcholine, causes depolarization of the neuron. Dr. Mahmoud H. Taleb

26. A. Excitatory pathways • Neurotransmitters can be classified as either excitatory or inhibitory, depending on the nature of the action they • elicit. 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: 1) • 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. 2) The influx of Na+ causes a weak depolarization or EPSP that moves the • postsynaptic potential toward its firing threshold. 3) 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 8.3 for an example of an excitatory pathway.) • 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: 1) • 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. 2) 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 8.4 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. 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. Dr. Mahmoud H. Taleb

27. Drugs Used in Parkinson's Disease • Levodopa and carbidopa Levodopa is a metabolic precursor of dopamine .It restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra. Dr. Mahmoud H. Taleb

28. B. Selegiline and rasagiline C. Catechol-O-methyltransferase inhibitors D. Dopamine-receptor agonists E. Amantadine F. Antimuscarinic agents The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. The actions of benztropine, trihexyphenidyl ,procyclidine and biperiden are similar. Dr. Mahmoud H. Taleb

29. Anxiolytic and Hypnotic Drugs Anxiety is an unpleasant state of tension, apprehension, or uneasiness 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 • (sometimes called anxiolytic or minor tranquilizers) and/or some form of behavioral or psychotherapy. Because many of the antianxiety drugs also cause some sedation, the same drugs often function clinically as both anxiolytic and hypnotic (sleep-inducing) agents. In addition, some have anticonvulsant activity. Figure 9.1 summarizes the • anxiolytic and hypnotic agents. Though also indicated for certain anxiety disorders, the selective serotonin reuptake inhibitors (SSRIs) will be presented in the chapter discussing antidepressants. Dr. Mahmoud H. Taleb

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31. 1- Benzodiazepines A. Mechanism of action The targets for benzodiazepine actions are the γ-aminobutyric acid (GABAA) receptors. [Note: GABA is the major inhibitory neurotransmitter in the central nervous system (CNS).] B. Actions Reduction of anxiety Sedative and hypnotic actions Anterograde amnesia Anticonvulsant Muscle relaxant: Dr. Mahmoud H. Taleb

32. Benzodiazepine Antagonist Flumazenil is a GABA-receptor antagonist that can rapidly reverse the effects of benzodiazepines. Other Anxiolytic Agents A. Buspirone The actions of buspirone appear to be mediated by serotonin (5-HT1A) receptors, although other receptors could be involved. B. Hydroxyzine C. Antidepressants Dr. Mahmoud H. Taleb

33. 2. Barbiturates A. Mechanism of action The sedative-hypnotic action of the barbiturates is due to their interaction with GABAA receptors, which enhances GABAergic transmission. The binding site is distinct from that of the benzodiazepines. Barbiturates potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings. In addition, barbiturates can block excitatory glutamate receptors. Anesthetic concentrations of pentobarbital also block high-frequency sodium channels. All of these molecular actions lead to decreased neuronal activity. Dr. Mahmoud H. Taleb

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35. 1- Depression of CNS:At low doses, the barbiturates produce sedation (calming effect, reducing excitement). At higher doses, the drugs cause hypnosis, followed by anesthesia (loss of feeling or sensation), and finally, coma and death. Thus, any degree of depression of the CNS is possible, depending on the dose. Barbiturates do not raise the pain threshold and have no analgesic properties. They may even exacerbate pain. Chronic use leads to tolerance. 2- Respiratory depression: Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death. 3- Enzyme induction: Barbiturates induce P450 microsomal enzymes in the liver. Therefore, chronic barbiturate administration diminishes the action of many drugs that are dependent on P450 metabolism to reduce their Dr. Mahmoud H. Taleb

36. C. Therapeutic uses 1- Anesthesia: Selection of a barbiturate is strongly influenced by the desired duration of action. The ultrashortacting barbiturates, such as thiopental, are used intravenously to induce anesthesia. 2- Anticonvulsant: Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and eclampsia. Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent febrile seizures. However, phenobarbital can depress cognitive performance in children, and the drug should be used cautiously. Phenobarbital has specific anticonvulsant activity that is distinguished from the nonspecific CNS depression. 3- Anxiety: Barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia. When used as hypnotics, they suppress REM sleep more than other stages. However, most have been replaced by the benzodiazepines. Dr. Mahmoud H. Taleb

37. E. Adverse effects CNS:Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness (Figure 9.8). The CNS depressant effects of barbiturates synergize with those of ethanol.1. Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes. This drug hangover may lead to impaired ability to function normally for many hours after waking. Occasionally, nausea and dizziness occur.. Precautions: As noted previously, barbiturates induce the P450 system and, therefore, may decrease the duration of action of drugs that are metabolized by these hepatic enzymes. Barbiturates increase porphyrin synthesis, and are contraindicated in patients with acute intermittent porphyria. Physical dependence:Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest. Withdrawal is much more severe than that associated with opiates and can result in death. Poisoning:Barbiturate poisoning has been a leading cause of death resulting from drug overdoses for many decades. Severe depression of respiration is coupled with central cardiovascular depression, and results in as hock-like condition with shallow, infrequent breathing. Treatment includes artificial respiration and purging the stomach of its contents if the drug has been recently taken. [Note: No specific barbiturate antagonist is available.] Hemodialysis may be necessary if large quantities have been taken. Alkalinization of the urine often aids in the elimination of phenobarbital . Dr. Mahmoud H. Taleb

38. Other Hypnotic Agents Dr. Mahmoud H. Taleb

39. CNS Stimulants Dr. Mahmoud H. Taleb

40. 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 11.1). 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 anesthetics are all volatile, halogenated hydrocarbons that derive from early research and clinical • experience with diethyl ether and chloroform. On the other hand, intravenous general anesthetics consist of a • number of chemically unrelated drug types that are commonly used for the rapid induction of anesthesia. Dr. Mahmoud H. Taleb

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42. II. Patient Factors in Selection of Anesthesia • During the preoperative phase, the anesthesiologist selects drugs that provide a safe and efficient anesthetic • regimen based on the nature of the surgical or diagnostic procedure as well as on the patient's physiologic, • pathologic, and pharmacologic state. • A. Status of organ systems • Liver and kidney: Because the liver and kidney not only influence the long-term distribution and clearance of • anesthetic agents but can also be the target organs for toxic effects, the physiologic status of these organs must • be considered. Of particular concern is that the release of fluoride, bromide, and other metabolic products of • the halogenated hydrocarbons can affect these organs, especially if the metabolites accumulate with repeated • anesthetic administration over a short period of time. • Respiratory system: The condition of the respiratory system must be considered if inhalation anesthetics are • indicated. For example, asthma and ventilation or perfusion abnormalities complicate control of an inhalation • anesthetic. All inhaled anesthetics depress the respiratory system. Additionally, they also are bronchodilators. • Cardiovascular system: Whereas the hypotensive effect of most anesthetics is sometimes desirable, ischemic • injury of tissues could follow reduced perfusion pressure. If a hypotensive episode during a surgical procedure • necessitates treatment, a vasoactive substance is administered. This is done after consideration of the • possibility that some anesthetics, such as halothane, may sensitize the heart to the arrhythmogenic effects of • sympathomimetic agents. Dr. Mahmoud H. Taleb

43. . Pregnancy: Some precautions should be kept in mind when anesthetics and adjunct drugs are administered to pregnant woman. There has been at least one report that transient use of nitrous oxide can cause aplastic anemia in the unborn child. Oral clefts have occurred in the fetuses of women who have receive benzodiazepines. Diazepam should not be used routinely during labor, because it results in temporary hypotonia and altered thermoregulation in the newborn. Dr. Mahmoud H. Taleb

44. B. Concomitant use of drug Multiple adjunct agents: Commonly, surgical patients receive one or more of the following preanesthetic medications: benzodiazepines, such as midazolam or diazepam, to allay anxiety and facilitate amnesia; barbiturates, such as pentobarbital, for sedation; antihistamines, such as diphenhydramine, for prevention of allergic reactions, or ranitidine, to reduce gastric acidity; antiemetics, such as ondansetron, to prevent the1. Concomitant use of additional nonanesthetic drugs: Surgical patients may be chronically exposed to agents for the treatment of the underlying disease as well as to drugs of abuse that alter the response to anesthetics. For example, alcoholics have elevated levels of hepatic microsomal enzymes involved in the metabolism of barbiturates, and drug abusers may be overly tolerant of opioids. Dr. Mahmoud H. Taleb

45. III. Induction, Maintenance, and Recovery from Anesthesia • Anesthesia can be divided into three stages: induction, maintenance, and recovery. Induction is defined as the • period of time from the onset of administration of the anesthetic to the development of effective surgical • anesthesia in the patient. Maintenance provides a sustained surgical anesthesia. • Recovery is the time from discontinuation of administration of the anesthesia until consciousness and protective • physiologic reflexes are regained. Induction of anesthesia depends on how fast effective concentrations of the • anesthetic drug reach the brain; recovery is the reverse of induction and depends on how fast the anesthetic drug • diffuses from the brain. Dr. Mahmoud H. Taleb

46. A. Induction • During induction, it is essential to avoid the dangerous excitatory phase (Stage II delirium) that was observed with • the slow onset of action of some earlier anesthetics (see below). Thus, general anesthesia is normally induced with • an intravenous anesthetic like thiopental, which produces unconsciousness within 25 seconds after injection. At • that time, additional inhalation or intravenous drugs comprising the selected anesthetic combination may be given • to produce the desired depth of surgical (Stage III) anesthesia. [Note: This often includes coadministration of an • intravenous skeletal muscle relaxant to facilitate intubation and relaxation. Currently used muscle relaxants include • pancuronium, doxacurium, rocuronium, vecuronium, cisatricurium, • succinylcholine.] For children, without intravenous access, nonpungent agents, such as halothane or sevoflurane, • are used to induce general anesthesia. This is termed inhalation induction. Dr. Mahmoud H. Taleb

47. B. Maintenance of anesthesia Maintenance is the period during which the patient is surgically anesthetized. After administering the selected anesthetic mixture, the anesthesiologist monitors the patient's vital signs and response to various stimuli throughout the surgical procedure to carefully balance the amount of drug inhaled and/or infused with the depth of anesthesia. Anesthesia is usually maintained by the administration of volatile anesthetics, because these agents offer good minute-to-minute control over the depth of anesthesia. Opioids, such as fentanyl, are often used for pain along with inhalation agents, because the latter are not good analgesics. Dr. Mahmoud H. Taleb

48. C. Recovery Postoperatively, the anesthesiologist withdraws the anesthetic mixture and monitors the return of the patient to consciousness. For most anesthetic agents, recovery is the reverse of induction; that is, redistribution from the site of action (rather than metabolism of the anesthetic) underlies recovery. The anesthesiologist continues to monitor the patient to be sure that he or she is fully recovered with normal physiologic functions (for example, is able to breathe on his/her own). Patients are observed for delayed toxic reactions, such as hepatotoxicity caused by halogenated hydrocarbons. Dr. Mahmoud H. Taleb

49. Depth of anesthesia Dr. Mahmoud H. Taleb

50. 1- Inhalation Anesthetics 1- Halothane 2-Enflurane 3- Nitrous oxide Dr. Mahmoud H. Taleb