dr. mahmoud h. taleb 1 pharmacology ii lecture 10 drugs that act in the central nervous system dr....
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Pharmacology IILecture 10
Drugs That Act in the Central NervousSystem
Dr. Mahmoud H. TalebAssistant Professor of Pharmacology and Toxicology
Head of Department of Pharmacology and Medical Sciences, Faculty of Pharmacy- Al azhar Universty
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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.
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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.
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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
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MonoaminesMonoamines 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;
PeptidesNitric Oxide
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11 - -Local AnestheticsClinical Pharmacology of Local AnestheticsLocal 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.
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Local anesthetics reversibly block impulse conduction along nerve axons and other excitable
membranes that utilize sodium channels as the primary means of action potential generation. This
action can be used clinically to block pain sensation from—or sympathetic vasoconstrictor impulses
to—specific areas of the body. Cocaine, the first such agent, was isolated by Niemann in 1860. It
was introduced into clinical use by Koller in 1884 as an ophthalmic anesthetic. Cocaine was soon
found to be strongly addicting but was widely used, nevertheless, for 30 years, since it was the only
local anesthetic drug available. In an attempt to improve the properties of cocaine, Einhorn in 1905
synthesized procaine, which became the dominant local anesthetic for the next 50 years. Since
1905, many local anesthetic agents have been synthesized. The goals of these efforts were reduction
of local irritation and tissue damage, minimization of systemic toxicity, faster onset of action, and
longer duration of action. Lidocaine, still a popular agent, was synthesized in 1943 by Löfgren and
may be considered the prototype local anesthetic agent.
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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.
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Cocaine
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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.
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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.
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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.
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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.
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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.
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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.
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Cocaine
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Thank youThank you