AGENTS THAT AFFECT THE AFFERENT INNERVATION(LOCAL ANESTHETICS, IRRITATIVE DRUGS, ASTRINGENT AGENTS, ADSORBENTS, SLIME AGENTS).(Novocainum, xycainum (lidocainum), trimecainum, anaesthesinum, dicainum, ultracainum, bypivacainum, taninnum, vismuti nitras, herba Hyperici, folia Salviae, flores Chamommilae, carbo activatus, carbolenum, Enterosgelum, amilum, semenum Lini, solutio Ammonii caustici, mentholum, charta sinapis, oleum Terebinthinae rectificatum).
ANATOMICAL AND PHYSIOLOGICAL PECULIARITIES OF AUTONOMIC NERVOUS SYSTEM. INDIRECT ACTING CHOLINERGIC STIMULANTS. CHOLINESTERASE REACTIVATORS (Proserinum, Pyridostigmini bromidum, Galanthamini hydrobromidum, Dipiroximum, Alloximum,Amizysilum, Cyclodolum).
AGENTS ACTING M-CHOLINERGIC RECEPTORS(Pilocarpini hydrochloridum, Aceclidinum, Atropini sulfas, Platyphyllini hydrotartras, Scopolamini hydrobromidum, Extractum Belladonnae siccum, Ipratropii bromidum (Atrovent), Pirensepinum (Gastrocepinum), Methacinum)
AGENTS THAT AFFECT THE AFFERENT INNERVATION (LOCAL ANESTHETICS, IRRITATIVE DRUGS, ASTRINGENT AGENTS, ADSORBENTS, SLIME AGENTS).(Novocainum, xycainum (lidocainum), trimecainum, anaesthesinum, dicainum, ultracainum, bypivacainum, taninnum, vismuti nitras, herba Hyperici, folia Salviae, flores Chamommilae, carbo activatus, carbolenum, Enterosgelum, amilum, semenum Lini, solutio Ammonii caustici, mentholum, charta sinapis, oleum Terebinthinae rectificatum).
LOCAL ANESTHETICS
Local anesthetics reversibly block impulse conduction along the axon. This action can be used to block pain sensation from 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. It was soon found to have strongly addicting central nervous system actions 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 (novocain), 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, shorter onset of action, and longer duration of action. Lidocaine, currently the most popular agent, was synthesized in 1943 by Lofgren and may be considered the prototype local anesthetic agent.
Drug groups
The local anesthetics are:
I. Esters: cocaine, procaine (novocain), tetracaine (dicaine), benzocaine (anaesthesine).
II. Amides: lidocaine (xycaine), bupivacaine (marcaine), prilocaine (citanest).
Chemical structure and its influence on the local anesthetics action
Most local anesthetic agents consist of a lipophilic group (frequently an aromatic ring) connected by an intermediate chain (commonly including an ester or amide) to an ionizable group (usually a tertiary amine). Since ester links (as in procaine) are more prone to hydrolysis than amide links, esters usually have a shorter duration of action).
Structure and Properties of Some Ester and Amide Local Anesthetics.1
Local anesthetics are weak bases. For therapeutic application, they are usually made available as salts for reasons of solubility and stability. In the body, they exist either as the uncharged base or as a cation. The relative proportions of these 2 forms is governed by their pKa and the pH the body fluids. Since the pKa of most local anesthetics is in the range of 8-9, the larger fraction in the body fluids at physiologic pH will be the charged, cationic form. The cationic form is thought to be the most active form at the receptor site (cationic drug cannot readily leave closed channels), but the uncharged fraction is very important for rapid penetration of biologic membranes: the local anesthetic receptor is not accessible from the external side of the cell membrane. This explains why local anesthetics are much less effective in infected tissues; these tissues have a low extracellular pH, so that a very low fraction of nonionized local anesthetic is available for diffusion into the cell.
Pharmacokinetics
Local anesthetics are usually administered by injection into the area of the nerve fibers to be blocked. Thus, absorption and distribution are not as important in controlling the onset of effects as in determining the rate of offset of anesthesia and the likelihood of central nervous system and cardiac toxicity. Topical application of local anesthetics, on the other hand, requires drug diffusion for both onset and offset of anesthetic effect.
Systemic absorption of injected local anesthetic from the site of administration is modified by several factors, including dosage, site of injection, drug-tissue binding, the presence of vasoconstricting substances, and the physicochemical and pharmacologic properties of the drug. Application of a local anesthetic to a highly vascular area such as the tracheal mucosa results in more rapid absorption and thus higher blood levels than if the local anesthetic had been injected into a poorly perfused area, such as tendon. Vasoconstrictor substances such as epinephrine reduce systemic absorption of local anesthetics from the depot site by decreasing regional blood flow in these areas. Neuronal uptake of the drug is presumably enhanced by the higher local drug concentration, and the systemic toxic effects of the drug are reduced, since blood levels are lowered by as much as one-third. The combination of reduced systemic absorption and enhanced uptake by the nerve is responsible for prolonging the local anesthetic effect by about 50 %. Vasoconstrictors are less effective in prolonging anesthetic properties of the more lipid-soluble, long-acting drugs, possibly because these molecules are highly tissue-bound.
The amide local anesthetics are widely distributed after intravenous bolus administration. There is evidence that sequestration occurs in storage sites, possibly fat tissue. After an initial rapid distribution phase, which probably indicates uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well perfused tissues, such as muscle and gut.
The ester type agents have the extremely short plasma half-lives (less than 1 minute for procaine) as they are hydrolyzed very rapidly by plasma cholinesterase. The amide linkage of amide local anesthetics is hydrolyzed by liver microsomal enzymes.
The local anesthetics are converted in the liver (amides) or in plasma (esters) to more water-soluble metabolites and then excreted in the urine. Acidification of urine will promote ionization of the tertiary base to the more water-soluble charged form, which is more readily excreted since it is not so easily reabsorbed by renal tubules. Toxicity from the amide type of local anesthetic is more likely to occur in patients with liver disease. For example, the average half-life of lidocaine may be increased from 1,8 hours iormal patients to over 6 hours in patients with liver disease.
Decreased hepatic removal of local anesthetics should also be anticipated in patients with reduced hepatic blood flow. For example, the hepatic elimination of lidocaine in animals anesthetized with halothane is slower than that measured in animals receiving nitrous oxide and curare. The reduced elimination may be related to decreased hepatic blood flow and to halothane-induced depression of hepatic microsomes. Propranolol may also prolong the half-life of amide local anesthetics such as lidocaine.
Pharmacodynamics
Mechanism of action. When progressively increasing concentrations of a local anesthetic are applied to a nerve fiber, the threshold for excitation increases, impulse conduction slows, the rate of rise of the action potential declines, the action potential amplitude decreases, and, finally, the ability to generate an action potential is abolished. All of these effects result from the binding of the local anesthetic to sodium channels; binding results in blockade of the sodium current. If the sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible, the refractory period is lengthened and the nerve can conduct fewer impulses. Elevation of extracellular potassium depolarizes the membrane potential and favors the inactivated state. This enhances the effect of local anesthetics.
Since local anesthetics are capable of blocking all nerves, their actions are not usually limited to the desired loss of sensation. Different types of nerve fibers differ significantly in their susceptibility to local anesthetic blockade on the basis of size and myelination. Upon application of a local anesthetic to a nerve root, the smaller B and C fibers are blocked first. The small type A delta fibers are blocked next. Thus, pain fibers are blocked first; other sensations disappear next; and motor function is blocked last.
Local anesthetics have weak neuromuscular blocking effects that are of little clinical importance. However, their effects on cardiac cell membranes are of major clinical significance. Some (novocaine, lidocaine) are useful antiarrhythmic agents at concentrations lower than those required to produce nerve block.
Regional (conduction) anesthetic techniques are classified according to the site of application: 1) infiltration, including extravascular and intravascular (intravenous regional anesthesia, Bier block); 2) peripheral nerve block (nerve or field block); 3) central neural block, ie, epidural (peridural, extradural, caudal) and subarachnoid (spinal, intrathecal); and 4) topical (surface).
To prevent accidental intravascular injection, needle placement always must be verified by gentle aspiration with a syringe before injection and periodically during administration. An intravenous infusion always should be started prior to injecting a substantial dose of a local anesthetic. Apparatus for administering oxygen and artificial ventilation, diazepam [sibason], vasopressors, intravenous fluids, thiopental, and any additional drugs and equipment that may be useful for resuscitation should be available.
Regional anaesthetic techniques
Topical, or surface, anesthesia involves the direct external application of a local anesthetic in a cream, ointment, drops, spray, or other form. Some forms are used to anesthetize traumatized skin; others are used for mucous membranes. Cationic forms of local anesthetics do not penetrate intact skin, but nonionized (base) forms do penetrate to a limited degree. Both cationic and nonionized forms penetrate abraded skin. Wounds, ulcers, and burns are treated with preparations that are relatively insoluble in tissue fluids. This generally reduces the possibility of systemic toxicity if the area of application is not too extensive and administration is not repeated too frequently. Mucous membranes of the nose, mouth, pharynx, trachea, bronchi, vagina, and urethra are readily anesthetized by both cationic and nonionized forms.
Topical anesthesia in ophthalmology is most common in cataract surgery, iridectomy, prior to removing foreign bodies and sutures, and prior to performing certain diagnostic procedures such as tonometry and gonioscopy. Anesthetics produce short-acting, rapid anesthesia.
However, since absorption from certain of these areas may be quite rapid, the smallest dose required for adequate analgesia should be administered to minimize the possibility of systemic reactions. The addition of a vasoconstrictor generally does not lessen the incidence of these reactions.
For this type of regional anesthesia we can use such drugs: tetracaine (dicaine), cocaine, benzocaine (anaesthesin), lidocaine (xylocaine).
Peripheral nerve block anesthesia blocks peripheral nerves at specific sites. In field block anesthesia, the solution is injected close to the nerves around the area to be anesthetized. Ierve block anesthesia, a localized perineural injection is made at an access point along the course of a nerve distant from operative site. Brachial, radial, medial and ulnar nerve blocks are used for the upper exrtemity. Blocks of the sciatic, femoral, obturator and lateral cutaneous femoral nerves and nerves of the ankle are used for the lower extremity. Peripheral nerve block may also be used for diagnostic purposes and to relieve pain.
Plexus anesthesia – the anesthetic is injected into different plexuses.
For these two types of anesthesia novocaine, lidocaine, prilocaine (citanest), etidocaine (duranest), bupivacaine (marcaine) may be useful.
In epidural anesthesia a local anesthetic agent is injected into the epidural space. In lumbar epidural anesthesia, the injection is usually made in an interspace between the second lumbar and first sacral vertebrae to avoid injury to the spinal cord, which ends at the first lumbar vertebra in 95 % of individuals. In caudal anesthesia, the solution is introduced into the caudal canal (a continuation of the epidural space) through the sacra hiatus.
In general, the number of spinal segments blocked is determined by the site of injection (lumbar or caudal), the position of the patient (fewer segments with sitting), the quantity of drug injected (more segments with larger dose). Increasing the concentration of the anesthetic shortens the onset time and increases the degree of motor blockade.
Physiologic changes are slower in onset with epidural anesthesia than with subarachnoid anesthesia. A test dose should be administered at least five minutes before the main dose in an attempt to detect inadvertent subarachnoid (spinal) injection. The amount of the anesthetic agent (lidocaine, prilocaine, mepivacaine, tetracaine, etidocaine, bupivacain, procaine-novocaine) required in epidural anesthesia and caudal block can be large (15-25 ml), meeting or even exceeding toxic levels unless the dose and concentration are carefully monitored.
1. Spinal anesthesia involves the injection of a local anesthetic agent into the subarachnoid space at the L-2 or L-5 interspace, where it blocks impulse conduction in the spinal nerve roots and the dorsal root ganglia. The level of anesthesia is determined by the site of injection; density and volume of the solution; position of the patient; and the volume of the spinal subarachnoid space.
In addition to isobaric solutions for use in spinal anesthesia, hyperbaric (with dextrose) solutions possessing a density greater than 1.001 or hypobaric (in distilled water) solutions with a density less than 1.000 are available to assure that the specific gravity is higher or lower than that of cerebrospinal fluid, respectively. The hypobaric (light) solitions gravitate caudad and the hyperbaric (heavy) solutions gravitate cephalad when the patient is in the head-down (Trendelenburg) position. Hypotension is the most important complication commonly associated with spinal anesthesia, that develops secondary to the sympathetic blockade that is always produced. If practical, the patient should be placed in a head-down position with the legs raised to promote venous return. Oxygen should be administered. The cardiac output can be increased by the administration of ephedrine and the judicious use of increased fluid administration. The repeated injection of a local anesthetic is associated with diminished effectiveness and duration of action (tachyphylaxis), probably as the result of local pH changes. If the concentration of the anesthetic in solution is increased, the duration is increased, but not proportionally. To minimize the danger of injecting a contaminated solution, only single-dose containers should be employed, and only local anesthetics specifically prepared for subarachnoid anesthesia should be used.
The dose administered for spinal anesthesia generally is too small, even if injected intravascularly, to produce systemic toxicity.
For this type of regional anesthesia such anesthetics may be used: lidocaine, procaine, dibucaine. The amount of the anesthetic agent required for spinal anesthesia is small (2-3 ml).
2. Infiltration anesthesia is the intracutaneous or subcutaneous injection of local anesthetics directly into tissues that are to be surgically cut or sutured, blocking the sensory nerve pathways. This may require a single injection or multiple injections in a ring surrounding the operative area.
In intravascular anesthesia, which is synonymous with intravenous regional anesthesia or Bier block, usually the entire distal portion of an extremity is anesthetized. A needle is inserted into a distal peripheral vein and secured in place. The extremity then is exsanguinated by gravity or with an elastic wrap. A pneumatic tourniquet is then applied to the upper arm or leg. For surgery on the hand, it is applied nearly always to the upper arm and, for the foot, it is applied below the knee. Prilocaine [Citanest] 0,5 % without epinephrine is preferred for this technique.
Table 1.
Local anesthetics principally employed for injection
|
|
Infiltra-tion |
Nerve block |
Intrave-nous regional |
Epidural
|
Subara- chnoid |
|
Amides Bupivacaine [Marcaine] |
+ |
+ |
NR |
+ |
+ |
|
Etidocaine [Duranest] |
+ |
+ |
– |
+ |
– |
|
Lidocaine [Xylocaine] |
+ |
+ |
+ |
+ |
+ |
|
Prilocaine [Citanest] |
+ |
+ |
++ |
+ |
– |
|
Aminobenzoate esters Novocain |
+ |
+ |
– |
NR |
+ |
|
Tetracaine [Dicaine] |
NR |
NR |
– |
+ |
NR |
+ = in current use
++ = drug of choice
– = not in current use or ineffective
NR = not recommended
Table 2
Local anesthetics employed for topical (surface) application
|
|
Eye |
Ear |
Nose |
Throat |
Uret-hra |
Rec- tum |
Skin |
|
Amides Dibucaine |
– |
+ |
– |
– |
– |
+ |
+ |
|
Lidocaine hydrochloride [Xylocaine] |
– |
+
|
+ |
+ |
+ |
–
|
– |
|
Esters Cocaine hydrochloride |
NR |
+ |
+ |
+ |
– |
– |
– |
|
Hexylcaine hydrochloride [Cyclaine] |
NR |
– |
+ |
+ |
+ |
– |
– |
|
Piperocaine hydrochloride [Metycaine] |
–
|
– |
+ |
+ |
+ |
+ |
– |
|
Proparacaine hydrochloride |
+ |
– |
– |
– |
– |
– |
– |
|
Benzocaine |
– |
+ |
+ |
+ |
+ |
+ |
+ |
|
Tetracaine hydrochloride [Dicaine] |
+ |
+ |
+ |
+ |
– |
+ |
+ |
+ = In current use
– = Not in current use or ineffective
NR = Not Recommended
Regional anesthesia has several disadvantages. Protective motor and sensory functions are lost in the body area of regional anesthesia with consequences similar to general anesthesia. Patients having spinal anesthesia may experience a spinal headache. In both spinal and epidural anesthesia, hypotension may occur in response to vasodilatation. With topical anesthesia of the mucous membranes of the throat (e.g. for bronchoscopy), the gag reflex may be suppressed and swallowing affected for about 1 hour after the application of the anesthetic. Compromised cardiopulmonary function may require rapid resuscitation or the administration of supportive medications. The care of a patient having a regional anesthetic should be as meticulous as for the patient having a general anesthetic.
Cocaine hydrochloride
Cocaine is a naturally occurring alkaloid that produces excellent topical anesthesia and intense vasoconstriction when applied to mucous surfaces. It is used for anesthesia in the ear, nose, and throat and in bronchoscopy. The addition of epinephrine is not only unnecessary (it does not delay absorption), but it may increase the likelihood of cardiac arrhythmias. The moistening of dry cocaine powder with epinephrine solution to form so-called “cocaine mud” for use on the nasal mucosa is particularly dangerous and is not recommended. Cocaine is not used parenterally.
Onset of action is rapid (one minute) with a duration of approximately one hour, depending upon the dose and concentration applied. Toxic symptoms occur frequently because cocaine is absorbed readily after topical application, in spite of its vasoconstrictor action, and dosage is difficult to monitor carefully.
Tetracaine hydrochloride
Tetracaine is not recommended for infiltration, peripheral nerve or lumbar epidural block. Tetracaine is approximately ten times more potent and toxic than procaine. The onset of action develops slowly following topical application, and the duration of anesthesia is approximately 45 minutes. Tetracaine is metabolized in the plasma and liver at a slower rate than procaine.
Procaine hydrochloride
Procaine (Novocainum) was the preferred local anesthetic for injection for many years, but it has been largely supplanted by other local anesthetics. Procaine has a slower onset of action than lidocaine, its duration of action is about one hour. It is ineffective topically.
Infiltration: up to 100 ml of a 0,25 % or 0,5 % solution.
Nerve block: up to 50 ml of the 1 % or 25 ml of the 2 % solution.
Lidocaine (Xycaine) hydrochloride
This amide is one of the most widely used local anesthetics for infiltration, intravenous regional, nerve block, epidural, and subarachnoid anesthesia; it also is commonly used for topical anesthesia.
Compared to procaine, the action of lidocaine is more rapid in onset, more intense, and of longer duration; lidocaine also is more potent. This anesthetic has excellent powers of diffusion and penetration. It has a local vasodilator action but is usually administered with epinephrine. When used alone, anesthesia after perineual injection lasts 60 to 75 minutes; with epinephrine – anesthesia lasts up to two hours.
When administered by extravascular injection, lidocaine is approximately one and one half times as toxic as procaine.
As a general guide, in healthy adults with normal hepatic function and hepatic blood flow, the maximal single dose recommended for topical use is 300 mg and for injection (excluding subarachnoid) is 300 mg (4,5 mg/kg) without epinephrine or 500 mg (7 mg/kg) with epinephrine. This dose should not be repeated at intervals of less than two hours.
Topical: the 2 % solution is generally recommended for topical anesthesia. The 4 % solution is used principally for laryngotracheal anesthesia.
Infiltration: without epinephrine, for extensive procedures, 25 to 60 ml of a 0,5 % solution or 10 to 30 ml of a 1 % solution. For minor nerve block a 0,5 % solution is adequate.
Lidocaine is the antiarrhythmic drug most commonly used by the intravenous route. It has an unusually low incidence of toxicity and a high degree of effectiveness in arrhythmia associated with acute myocardial infarction.
Because very extensive first-pass hepatic metabolism, only 3 % of orally administered lidocaine appears in the plasma. Thus, lidocaine must be given parenterally by the intravenous route, of 0,2 % solution.
Lidocaine’s major indication is suppression of ventricular tachycardia and prevention of fibrillation after acute myocardial infarction.
Toxicity of local anesthetic agents
Ultimately, local anesthetic agents are absorbed from the site of administration. If blood levels rise too high, effects on several organ systems may be observed.
Central Nervous System
Cocaine has been used for at least 1200 years in the custom of chewing coca leaves by natives of the South American Andes. Coca was first imported to Europe from the western hemisphere in 1580. Cocaine was isolated as the active material in 1860. Its anesthetic properties, especially its topical anesthetic action, were discovered in the 1870s and 1880s. Sigmund Freud was intrigued by the drug and thought it might even be a panacea, but his enthusiasm was dampened by its disastrous effects on a friend who became addicted. A colleague of Freud’s, Karl Koller, is credited with first using the drug as a topical anesthetic for eye surgery, a use that still prevails. Cocaine appears to facilitate catecholaminergic neurotransmission by increasing its release and reducing reuptake. Psychic dependence is strong (cocaine is one of the most strongly reinforcing drugs). Recent patterns of abuse of this drug, have revealed a typical pattern of withdrawal manifested by signs and symptoms opposite to those produced by the drug. Users become sleepy, have a ravenous appetite, are exhausted, and may suffer mental depression. This syndrome may last for several days after the drug is withdrawn. Tolerance develops quickly, so that abusers may take monumental doses. Subject may enter a paranoid schizophrenialike state. Typically, it develops delusions that bugs are crawling under skin, which leads to characteristic discrete excoriations.
Two types of administration of cocaine are current. One may “snuff” the drug by sniffing a “line” (a measured amount of drug in a folded piece of paper applied to the nose), or one may smoke “free base”. Cocaine is supplied as a hydrochloride salt, and free base is made by alkalinizing the salt and extracting with nonpolar solvents. When free base is smoked, entry through the lungs is almost as fast as by intravenous injection, so that effects are even more accentuated. Intravenous injection is rarely used, as the possibility of overdose is considerable. The purity and potency of cocaine available to users varies widely. Overdoses of cocaine are usually rapidly fatal, victims dying within minutes from respiratory depression and seizures. Those who survive for 3 hours usually recover fully. Intravenous administration of diazepam and propranolol may be the best treatment.
Other local anesthetics have been thought to lack the euphoriant effects of cocaine. Other central nervous system effects include sleepiness, light-headedness, visual and auditory disturbances, and restlessness. At higher concentrations, nystagmus and shivering may occur. Finally, overt tonic-clonic convulsions followed by central nervous system depression and death may occur with all local anesthetics, including cocaine. Local anesthetics apparently lead to depression of cortical inhibitory pathways, thereby allowing unopposed activity of excitatory components. This transitional stage of unbalanced excitation may be followed by generalized central nervous system depression if higher blood levels of local anesthetic are reached. Signs and symptoms of central nervous system toxicity are also circumoral paresthesias, tinnitus, tremors, and shivering; convulsions may follow. Subconvulsive doses of lidocaine and procaine are often associated with sedation or sleep, which has not been reported with other local anesthetics. If the drug plasma level is high, ventilatory depression, progressing to respiratory arrest and coma, may develop as a result of generalized central nervous system depression.
The most important and initial treatment should be to ensure and maintain a patent airway and to support ventilation with oxygen and assisted or controlled respiration if required.
Most serious toxic reactions to local anesthetics are due to convulsions from excessive blood levels. These are best prevented by administering the smallest dose of local anesthetic required for adequate anesthesia. When large doses must be administered, premedication with a benzodiazepine, eg, diazepam, 0,1-0,2 mg/kg parenterally, probably provides significant prophylaxis against seizures.
Cardiovascular System
The cardiovascular effects of local anesthetics result partly from direct effects upon the cardiac and smooth muscle membranes and partly from indirect effects upon the autonomic nerves. Local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. They also depress the strength of cardiac contraction and cause arteriolar dilatation (except for cocaine, which causes vasoconstriction) both leading to hypotension. Although cardiovascular collapse and death usually occur only after large doses, they may result occasionally from the small amounts used for infiltration anesthesia. Acute circulatory failure is treated with fluids and vasopressors (eg, ephedrine) administered intravenously. If respiratory arrest occurs or asystole is suspected, artificial ventilation and external cardiac massage must be instituted immediately.
As noted above, cocaine differs from the other local anesthetics in its cardiovascular effects. The blockade of norepinephrine reuptake results in vasoconstriction and hypertension. It may also precipitate cardiac arrhythmias. The vasoconstriction produced by cocaine can lead to ischemia of the nasal mucosa and, in chronic users, to ulceration of the mucous membrane and even damage to the septum.
For prevention local anesthetics’ toxicity vasoconstrictors may be added to local anesthetic solutions used for infiltration, peripheral nerve block anesthesia to decrease the rate of absorption. In general, this prolong the anesthetic effect and reduces the risk of systemic reactions, as well as increases the frequency of complete conduction block at low anesthetic concentration. The addition of a vasoconstrictor is more appropriate than increasing the concentration to prolong the duration. Epinephrine is the vasoconstrictor most commonly used for infiltration, nerve block anesthesia.
Local anesthetic solutions containing epinephrine should not be used for nerve blocks in areas supplied by end-arteries (eg, digits, ears, nose, penis) because they may cause ischemia, which could progress to necrosis. The total dosage of epinephrine should not exceed 0,2 mg.
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.
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.
Systemic effects (anxiety, restlessness, tremors, palpitations, tachycardia, anginal pain, dizziness, headache, and hypertension) may be produced by the epinephrine that is added to local anesthetics for parenteral use. These reactions are seen most frequently in office dentistry.
Local Reactions: The most common local adverse reaction caused by local anesthetics is contact dermatitis, characterized by erythema and pruritus that may progress to vesiculation and oozing. This occurs most commonly in individuals (eg, physicians, dentists) who are frequently exposed to ester-type local anesthetics or who are on prolonged self-medication (eg, hemorrhoidal preparations). These reactions have become rare since the amides were introduced.
Repeated corneal application of topical anesthetics should be avoided since keratitis, which occasionally may lead to permanent reduction in visual acuity, can occur.
Allergic reactions: The ester type local anesthetics are metabolized to p-aminobenzoic acid derivatives. These metabolites are responsible for allergic reactions in a large percentage of the population. Amides are not metabolized to p-aminobenzoic acid, and allergic reactions to agents of the amide group are extremely rare.
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.
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, 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.
However, new research into the mechanisms of cardiac and spinal toxicity and alternative drug targets for spinal analgesia (eg, 2 receptors) suggest that it may be possible to find better drugs, at least for spinal anesthesia. In an attempt to extend the duration of the local anesthetic action, a variety of novel delivery systems are in development (eg, polymers). Transdermal local anesthetic delivery systems are also being investigated.
Local Anesthetic Systemic Toxicity
- Overview
- Systemic Toxicity Cause: Excessively high plasma local anesthetic concentration
- Plasma concentration — determinants
- Rate of entry into systemic circulation balanced by redistribution to tissue sites & clearance
- Most common cause of toxic plasma local anesthetic concentrations –
- Accidental direct intravascular injection during peripheral nerve block or epidural anesthesia
- Other cause of toxic plasma levels: — excessive absorption from injection site (no intravascular injection)
- Extent of systemic absorption — dependencies
- Initial dose of administered
- Injection site vascularity
- Whether or not epinephrine was used to provide local vasoconstriction
- Properties of the drug itself
- CNS Toxicity-local anesthetics
- Symptom development:
- Tongue and circumoral numbness (low concentration)
- CNS changes with local anesthetic entering the brain
- Initial symptoms: tinnitus, vertigo, restlessness
- Subsequent symptoms: slurred speech & skeletal muscle fasciculation (muscle twitching: often immediately precedes seizures)
- Tonic-clonic seizures
- Presentation: generalized seizure (tonic general muscular contractions) with alternating contractions and relaxations.
- Duration: one- two minutes
- Consciousness: Loss of Consciousness
- Factors influencing CNS toxicity
- Plasma concentration– specific drug dependent
- Lidocaine (Xylocaine), mepivacaine (Carbocaine), prilocaine (Citanest): CNS effects (5-10 ug/ml):
- Bupivacaine (Marcaine): CNS effects [seizures] (4-5 ug/ml)
- Rate of injection — (i.e. rate of rise of serum concentration): may be more important than total amount of drug injected
- Lidocaine (Xylocaine) — must also consider active metabolites, e.g.monoethylglycinexylidide, which may contribute to additive toxicity with lidocaine (Xylocaine) following epidural administration
- Inverse relationship between PaCO2 and local anesthetic seizure thresholds (possibly related to variation in cerebral blood flow & drug delivery)
- Hyperkalemia– promoting depolarization: increased local anesthetic toxicity
- Hypokalemia-promoting membrane hyperpolarization: decreased local anesthetic toxicity
- Increased (probably) lidocaine (Xylocaine) neurotoxicity in patients treated with mexiletine (Mexitil) during perioperative time frame.
- Treatment: Seizures
- Assure adequate ventilation with oxygen
- Rapid onset of arteriole hypoxemia & metabolic acidosis
- Add supplemental oxygen when local anesthetic toxicity first appears
- Seizure suppression
- IV midazolam (Versed) or diazepam (Valium)
- Overview — Neurotoxicity as a consequence of local anesthetic injection into subarachnoid or epidural spaces
- Effects:
- Groin numbness
- Long-lasting, isolated myotomal (muscle segment) weakness
- Cauda equina syndrome
- Subarachnoid-space injections:
- Transient radicular irritation
- Permanent neurological injury following regional anesthesia: rare
- Transient Radicular Irritation
- Anatomical Location: lumbosacral nerves
- Manifestation: moderate/severe lower back, buttocks, posterior thigh pain
- time to onset: by 24 hours following spinal anesthesia complete recovery
- Type of pain (delayed onset): neural inflammatory
- Pain treatment: if severe, opioids
- Time to recovery: within one-week
- Pharmacological issues:
- Transient radicular irritation — may not be dependent on anesthetic concentration {frequency comparable following several lidocaine (Xylocaine) concentrations}
- Spinal anesthesia with tetracaine (pontocaine): reduced incidence of transient radicular irritation relative to lidocaine (Xylocaine)
- Transient ischemia due to lengthened exposure to local anesthetic as a result of concurrent epinephrine or phenylephrine (Neo-Synephrine) use {in the anesthetic solution} may contribute to transient neurological symptoms
- Cauda equina Syndrome
- Definition: injuries (diffuse) across lumbosacral plexus causing:
- Sensory anesthesia
- Bowel & bladder sphincter dysfunction
- Paraplegia
- Circumstances of clinical occurrence:
- Microcatheters (28 gauge) delivering hyperbaric 5% lidocaine (Xylocaine) may cause nonhomogeneous local anesthetic distribution– pooling of high anesthetic concentration on stretched nerves (lithotomy position).
- Following intrathecal lidocaine (Xylocaine) [100 mg 5% lidocaine (Xylocaine), 25-gauge needle]
- Intended epidural anesthesia
- Anterior Spinal Artery Syndrome
- Manifestation: lower-extremity paresis (variable sensory deficit following neural blockade resolution)
- Possible mechanisms
- Thrombosis
- Anterior artery spasm
- Hypotension/vasoconstrictor drugs
- Possible Predisposing conditions:
- Advanced age
- Peripheral vascular disease
- Differential diagnosis — similar symptoms to that caused by:
- Epidural abscess-mediated or hematoma-mediated spinal cord compression
Preparations Available
Articaine (Septocaine)
Parenteral: 4% with 1:100,000 epinephrine
Benzocaine (generic, others)
Topical: 5, 6% creams; 15, 20% gels; 5, 20% ointments; 0.8% lotion; 20% liquid; 20% spray
Bupivacaine (generic, Marcaine, Sensorcaine)
Parenteral: 0.25, 0.5, 0.75% for injection; 0.25, 0.5, 0.75% with 1:200,000 epinephrine
Butamben picrate (Butesin Picrate)
Topical: 1% ointment
Chloroprocaine (generic, Nesacaine)
Parenteral: 1, 2, 3% for injection
Cocaine (generic)
Topical: 40, 100 mg/mL solutions; 5, 25 g powder
Dibucaine (generic, Nupercainal)
Topical: 0.5% cream; 1% ointment
Dyclonine (Dyclone)
Topical: 0.5, 1% solution
Levobupivacaine (Chirocaine)
Parenteral: 2.5, 5, 7.5 mg/mL
Lidocaine (generic, Xylocaine, others)
Parenteral: 0.5, 1, 1.5, 2, 4% for injection; 0.5, 1, 1.5, 2% with 1:200,000 epinephrine; 1, 2% with
1:100,000 epinephrine, 2% with 1:50,000 epinephrine
Topical: 2.5, 5% ointments; 0.5, 4% cream; 0.5, 2.5% gel; 2, 2.5, 4% solutions; 23, 46 mg/2 cm2
patch
Lidocaine and etidocaine eutectic mixture (EMLA cream)
Topical: lidocaine 2.5% plus etidocaine 2.5%
Mepivacaine (generic, Carbocaine, others)
Parenteral: 1, 1.5, 2, 3% for injection; 2% with 1:20,000 levonordefrin
Pramoxine (Tronothane, others)
Topical: 1% cream, lotion, spray, and gel
Prilocaine (Citanest)
Parenteral: 4% for injection; 4% with 1:200,000 epinephrine
Procaine (generic, Novocain)
Parenteral: 1, 2, 10% for injection
Proparacaine (generic, Alcain, others)
0.5% solution for ophthalmic use
Ropivacaine (Naropin)
Parenteral: 0.2, 0.5, 0.75, 1.0 % solution for injection
Tetracaine (Pontocaine)
Parenteral: 1% for injection; 0.2, 0.3% with 6% dextrose for spinal anesthesia
Topical: 1% ointment; 0.5% solution (ophthalmic); 1, 2% cream; 2% solution for nose and throat;
2% gel
Astrigent agents
Tannins
are astringent, bitter-tasting plant polyphenols that bind and precipitateproteins. The term tannin refers to the source of tannins used in tanning animal hides into leather; however, the term is widely applied to any large polyphenolic compound containing sufficient hydroxyls and other suitable groups (such as carboxyls) to form strong complexes with proteins and other macromolecules. Tannins have molecular weights ranging from 500 to over 3,000.
Tannins are usually divided into hydrolyzable tannins and condensed tannins (proanthocyanidins). At the center of a hydrolyzable tannin molecule, there is a polyol carbohydrate (usually D-glucose).
The hydroxyl groups of the carbohydrate are partially or totally esterified with phenolic groups such as gallic acid (in gallotannins) or ellagic acid (in ellagitannins). Hydrolyzable tannins are hydrolyzed by weak acids or weak bases to produce carbohydrate and phenolic acids. Condensed tannins, also known as proanthocyanidins, are polymers of 2 to 50 (or more) flavonoid units that are joined by carbon-carbon bonds, which are not susceptible to being cleaved by hydrolysis. While hydrolyzable tannins and most condensed tannins are water soluble, some very large condensed tannins are insoluble.
Tannins may be employed medicinally in antidiarrheal, hemostatic, and antihemorrhoidal compounds. Also, they produce different colors with ferric chloride (either blue, blue black, or green to greenish black) according to the type of tannin.
Examples of gallotannins are the gallic acidesters of glucose in tannic acid (C76H52O46), found in the leaves and bark of many plant species.
Quercus robus
Green Tea Farm
Adsorbents agents
Carbo activatus
DESCRIPTION
Activated charcoal is a type of amorphous carbon prepared by destructive distillation of such materials as wood, vegetables and coconut shells, materials that have much higher surface areas than charcoal itself. It is a fine, black powder of largely pure carbon. The large surface area of activated charcoal confers a great adsorptive capacity to this material. It is this great adsorptive capacity that is the basis for its many industrial as well as medical uses. There are different types of activated charcoal with different adsorption characteristics. The adsorptive characteristics are determined by the configuration of the surface of activated charcoal.
Activated charcoal is widely used in the treatment of acute poisoning (overdose) with such substances as acetaminophen, salicylates, barbiturates and tricyclic antidepressants. Activated charcoal strongly adsorbs aromatic substances such as the above, reducing their absorption from the gastrointestinal tract. Most inorganic poisons are not significantly adsorbed by activated charcoal. A major industrial use of activated charcoal is as a decolorizer. For example, it is used in the late stages of sugar refining to produce white sugar. Activated charcoal is commonly used in air and water filters.
Activated charcoal, in addition to some other substances, has been used in Russia for the treatment of a number of disorders and diseases, including hyperlipidemia, liver, biliary tract and renal diseases. The practice is known as enterosorption and carbon sorption therapy, when activated charcoal is the principle therapeutic component. Oral activated charcoal is known to lower cholesterol levels.
Activated charcoal is also known as active carbon, activated carbon, adsorbent charcoal, carbo activatus, carbo medicinalis, carbon active, carbon attivo, decolorizing charcoal, activkohle (German) and medicinal charcoal.
ACTIONS AND PHARMACOLOGY
ACTIONS
Activated charcoal is a gastrointestinal adsorbent. It may also have hypocholesterolemic activity.
MECHANISM OF ACTION
The large surface area of activated charcoal confers a great adsorptive capacity to this material. The adsorptive capacity of this substance differs for various chemical entities. Activated charcoal is most effective in adsorbing aromatic or benzenoid-type substances. Less well adsorbed are non-aromatic (non-benzenoid) substances, such as the various fatty acids and fatty alcohols. Inorganic substances are poorly adsorbed by activated charcoal. Aromatic substances, such as acetaminophen, salicylates, barbiturates and tricyclic antidepressants, are very strongly adsorbed by activated charcoal, and that is why activated charcoal is commonly used in the management of overdosage of these substances. Adsorption of these drugs reduces their absorption from the gastrointestinal tract.
The mechanism of the hypocholesterolemic effect of activated charcoal is not entirely clear. It is thought that the cholesterol-lowering effect of activated charcoal is caused by its interference with the enterohepatic circulation of bile acids.
PHARMACOKINETICS
Activated charcoal is not absorbed via the gastrointestinal tract, and all ingested activated charcoal is excreted in the feces.
INDICATIONS AND USAGE
Results have been mixed in studies using charcoal in patients with gas complaints. There is some evidence that activated charcoal can favorably affect lipids and that it might be helpful in alleviating symptoms associated with cholestasis of pregnancy. Activated charcoal looks promising for the treatment of uremic pruritis, as well as for congenital erythropoietic porphyria.
RESEARCH SUMMARY
There are inconsistent results in studies related to activated charcoal’s efficacy in reducing intestinal gas and symptoms related thereto. In one double-blind study, the substance significantly reduced bloating and abdominal cramps associated with gaseousness. Some other studies have confirmed this effect, and some others have not, discrepancies that may be related to dosing and sampled populations. One researcher reported that activated charcoal effectively adsorbs intestinal gas in healthy subjects but that it “has not been properly investigated in patients with gas complaints.”
Oral activated charcoal has significantly lowered plasma total cholesterol and LDL-cholesterol in both animals and humans. It has also raised HDL-cholesterol in some studies. In one crossover study of seven subjects ingesting 4, 8, 16 or 32 grams per day of activated charcoal, serum total and LDL-cholesterol were decreased (maximum 29% and 41% respectively) and the ratio of HDL/LDL-cholesterol was increased (maximum 121%) by activated charcoal in a dose-dependent pattern.
Ten additional subjects with severe hypercholesterolemia took daily, in random order, for three weeks, 16 grams of activated charcoal, 16 grams of cholestyramine or 8 grams of activated charcoal plus 8 grams of cholestyramine. Activated charcoal reduced total and LDL-cholesterol concentrations 23% and 29%, respectively; cholestyramine reduced them 32% and 39%; in combination, they reduced them 30% and 38%. The ratio of HDL/LDL-cholesterol increased from 0.13 to 0.23 with activated charcoal, to 0.29 with cholestyramine and to 0.25 with the combination. Cholestyramine increased serum triglycerides, but activated charcoal did not. Research is ongoing.
Given that elevated serum bile acid levels are thought to play a role in cholestasis of pregnancy, activated charcoal was administered to women with this condition to see if it could decrease these levels. The women were given 50 grams of the substance three times a day for eight days. By day eight, serum total bile acid concentrations were significantly reduced. Outcome of pregnancy was good. This preliminary study needs followup to see whether activated charcoal might be an option in the treatment of entrahepatic cholestasis of pregnancy.
Activated charcoal given as an oral dose of 6 grams provided symptomatic relief in nearly 50% of patients with uremic pruritis, a poorly understood symptom of uremia. The studies have, however, been limited. More research is needed.
Finally, activated charcoal was more effective in reducing plasma porphyrin levels than oral cholestyramine in a patient with congenital erythropoietic porphyria or Gunther’s disease. Again, more research is needed.
CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
Activated charcoal is contraindicated in those whose gastrointestinal tract is not anatomically intact.
PRECAUTIONS
Activated charcoal adsorbs a wide range of drugs and nutrients. Those using activated charcoal should avoid using it within two hours of drug, food, nutritional supplement or herb intake or within two hours before their intake.
ADVERSE REACTIONS
Black stools (from the activated charcoal) occur frequently. Other reported adverse reactions include nausea, vomiting, blackening of the teeth and mouth, abdominal discomfort, diarrhea (more frequent) and constipation (less frequent).
There are occasional reports of drug failure in those who use activated charcoal concomitantly with a drug.
INTERACTIONS
Activated charcoal adsorbs a wide range of drugs and nutrients. Therefore, those using activated charcoal should avoid using it within two hours of drug, food, nutritional supplement or herb intake or within two hours before their intake.
OVERDOSAGE
None reported.
DOSAGE AND ADMINISTRATION
Those who use activated charcoal as an antflatulant typically use 500 to 1000 milligrams as needed. Those who use activated charcoal for its possible cholesterol-lowering effect take 5 to 8 grams two to three times daily. Those who use activated charcoal combine it with plenty of water and must not use it within two hours before or after ingesting any drug, food, nutritional supplement or herb.
HOW SUPPLIED
Capsules — 250 mg, 260 mg, 280 mg, 350 mg
Enteric Coated Tablets — 250 mg
Granules
Liquid — 15 g/75 ml, 25 g/120 ml, 30 gm/120 ml
Tablets — 250 mg
Herba hyperici
Hyperici herba (Hyp) is the aerial part collected during the flowering period from the well-known herb, Hypericum perforatum.
Black lipid membrane experiments were performed to investigate the effect of the ethanolic Hyp extract on the electrical properties (capacitance and conductance) of artificial lipid bilayers.
Folia Salviae
Flores Chamommilae
Anatomical and physiological peculiarities of autonomic nervous system
Langley originally defined the autonomic nervous system (s/a ANS) as consisting as nerve cells and fibers by which efferent impulses pass to tissues other than skeletal muscle. So ANS is motor system controlling visceral organs for homeostasis. There is a sensory component of ANS. Sensory nerves innervating viscera are part of ANS. Sensory components establish reflex loops for smooth control of ANS (ex. baro and chemoreceptor reflexes).
Baroreceptor Reflex In bifurcation of common carotid artery, there is a region of thinning of common carotid (this region pulses when you squeeze it) that is richly innervated by autonomic fibers from petrosal ganglion at neck. When blood pressure goes up, these sensory nerves activate. This is a bipolar neuron: one pole -> in carotid sinus and other pole in dorsal medulla. Brain processes information and send efferent impulse to heart slowing heart and reducing contractility letting blood pressure go down. If heart go down too much, sympathetic reflex speeds it up.
Chemoreceptor Of Carotid Body They sense O2 levels in blood. CO2 levels go up. CO2 go to dorsal medial medulla. Brain tells lung to breathe fast.
Baroreceptor And Chemoreceptor Reflexes
Baroreceptor reflex maintains blood pressure iarrow range. Chemoreceptor reflex maintain O2 levels.
ANS – Afferent and efferent components that mediate reflex loops.
ANS Functions
1. Secretion of gland.
2. Actions of many smooth muscles.
3. Extrinsic control of heart.
4. Variety of metabolic processes including release of catecholamines, glucagon, insulin, and others.
Two Divisions Of ANS
1. Sympathetic
2. Parasympathetic
Anatomic Distinction Of Sympathetic And Parasympathetic
Depends on position of ganglia.
Parasympathetic neurons are in brain (medulla) and sacral spinal cord.
Sympathetic neurons are in the thoracolumbar spinal cord.
ANS – All autonomic preganglionic neurons make synapses with clusters of neurons called ganglia.
Spinal Cord And The Sympathetic System – The spinal cord has grey matter and white matter. The spinal cord has the intermedial lateral cell column which has the origin of sympathetic preganglionic neurons which send axons through ventral root where they synapse on a ganglion. The ganglionic neurons send out postganglionic neuron to target cell (i.e. a visceral organ like the heart). The ganglion are found in a chain of ganglion that is close to spinal cord in paravertebral ganglionic chain. Sympathetic system has short preganglionics and long post ganglionic axons.
Diffusion Effect Of The Sympathetic System
The nervous system.
When this axon comes out spinal cord, it goes up and down the chain to synapse on adjacent ganglion so have diffusion effect so one preganglionic neuron can stimulate neuron in multiple ganglion. Have collateralization of terminals in ganglion so one can stimulate many ganglia giving global discharge of sympathetic system -> this is useful for fight or flight.
Brain And The Parasympathetic Nervous System
Long presynaptic acetylcholine fiber comes off of brain. Short postsynaptic with nicotinic receptor goes to target organ.
So the preganglionic neuron is long and the postganglionic neuron is short. The postganglionic neuron is usually on surface of innervated organ.
Discrete Effect Of The Parasympathetic Nervous System
Activity of parasympathetic nervous system give discrete activation of specific organ (not a global effect). Ganglia not only relay stations, but serve as integrated areas. Have multiple ganglia on heart (not just one). Different ganglia control aspects of cardiac function through different pathways: one controls cardiac rate, one controls AV conduction, and one controls myocardial contractility.
Efferent ANS
This includes the sympathetic and parasympathetic systems.
Sensory Component Of ANS
Major sensory neurons are found in the dorsal root ganglia. They are not as well understood as efferent component. They utilize different neurotransmitter.
Neurotransmitter Of ANS
With respect to preganglionic neuron (be it parasympathetic or sympathetic), it will release acetylcholine (s/a Ach) and the receptor effected is nicotinic.
In sympathetic nervous system, postganglionic neuron has norepinephrine and receptor that is activated depends on target system ( and receptors). In heart, have receptor.
In parasympathetic nervous system, parasympathetic postganglionic releases acetylcholine as does its preganglionics. This acetylcholine of the postganglionic influences a muscarinic receptor.
Sensory Neurons And Neuropeptides
The sensory neurons have variety of neuropeptides (a dozen have been identified). An example is substance P. Substance P is probably a neurotransmitter contained in sensory neurons that mediate sensation of pain. Pain is carried by unmyelinated sensory neurons that release substance P to dorsal root of spinal cord.
Multiple Neurotransmitters
It is found neurons have multiple neurotransmitters (NT).
In sympathetic system, norepinephrine (NorEp) is commonly cofound with neuropeptide y (NPY). Stimulation of sympathetic nerves causes vasoconstriction. NPY is a more potent vasoconstrictor than NorEp.
Cholinergic neurons have VIP (vasoactive intestinal polypeptide).
These multiple transmitters -> one transmitter modulate action of other compound released.
ANS
It regulates activities not considered under voluntary control and function below the level of consciousness. Examples of these activities are respiration, circulation, digestion, body temperature, metabolism, sweating, and secretion of certain endocrine glands.
Sympathetics And Parasympathetics Acting As Physiological Antagonists
ANS maintain constant internal environment to maintain homeostasis. In most cases, sympathetics and parasympathetics act as physiological antagonist.
(Heart: Sympathetic accelerate cardiac rate. Parasympathetic diminishes cardiac rate).
(Eye: Sympathetics open pupil. Parasympathetics close pupil).
Most viscera innervated by both divisions of ANS. Level of activity in any given organ represent effect of activation of parasympathetics and sympathetics effects on organ.
Physiological antagonist effect may occur by action on same cell.
In heart and intestine, sympathetics and parasympathetics act on same effector cell for antagonist response.
In eye, sympathetics act by controlling radial muscle of eye. If contract radial muscle pupil get larger.
Parasympathetics affect different muscle (sphincter muscle). If contract sphincter muscles pupil get smaller.
Sympathetics And Parasympathetics Acting In Tandem
Parasympathetics gives copious watery salivary secretion. Sympathetic activation gives thick viscous secretion.
Cases Where Parasympathetics And Sympathetics Don’t Innervate An Organ
Both parasympathetic and sympathetic don’t innervate an organ (i.e. blood vessels just get sympathetic activation -> no antagonism is possible).
Physiological Characteristics Of Sympathetic Nervous System
Sympathetic nervous system is on continuously (i.e. basal tone). It varies minute to minute and from organ to organ. Sympathoadrenal system often acts as a unit to facilitate fight or flight. Activation of sympathetic nervous system increases blood pressure, increases heart rate, blood goes to skeletal muscle, blood vessel dilate, pupils dilate, and bronchioles dilate. In a controlled environment and in the absence of stress, sympathetics not needed for life. In chemosympathonectomy (using drugs to destroy sympathetic system), animals do just fine.
Parasympathetic
It is organized for discrete activation of localized target organ. Its main function is conservation of energy and maintenance of organ function during periods of normal activity. See decrease in heart rate, blood pressure, enhanced GI mobility and secretion, emptying of bladder, and constriction of pupils.
Neurophysiology
Action potential (AP). Axonal conduction. Membrane potential. – 70 mV in interior of axon with respect to exterior. High [K+] intracellularly and low Na+ and Cl- intracellularly. Energy requiring ionic pumps maintain concentration. Depolarization -> get permeability of membrane to sodium. See delayed opening of potassium channels and repolarization process propagated down axons. When axon terminal invaded by action potential, Ca++ flows in.
Axon Terminal
Synaptic vesicles (sacs with neurotransmitter). These sacs go to terminal membrane where they fuse with membrane and contents get ejected. We would predict the membrane would get longer, but some membrane gets pinched off to form new synaptic vesicle.
Neurons
For ANS neurotransmitters, neurotransmitter synthesized in nerve terminal.
By contrast, the neuropeptide must be synthesized at the perikaryon (cell body) by protein synthesis machinery. These compounds are transmitted down axon to terminal.
Synaptic Сleft
The neurotransmitter diffuse down synaptic cleft where they interact with post or pre synaptic receptors.
Ways Of Stopping Neurotransmitter
When transmitter released, to stop process, neurotransmitter can diffuse away in blood stream (get lower concentration of neurotransmitter) or can have metabolic enzyme process (i.e. acetylcholinesterase metabolize Ach).
In case of NorEp, there is an active transport system that brings NorEp back into the cytoplasm of the nerve terminal and there is an active transport system that takes NorEp back into synaptic vesicle.
Ways Of Stopping Neurotransmitter
Diffusion
Degradation
Reuptake
Neuropeptides
These peptides are degraded by peptidases. No reuptake. Demonstrated they are found in vesicles.
Mechanism Of Action Of Drugs That Influence ANS
1. Drug can interfere with synthesis of the neurotransmitter. (hemicholinium, methyl paratyrosine)
For example, on cholinergic side, hemicholinium interferes with synthesis of Ach. Precursor for biosynthesis of catecholamines is tyrosine (later on it is dopamine). Use structural analog of tyrosine -> methyl para tyrosine -> inhibit biosynthesis of catecholamines on adrenergic side.
2. Metabolic transformation by same pathway of precursor of the neurotransmitter.
(methyl DOPA)
The biosynthetic enzyme of catecholamine aren’t substrate specific. So on adrenergic side, methyl DOPA (not DOPA) can be metabolized to methyl dopamine and methyl norepinephrine. Methyl norepinephrine gets released due to action potential, but don’t have same activity of endogenous neurotransmitter. So false transmitter blocked effect of sympathetic nervous system.
3. Blockade of neurouptake (cocaine, tricyclic antidepressants, reserpine)
NorEp gets reuptaken -> drugs can block reuptake. Cocaine blocks NorEp uptake. Tricyclic antidepressant drugs block reuptake of the neurotransmitter.
Active transport process take NorEp from synaptic cleft to cytoplasm. Active transport take NorEp from cytoplasm to synaptic vesicle -> reserpine blocks that active transport process.
4. Other drugs cause release of content at nerve terminal.
(black widow toxin, amphetamine) Black widow toxin has cholinergicomimetic effect via release of Ach. Amphetamine is sympathomimetic -> effect by release of catecholamines.
5. Other drugs block release of neurotransmitter. (botulinum toxin, bretylium) Botulinum toxin prevents release of Ach. Drug called bretylium blocks release of NorEp.
6. Lots of drugs mimic effect of endogenous neurotransmitter postsynaptically.
(muscarine, nicotine, phenylepinephrine, clonidine, isoproterenol) On cholinergic side, muscarine mimics muscarinic effects of Ach. Nicotine mimics nicotinic effects of Ach.
On adrenergic side, variety of receptor types: and . 1 receptor activation is mimicked by drug called phenylepinephrine. 2 receptor activation is mimicked by clonidine. Isoproterenol mimics either receptor.
7. You can also block effect of neurotransmitter postsynaptically. (atropine, curare, trimethaphan, phenoxybenzamine, propranolol) Muscarinic effects of Ach blocked by atropine. Nicotinic effects of Ach on skeletal muscle blocked by curare. Nicotinic effects at ganglia blocked by trimethaphan. On adrenergic side, receptor blocked by phenoxybenzamine. receptors blocked by propranolol (a nonspecific blocker).
8. Inhibition of enzymatic degradation (anticholinesterase drugs, monamine oxidase inhibitors) On cholinergic side, have anticholinesterase drugs. On adrenergic side, monoamine oxidase inhibitors.
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Indirect acting cholinergic stimulants. Cholinesterase reactivators
Since acetylcholine is inactivated by cholinesterases, inhibition of cholinesrerases leads to a rise in acetylcholine concentration. If this rise remains moderate, it can have beneficial effects but if is too high it causes toxic effects.
Cholinesterase inhibitors, also called anticholinesterase agents, are schematically classified, according to their intensity and duration of action and consequently of their toxicity, into reversible and irreversible inhibitors.
In human beings, inhibition of cholinesterases induces, by accumulation of acetylcholine, muscarinic and nicotinic effects. These effects are predominately central or peripheral according to whether the inhibitor penetrates or not into the brain.
Inhibition of cholinesterases of insects is a way to obtain their destruction.
Reversible inhibitors
The reversible inhibtors, which inhibit enzyme in a transitory way, as long as their concentration is sufficient, are used in therapeutics and, for the majority of them, are known for a long time.
Physostigmine or eserine
Physostigmine, also callad eserine, alkaloid obtained from calabar bean, gives primarily muscarinic effects and crosses the blood-brain barrier.
It increases the gastric and intestinal peristalsis and induces bronchoconstriction and contraction of ureters.
It increases bronchial and digestive secretions (gastric, intestinal, salivary), as well as lacrimal secretion. Its cardiovascular action is complex but, in general, it has a muscarinic action: bradycardia and decrease of the force of cardiac contractions.
Eserine elicits miosis, spasm of accommodation, fall of intraocular pressure, hyperemia of conjunctiva and lacrymation. Generally, it stimulates neuromuscular transmission, what results in muscle fasciculations. In addition to its indirect action by inhibition of cholinesterases, it could directly stimulate neuromuscular nicotinic receptors. It does not have an action on the uterus. Eserine is indicated in treatment of paralytic ileus, intestinal atonicity, glaucoma, myasthenia, post-anesthetic long-lasting curarization. It was tested in the treatment of Alzheimer’s disease using transdermal preparations which make possible to obtain relatively stable plasma concentrations. The multiplicity of effects of eserine is often a disadvantage in therapeutics where only an effect is generally sought.
Neostigmine
Neostigmine, better tolerated than eserine, acts less on eye, cardiovascular system and central nervous system, but it is more active on digestive tract and bladder. Neostigmine is used in the treatment of the postoperative atonicity (intestine, bladder), and of myasthenia in high dose combined or not with atropine.
It accelerates decurarization as an indirect antidote of competitive neuromuscular inhibitors.
Pyridostigmine
Pyridostigmine has pharmacological properties close to those of neostigmine, with perhaps a more progressive and more durable action. It is used in the treatment of intestinal atonicity and myasthenia.
Ambenonium
Ambenonium is a long-acting inhibitor of cholinesterase, about five to six hours after oral intake, used in the treatment of myasthenia gravis.
Tacrine
Tacrine or 9 amino-1,2,3,4-tétrahydroacridine is an anticholinesterase agent which penetrates into the brain and has been used in the treatment of Alzheimer’s disease. It was successively proposed as a disinfectant, as antagonist of morphine respiratory depression and finally used in the treatment of Alzheimer’s disease for which it attenuates certain symptoms.
Tacrine has various adverse effects of muscarinic type but its major disadvantage is its hepatic toxicity which usually results in a rise of transaminases. A metabolite of tacrine could be responsible for this hepatic toxicity. It is not used now.
Donepezil
Donepezil is a selective and reversible inhibitor of acetylcholinesterase, having little effect on butyril-cholinesterase and penetrating well iton brain. Its half-life of plasma elimination is about 70 hours and just a once-daily intake is enough. Donepezil is indicated in the supportive care of Alzheimer’s disease.
The most frequent adverse effects of the donepezil are digestive disorders (diarrhea, nausea, vomiting, abdominal pains). It can also induce dizziness and bradycardia but without hepatic toxicity, the major undesirable effect of tacrine.
Rivastigmine
Rivastigmine is a new anticholinesterase, quite well absorbed by oral route and crossing well the blood-brain barrier. It is used twice daily in the supportive care of Alzheimer’s disease. It does not present hepatic toxicity.
Galantamine
Galantamine, also written galanthamine, is a product known for about fifty years. Recent studies showed that it could have an interest in the treatment of Alzheimer’s disease. It is metabolized by cytochromes CYP 2d6 and CYP3A4 and interactions with drugs inhibiting these cytochromes were described.
Notice
Huperzine is an alkaloid of vegetable origin, known for many years, which inhibits cholinesterases reversibly and penetrates into the brain. It was proposed as a dietary supplement of vegetable origin intended to reduce memory disorders.
Irreversible inhibitors
Irreversible inhibitors of cholinesterases, while being fixed at enzymes by covalent bonds, inhibit them irreversibly. In fact they are mainly organophosphorus compounds which, because of their toxicity, are only exceptionally used in therapeutics.
One of the least toxic among more than 50 000 derivatives which were prepared, diisopropyle fluorophosphate or D.F.P., was tested in treatment of myasthenia, paralytic ileus and of glaucoma as an ophthalmic solution. It was at the origin of poisonings and is not released on the market any more.
The sulfur organophosphorus compound ecothiopate, was used in therapeutics in the form of an ophthalmic solution, in the treatment of glaucoma. It has very long action and its use has to be very spaced (once-daily to twice a week).
Malathion is the active product of certain preparations intended for the treatment of lice of the scalp (lice). When it is applied strictly to the hair, the scalp being intact, one does not observe general effects.
Metrifonate and dichlorvos are organophosphorus compound inhibitors of cholinesterases, having antihelminthic activity against Schistosoma mansoni and haematobium. In the body metrifonate is partly converted to dichlorvos which is considered as the active product. Irreversible inhibitors of cholinesterases are largely used in agriculture as insecticides and some of them, because of their very great toxicity, were retained as chemical warfare agents, also called nerve gases. Other derivatives such as formathion, diethion, malathion and diazinon are very much used as insecticides. Generally, the substitution of the phosphorus atom by a fluorine atom or a cyanide group increases toxicity and one obtains compounds such as tabun, sarin and soman classified as nerve gas.
Anticholinesterase poisoning
The symptoms of poisoning by organophosphorus compounds depend on the conditions of poisoning and more particularly on its severity.
Between latent forms, detected by cholinesterases determination, and forms quickly fatal, there are many intermediate forms. The following symptomatology is generally observed:
- muscarinic signs: miosis, nausea, salivation, vomiting, diarrhea, sweats, bradycardia, bronchial obstruction.
- nicotinic signs, neuromuscular (twitchings, fasciculations, cramps, paralysis in the case of severe poisoning) and cardiac (tachycardia, rise in arterial pressure).
- central signs :headache, drowsiness, disorientation, coma or generalized convulsions.
In severe forms where the disorders appear very quickly, death, preceded by a loss of consciousness and seizures, comes from a respiratory arrest by central inhibition and paralysis of the neuromuscular transmission phrenic nerve/diaphragm. The bronchial hypersecretion worsens moreover the respiratory failure.
Persistence of various neuropsychiatric disorders a long time after an acute poisoning or following a chronic poisoning by irreversible anticholinesterases is possible.
Treatment of poisoning by anticholinesterases consists of discontinuation of the poison, administration of atropine and possibly of pralidoxime, a cholinesterase reactivator.
- Atropine which inhibits muscarinic effects is administered by parenteral route in doses higher than in its usual indications (1 mg possibly renewed)
- Pralidoxime, which reactivates inhibited cholinesterases, is administered by parenteral route, generally intravenous, at renewable dose of 0,5 g in adult. It acts by detaching the phosphate group of the inhibitors from the esterasic site. It should be noticed that in animal experiments, pralidoxime in large dose can partially inhibit cholinesterases and may cause transient neuromuscular blockade. Thus, it should not be administered as an antidote in too high doses. Obidoxime is another reactivator of cholinesterases
- Recent data show that, during severe poisonings by organophosphorus compounds, the stimulation of acetylcholine receptors by acetylcholine which accumulates induces glutamate release which makes sodium and calcium enter the cell inducing cellular damage. The use of antagonists of glutamate can thus be considered.
Agents acting M-cholinoreceptors
Muscarinic receptor antagonists, called previously parasympatholytic and now muscarinic, cholinolytic, antimuscarinic, atropinic drugs, inhibit the muscarinic effects of acetylcholine. The drugs of this group are atropine, scopolamine and their derivatives.
Atropine
Atropine is an alkaloid extracted of the leaves of a shrub called Atropa belladonna, which acts primarily at the peripheral level.
Action on the autonomic nervous system
Atropine is a competitive inhibitor of acetylcholine muscarinic receptors. Its action results in a decrease of the parasympathetic tonus, so that the influence of the sympathetic nerve becomes dominating.
Cardiovascular action
1. Cardiac action: atropine effect results primarily in modifications of the heart rate:
o in very low dose, it can give a slight cardiac slowing attributed to a central vagal stimulation and to peripheral parasympathetic effect leading to a transient increase of acetylcholine release.
o in therapeutic dose there is generally cardiac acceleration by reduction of vagal tone, and suppression of reflex bradycardia during arterial hypertension.
2. Vascular action:, atropine does not have vascular effects since there is no parasympathetic tonus on the vessels but it inhibits vasodilation caused by an intravenous injection of acetylcholine.
3. Action on the arterial pressure:
o in therapeutic dose, atropine does not induce modifications of arterial pressure in spite of incresed cardiac rate.
o in very high or toxic dose, it induces a fall of the arterial pressure by depression of the vasomotor centers and cutaneous vasodilation, perhaps secondary to an histamine release.
Eye Action
Atropine inhibits parasympathetic influence on the eye, which results in:
- passive pupil dilation or mydriasis and increase of the diameter of the iris.
- tendency to elevation of intraocular pressure by increase in the diameter of the iris which, in patients predisposed to narrow-angle glaucoma, obstructs evacuation of aqueous humor by the Schlemm channel . Atropine is thus contraindicated in these patients.
- Accommodation paralysis or cycloplegia, disturbing vision .
After local administration in the form of ophthalmic solution, atropine effects last very long: dilation of the pupil can persist several days.
Action on smooth muscles
Acetylcholine contracts smooth muscles except vascular muscles and atropine has an antispasmodic action by inhibiting this acetylcholine effect.
On the digestive tract, atropine decreases tone, amplitude and frequency of the peristaltic contractions; it decreases hypertonicity produced by morphine, which justifies its combination to morphine in the treatment of colic pain.
On isolated intestine, atropine gives a reduction of tonus and peristalsis, prevents and inhibits contracture elicited by acetylcholine.
Antispasmodic action of atropine is also exerted on biliary tract, bronchi, urinary routes: ureters and bladder. Urographies showed that atropine dilates ureters.
The bladder receives sympathetic and parasympathetic innervation. The sympathetic nerve tends to dilat the bladder and constrict its internal sphincter. The parasympathetic, on the contrary, constricts bladder and relaxes the internal sphincter. The suppression of the influence of the parasympathetic by atropine gives an increase in the tone of the internal sphincter and a dilation of the bladder, which can induce urinary retention, especially in case of prostate hypertrophy.
Atropine practically has no action on uterus.
Action on secretions
Atropine reduces the majority of secretions:
- Digestive: inhibition of salivary secretion results in a feeling of thirst, of dryness of the mouth. The reduction of gastric secretion explains why atropine was used in therapeuticsas a gastric antisecretory. It hardly modifies pancreatic secretioor biliary.
- Bronchial: bronchial secretion is reduced.
- Cutaneous: it inhibits sudation, which gives a dry and hot skin. It is necessary to be wary about its use when ambient temperature is high or in patients with fever, because the inhibition of sudation increases temperature, particularly in infants, with the risk of provoking hyperthermia.
- Lacrimal secretion is reduced, lacteous secretion during lactation is little or not modified.
Action on central nervous system
In therapeutic doses, in human beings, atropine has only little or no action on the central nervous system, sometimes a respiratory stimulation.
Atropine was for a long time the only drug to have some efficacy in Parkinson’s disease. In animals, it inhibits tremors elicited by cholinomimetic agents such as oxotremorine.
Atropine and scopolamine, lower the cerebral acetylcholine concentration in animal experiments: the inhibition of acetylcholine receptors elicited causes an exaggerated release of acetylcholine, which is hydrolysed by cholinesterases.
In high dose, the stimulant action of atropine appears with restlessness, ataxia, and +++++ , hyperthermia, dizziness, visual and memory disturbances, hallucinations, delusion. This picture can evoke an acute schizophrenic episode or an alcoholic delirium. However, in severe intoxication, a CNS depression and a respiratory arrest can occur.
Metabolism
Atropine is quickly absorbed by digestive route and one resorts to its administration by parenteral route only when one wants to obtain a very fast effect, for example in the treatment of colic pain. Its plasma half-life is of approximately four hours.
Part of atropine administered in the form of ophthalmic solution is likely to diffuse into the general circulation.
It crosses the placental barrier and traces can be found in various secretions, of which breast milk.
The duration of action of atropine administered by general route would be of approximately six hours.
Therapeutic use
Atropine has several therapeutic uses:
In administration by general route
1. Treatment of painful syndromes with spasmodic component, i.e. involving an exaggerated contraction of smooth muscles, such as biliary and renal colic pain.
2. In anesthesiology: prevention of respiratory tract secretion, bronchospasm, laryngospasm and reflexe reactions such as bradycardia, before surgical operations.
3. Treatment of poisonings:
o by cardiac glycosides, to increase lowered cardiac rate
o by anticholinesterase agents and mushrooms of Amanita muscarina type, to reduce muscarinic symptoms. In poisonings by anticholinesterase agents such as organophosphorus compounds, atropine is administered in large doses in combination with pralidoxime.
Atropine is not used any more as a gastric antisecretory. After being used as a gastric antisecretory in the treatment of ulcer, atropine was replaced by a more specific muscarinic receptor antagonist of gastric secretion, pirenzepine which, itself, was withdrawn from the market because much more active products, acting by different mechanisms, were marketed.
Atropine and scopolamine were the first drugs used in the treatment of Parkinson’s disease but they have been replaced by other muscarinic receptor antagonists such as trihexyphenidyl and, benztropine, and especially by L-dopa which has a different mechanism of action.
In local administration: ophthalmic solution
Atropine is a powerful mydriatic with a very long duration of action, now generally replaced by tropicamide
Adverse effects and contraindications
The principal adverse effects of atropine are a dry mouth, constipation, dryness of skin, tachycardia, mydriasis.
The contraindications are primarily glaucoma, because atropine raises intraocular pressure in patients with narrow angle, and prostate hypertrophy (difficulty in micturition and risk of urine retention ).
Scopolamine, also called hyoscine, has a chemical structure very close to that of atropine. Its peripheral effects are similar to those of atropine, but its central effects differ: it has a sedative and tranquillizing action, it induces sleep, reinforces the action of hypnotics and tranquilizers and has an amnestic effect. However in patients who experience strong pains, it can have an exciting effect and elicit hallucinations.
Scopolamine is used by injectable route as an antispasmodic in certain acute pains with spasmogenic component of digestive or gynaecological localization and in the treatment of agonic rails by obstruction of the higher air routes by excess of salivary secretion.
By percutaneous route it is primarily used as an antiemetic agent in the prevention of motion sickness. It should be noted that scopolamine was marketed a long time in France under the name of Buscopan , proprietary name always used in many countries. It is exceptional that all properties of atropine are simultaneously useful in the same patient and effort has been made to obtain compounds having a greater specificity of action and particular pharmacokinetic features. Their adverse effects and their contraindications are however quite similar to those of atropine.
Mydriatic agents
Tropicamide is a muscarinic receptor antagonist used as a mydriatic.
Tropicamide is different from atropine by its shorter duration of action which is approximately 1 hour and half. The effect appears in 10 minutes, is maximum in 15 or 20 minutes. The pupil finds its normal diameter in approximately 6 hours.
Cyclopentolate is presented in the form of an ophthalmic solution with mydriatic effect of shorter duration than atropine.
Gastric acid secretion inhibitors
Numerous muscarinic receptor antagonists, including pirenzepine which has a quite specific action on the stomach, have been used in the management of peptic ulcer disease. Pirenzepine was withdrawn from the market after the introduction in therapeutics of H2antihistamines and proton pump inhibitors which are more effective and better tolerated.
Bronchodilatators
The two muscarinic receptor antagonists used as bronchodilatators are oxitropium and ipratropium.
They are given by pulmonary route, in the form of aerosol, in the preventive and curative treatment of asthma. Their efficacy is however lower than that of beta-mimetics.
The advantage of these products compared to atropine result from a pharmacokinetic particularity: as they involve a quaternary ammonium in their chemical formula, they are only little or not absorbed by bronchi and thus have a predominantly local effect.
There is also a preparation for nasal use for rhinorrhea treatment.
Tiotropium, anticholinergic of long duration of action, used in inhalation, is released on the market in Switzerland and Belgium but not in France.
With vesical indications
Tolterodine is a cholinergic antagonist whose effect on the bladder prevails. It is used in the treatment of vesical instability with symptoms of pressing micturition or incontinence.
Oxybutynine, which is a muscarinic receptor antagonist and has direct effects on smooth muscles, is proposed for the treatment of urinary incontinence of adults and could be used in the treatment of infantile enuresis.
Trospium, an anticholinergic known for a long time, involving a quaternary ammonium group in its structure, was the subject of recent studies in urinary disorders.
Used as antispasmodics
Muscarinic receptor antagonists have antispasmodic properties, but all the antispasmodic agents are not necessarily muscarinic receptor antagonists. The antispasmodic effect of some of them results from a direct effect on smooth muscle, often by calcium-channel antagonism.
Muscarinic receptor antagonists used as antispasmodics are, in addition to atropine itself, dihexyverine, prifinium and propantheline.
Among antispasmodic drugs having at the same time a muscarinic receptor antagonist effect and a direct effect on smooth muscles one can quote tiemonium., although its effect on smooth muscle activity predominates over its muscarinic receptor antagonist activity
1. http://www.youtube.com/watch?v=7_frccgVAWQ&feature=related
2. http://www.youtube.com/watch?v=CGNpELKAqQw&feature=player_detailpage
3. http://www.youtube.com/watch?v=SCasruJT-DU&feature=related
4. http://www.youtube.com/watch?v=7tBWl4GE8rk&feature=related
5. http://www.youtube.com/watch?v=g_H5PWlr3lk&feature=related
6. http://www.youtube.com/watch?v=RUhn2rvt9eA&feature=related
7. http://www.youtube.com/watch?v=HXx9qlJetSU&feature=related
8. http://www.youtube.com/watch?v=LT3VKAr4roo&feature=related
9. http://www.youtube.com/watch?v=PhD6CEOcuno
10. http://www.youtube.com/watch?v=GTDhbBzigNk&feature=related
11. http://www.apchute.com/moa.htm
12. http://www.youtube.com/watch?v=HXx9qlJetSU&feature=related
13. http://www.youtube.com/watch?v=LT3VKAr4roo&NR=1
14. http://www./watch?v=9nUY6o–LCWY&feature=related
List of literature
1. Pharmacology at your palms: reference book / Drogovoz S.M., Kutsenko T.A. – Kharkiv: NPhaU, 2008. – 80 p.
2. Pharmacology secrets / edited by Patricia K. Anthony. – Hanley Belfus, INC/ – Philadelphia, 2002. – 305 p. www.hanleyandbelfus.com
3. Rang and Dale’s Pharmacology / H.P. Rang, M.M. Dale, J.M. Ritter, R.J. Flower // Churchill Livingstone, 2007. – 829 p. www.studentconsult.com
4. Tripathi K.D. Essentials of medical pharmacology 6 th Edition. – Jaypee Brothers Medical Publishers (P) LTD New Delhi, 2008. – 875 p.
5. Stefanov O., Kucher V. Pharmacology with general prescription. – Kiev, 2004. – 150 p.
6. Multimedia lectures from pharmacology for 3d course students
7. http://intranet.tdmu.edu.ua/education.php
