Pharmacology - Tay Sai Gon College

Inhibits neuromuscular transmission causing muscle weakness, respiratory paralysis. Relaxes smooth muscles due to ganglion paralysis and direct effects on smooth muscles. On the cardiovascular system: due to the "membrane stabilizing" effect, anesthetics reduce excitability, reduce conduction and reduce contractility of the heart muscle. Can cause arrhythmia, even ventricular fibrillation. On the blood vessels, most cause vasodilation, hypotension (except cocaine). On the blood: high doses (over 10 mg/kg) of prilocaine cause oxidation, converting Hb into metHb.

Adverse effects and toxicity

- This type of effect is caused by the drug entering the circulatory system at high concentrations, causing neurological manifestations (nausea, vomiting, disorientation, tremors, respiratory paralysis), or cardiovascular manifestations (conduction disorders, atrioventricular block...).

- Specific effects related to anesthesia technique: hypotension, respiratory arrest due to spinal anesthesia, nerve damage due to needle puncture or drug compression.

- The type of hypersensitivity or allergic reaction depends on each individual. It is common with derivatives with substitution at the para position of the aromatic ring (ester of para aminobenzoic acid), ester-linked type (procaine). It is very rare with those with amide-linked type (lidocaine).

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Drug interactions: To overcome the vasodilating effect of anesthetics (except cocaine which causes vasoconstriction), it is often combined with adrenaline, especially when performing infiltration anesthesia. Adrenaline causes vasoconstriction, which prevents the penetration of anesthetics into the general circulation and prolongs the duration of anesthesia. Drugs that increase the effect of anesthetics: morphine-type analgesics, neuroleptics (clopromazine). Drugs that easily increase the toxicity of anesthetics: quinidine, beta-adrenergic blocking drugs (disrupting myocardial conduction). Anesthetics synergize with the effect of curare. Sulfamides are a two-way antagonist of anesthetics derived from para-amino benzoic acid (such as procaine).

Assign

- Surface anesthesia: stomatitis, pharyngitis, endoscopy preparation, used in ophthalmology.

- Conduction anesthesia: some pain conditions, upper limb surgery, in obstetrics and gynecology (epidural anesthesia).

- Other indications: arrhythmia (see arrhythmia treatment).

Contraindications

- Cardiac conduction disorders.

- Have allergies (find another group of drugs).

Precautions when using the drug: Use the correct total dose and choose the optimal concentration. Do not use the drug too diluted and do not exceed 1% if injected intrathecally. Inject into the area that needs anesthesia. Do not inject into the blood vessels or directly into the nerves. Stop the drug immediately if there are any unusual symptoms.

2.1.2. COMMONLY USED ANESTHESIA DRUGS

Cocaine (toxic, table A): addictive. Therefore, it is used less and less. It is the only anesthetic of plant origin (leaves of Erythroxylon coca) found in abundance in South America. Effects: Anesthesia (permeates mucous membranes, used in otolaryngology or ophthalmology). On the central nervous system (causes stimulation, euphoria, hallucinations, reduces fatigue; high doses cause tremors and convulsions). On the autonomic nervous system (indirect sympathomimetic effect due to inhibition of noradrenaline reuptake at sympathetic nerve endings, causing rapid heartbeat, vasoconstriction, increased blood pressure). Toxicity: Acute (strong vasoconstriction - cyanosis, nervousness, fear, easy fainting; central nervous system stimulation - hallucinations, convulsions). Chronic (easy to become accustomed to the drug and addicted, pale face, dilated pupils, necrosis of the nasal septum).

Procaine (novocaine - toxic, group B): An anesthetic with an ester link, soluble in water. Anesthetic effect is 4 times worse than cocaine, 3 times less toxic. Does not penetrate mucous membranes, does not cause vasoconstriction, on the contrary, due to its ganglion blocking effect, it dilates blood vessels and lowers blood pressure. When anesthetizing, it should be combined with adrenaline to cause vasoconstriction, increasing the duration of anesthesia. Used as a conduction anesthetic, 1% - 2% solution not exceeding 3mg/kg body weight. Toxicity: allergy, convulsions and then central nervous system inhibition. There are now many better drugs so they are used less and less.

Lidocaine (xylocaine): Synthetic drug (1948). Currently widely used. An anesthetic with an amide bond, soluble in water. A good surface anesthetic and conduction anesthetic. Three times stronger than procaine, but twice more toxic. Fast and long-lasting effect due to slow metabolism. Because it does not cause vasoconstriction, if used with adrenaline, the duration of action will be longer but the toxicity will be reduced. Toxicity: On the central nervous system (anxiety, restlessness, nausea, headache, tremors, convulsions and depression, central nervous system depression). On the respiratory system (rapid breathing, then difficulty breathing, respiratory arrest). On the cardiovascular system (tachycardia, hypertension, followed by signs of inhibition: bradycardia, hypotension, due to central inhibitory effects).

Bupivacaine (Marcaine): Is a group of local anesthetics with amide linkages such as lidocaine. Anesthetic characteristics: slow onset of anesthesia, long-lasting anesthetic effect, 16 times stronger than procaine, high concentrations block motor seizures. Used for regional anesthesia, nerve trunk anesthesia, nerve plexus anesthesia and spinal anesthesia. Spinal anesthesia solution has a specific gravity of 1.020 at 37 o C (4mL tube = 20mg bupivacaine hydrochloride): inject 3mL into the spinal cord in a sitting position, has anesthetic and muscle softening effects (abdominal muscles, lower limb muscles lasting 2

- 2.5 hours). Easily soluble in lipids, 95% bound to plasma proteins, completely metabolized in the liver by Cyt.P 450 and excreted through the kidneys. Toxicity: stronger cardiotoxicity than lidocaine (causing severe ventricular arrhythmias and myocardial depression, because bupivacaine strongly binds to the Na + channel of the myocardium and inhibits the vasomotor center. Regional anesthesia, depending on the purpose, depending on the age of the patient, use a 0.25 - 0.50% solution (can be accompanied by adrenaline to cause vasoconstriction), inject from a few ml to 20 ml. The total dose for one anesthesia does not exceed 150 mg.

Ethyl chloride (Kélène - C 2 H 5 Cl): Is a colorless solution, boiling at 12 C. Has a irritating effect.

anesthetic but strongly inhibits respiration and circulation. Indications: Injection of abscesses, boils, sports injuries. The medicine is contained in a glass bottle with a metal valve for convenient use when spraying into the area requiring anesthesia.

2.2. BARBITURATE

Barbiturates are all group B poisons.

Pharmacological effects

On the nervous system: Barbiturates inhibit the central nervous system. Depending on the dosage, method of use, patient's condition and type of barbiturate, they can have sedative, sleep-inducing or anesthetic effects.

Barbiturates produce sleep similar to physiological sleep, making sleep come quickly, reducing the overall amount of paradoxical sleep. At anesthetic doses, barbiturates depress the spinal cord, reduce polysynaptic reflexes, and can reduce cerebrospinal fluid pressure when used in high doses. Barbiturates are also anticonvulsants and antiepileptics.

On the respiratory system: By directly inhibiting the respiratory center in the medulla oblongata, barbiturates reduce the amplitude and frequency of breathing. In high doses, the drug destroys the respiratory center, reduces the response to CO2 , and can cause Cheyne-Stokes breathing. Coughing, sneezing, hiccups, and laryngospasm are signs that may occur when using barbiturates for anesthesia. Barbiturates reduce oxygen use in the brain during anesthesia.

On the circulatory system: At hypnotic doses, barbiturates have little effect on circulation. At anesthetic doses, the drug reduces cardiac output and lowers blood pressure. Barbiturates inhibit the heart at toxic doses.

Undesirable effects: When using phenobarbital, the rate of people experiencing adverse reactions is about 1%.

- Whole body: sleepy.

- Blood: giant red blood cells in peripheral blood.

- Neurological: nystagmus, ataxia, irritability, fear, confusion (common in elderly patients).

- Skin: allergic rash (common in young patients). Rarely, arthralgia syndrome and porphyrin metabolism disorder due to phenobarbital.

Acute poisoning: Acute phenobarbital poisoning is mostly caused by people taking the drug with the intention of committing suicide. At doses 5 to 10 times the sleeping dose, the drug can be life-threatening. Death usually occurs when the blood concentration of phenobarbital is higher than 80 micrograms/mL.

Symptoms of poisoning: The patient becomes sleepy and gradually loses reflexes. If the poisoning is severe, all tendon reflexes, including the corneal reflex, may be lost. The pupils are dilated, but still react to light.

blood; skin vasodilation and possible hypothermia; respiratory disorders, slow and shallow breathing, reduced respiratory flow, reduced alveolar ventilation; circulatory disorders: decreased blood pressure, cardiovascular collapse. Finally, the patient becomes comatose and dies due to respiratory paralysis, cerebral edema, and acute renal failure.

Chronic poisoning: Chronic barbiturate poisoning is common in patients who abuse drugs leading to drug addiction. Symptoms of poisoning include: convulsions, mental panic, delirium...

Drug interactions: Barbiturates strongly induce liver microsomes, thus reducing the effects of drugs metabolized through liver microsomes when used in combination (such as antidiabetic sulfonamides, contraceptives, estrogens, griseofulvin, cortisone, synthetic corticosteroids, diphenylhydantoin, coumarin derivatives, aminazin, diazepam, doxycycline, lidocaine, vitamin D, digitalin...). Some drugs can change the effects of barbiturates such as ethyl alcohol, reserpine, aminazin, haloperidol, antidiabetic drugs, liver microsome inhibitors (cimetidine, chloramphenicol...) which increase sleep. barbiturates.

2.3. BENZODIAZEPINE DERIVATIVES

Synthesized in 1956, today it is used more than barbiturates because it is less toxic and has fewer interactions with other drugs. Benzodiazepines have sedative, anxiolytic, sleep-inducing, muscle-relaxing and anticonvulsant effects. Often used to treat insomnia or difficulty falling asleep due to anxiety.

Lesson 3: DRUGS AFFECTING THE VEGETATIVE NERVOUS SYSTEM

Target:

Present the indications and contraindications of some drugs that act on the autonomic nervous system. Follow instructions for safe drug use.

3.1. DRUGS ACTING ON THE CHOLINERGIC SYSTEM

3.1.1. MUSCARINIC SYSTEM STIMULANTS (SYSTEM M)

Acetylcholine: There are two types of cholinesterase: Acetylcholinesterase or true cholinesterase (specific cholinesterase), located in neurons and skeletal muscle motor endplates to neutralize the effects of acetylcholine on receptors. Butyryl cholinesterase, or pseudo-cholinesterase (non-specific cholinesterase), found in large amounts in plasma, liver, and glial cells (nevroglia). Physiological effects are not important and are not fully understood. When blocked, it does not cause important functional changes. Acetylcholine synthesis can be inhibited by hemicholin. Botulinus toxin inhibits the release of acetylcholine into free form. Acetylcholine is a neurotransmitter found in many places in the body, so its effects are very complex:

- At low doses (10 mg/kg intravenous injection in dogs), the main effect is on the parasympathetic postganglionic (muscarinic system):

+ Slows heart rate, dilates blood vessels, lowers blood pressure.

+ Increase intestinal motility.

+ Bronchospasm, causing asthma attacks.

+ Constriction of the pupils.

+ Increased secretions, saliva and sweat.

Atropine completely abolishes these effects.

- At high doses (1 mg/kg in dogs) and in animals pre-injected with atropine sulfate to block the effects on the M system, acetylcholine causes nicotine-like effects: stimulating the autonomic ganglia, adrenal medulla (N system), increasing heart rate, vasoconstriction, increasing blood pressure and stimulating respiration via the carotid sinus reflex.

Clinical application: Because acetylcholine is destroyed very quickly in the body, it is rarely used clinically. It is only used to dilate blood vessels in Raynaud's disease (cyanosis of the extremities) or necrotic manifestations. The vasodilatory effect of ACh only occurs when the vascular endothelium is intact. If the vascular endothelium is damaged, ACh cannot cause vasodilation.

Subcutaneous or intramuscular injection 0.05 - 0.1 g, 2 - 3 times daily

1 mL tube = 0.1g acetylcholine chloride

Muscarin: Typical effect on the parasympathetic postganglionic system, therefore called the muscarinic system. 5-6 times stronger than acetylcholine and not destroyed by cholinesterase. Not used for treatment. However, muscarinic poisoning can occur due to eating poisonous mushrooms (constricted pupils, foaming at the mouth, profuse sweating, difficulty breathing due to airway spasm, vomiting, diarrhea, bedwetting, slow heart rate, low blood pressure...). Treatment: high dose atropine. Can inject intravenously each dose of 1 mg atropine sulfate.

Pilocarpine (group A poison): Strongly stimulates the parasympathetic postganglionic ganglion, has a longer effect than acetylcholine; causes increased salivation, sweating and increased intestinal motility. Unlike muscarine, it also has the effect of stimulating the ganglia, releasing adrenaline from the adrenal medulla, so in animals that have been pre-injected with atropine, pilocarpine will increase blood pressure. Average dose 0.01 - 0.02g. Usually only eye drops of 0.5 - 1% pilocarpine base oil solution or 1 - 2% pilocarpine nitrate or hydrochloride water solution are used to treat glaucoma or to counteract the mydriatic effect of atropine.

3.1. 2. MUSCARINIC SYSTEM ANTAGONISTS (SYSTEM M)

Atropine (toxic, table A): Atropine and its relatives are competitive antagonists of acetylcholine at muscarinic receptors. Only at very high doses and by intra-arterial injection do these antagonistic effects appear on ganglia and on the motor endplates of skeletal muscles.

Common effects are: On the eyes, dilates the pupils and loses the ability to accommodate, so you can only see far away. Because the ciliary muscles relax, the eye fluid ducts are compressed, increasing eye pressure. Therefore, atropine should not be used for people with glaucoma. Stops the secretion of liquid saliva, reduces the secretion of sweat, gastric juice, and intestinal juice. Dilates the airways, especially when they are constricted due to parasympathetic overactivity. Has little effect on normal airways. Accompanied by reduced secretion and stimulation of the respiratory center, so atropine is often used to stop asthma attacks. Has little effect on normal intestinal motility, but reduces when the intestines increase peristalsis and spasm. The effect of atropine on the heart is complex: low doses stimulate the vagus nerve center in the medulla oblongata, causing the heart to beat slowly; higher doses inhibit the heart's muscarinic receptors, causing the heart to beat faster. The rabbit heart is not controlled by parasympathetics, so atropine has no effect. Atropine has little effect on blood pressure because many vascular systems do not have parasympathetic nerves. It only dilates the skin vessels, especially in hot environments, because the drug does not cause sweating, so the vessels dilate even more to counteract the tendency to increase temperature. Toxic doses, affecting the brain, cause stimulation, delirium, hallucinations, fever, and finally coma and death due to bulbar paralysis. Treatment of poisoning with anticholinesterase drugs (physostigmine) injected intravenously every 2 hours and to counteract symptoms of central nervous system stimulation with benzodiazepines. Clinical application: Eye drops of 0.5 - 1% atropine sulfate solution

Maximum pupil dilation after 25 minutes, used for fundoscopy or treatment of iritis, keratitis. It takes several days for the pupil to return to normal. Eserin salicylate (0.2% solution) or pilocarpine hydrate or nitrate (1% solution) can be used to shorten the effect of atropine. The smooth muscle relaxant effect is used to stop asthma attacks, gallbladder pain, kidney pain, stomach pain. Inject before anesthesia to avoid excessive secretion of phlegm, avoid cardiac arrest due to vagal reflex. Conduction disorders such as atrioventricular block (Stockes - Adams) or bradycardia due to the influence of the vagus nerve. Treatment of muscarinic mushroom poisoning and poisoning with cholinesterase inhibitors. Contraindications: glaucoma, urinary retention due to prostate enlargement.

Preparation and dosage: Used as base or sulfate. Intravenous injection 0.1 - 0.2 mg; subcutaneous injection 0.25 - 0.50 mg (maximum dose 1 time: 1 mg; 24 hours: 2 mg); oral 1 - 2 mg (maximum dose 1 time: 2

mg; 24 hours: 4 mg).

Atropine sulfate tube 1 mL = 0.25 mg; tablet 0.25 mg; Atropine sulfate tube 1 mL = 1 mg (toxic table A), only used to treat poisoning with cholinesterase inhibitors.

3.1.3. NICOTINE SYSTEM STIMULANTS (SYSTEM N)

These drugs are rarely used in treatment.

Nicotine (a - pyridyl - methyl pyrrolidine - toxic, table A): Found in cigarettes and tobacco in the form of organic acid (0.5 - 8.0%). When smoking, nicotine is released in the form of free base. On average, smoking 1 cigarette absorbs about 1 - 3 mg of nicotine. The lethal dose is about 60 mg. On the plant ganglia, low doses (0.02 - 1.0 mg/kg on dogs, intravenous injection) stimulate; high doses (10 - 30 mg/kg on dogs) paralyze the ganglia by causing depolarization and then competing with acetylcholine.

Effect: On the cardiovascular system, causes a three-phase effect: temporary hypotension, severe hypertension, and finally prolonged hypotension. On respiration, stimulates increased amplitude and frequency. Dilates pupils, increases secretion, and increases intestinal motility.

3.1.4. NICOTINIC SYSTEM BLOCKERS (SYSTEM N)

Divided into two types: autonomic ganglion blockers, affecting smooth muscle activity, and motor endplate blockers of skeletal muscle.

- Type of nicotinic blockade of the ganglion: Also called ganglionic drugs, because they block the flow of nerve impulses from preganglionic fibers to postganglionic fibers. The common mechanism is to compete with acetylcholine at the receptor in the postsynaptic membrane of the ganglion. In clinical practice, ganglionic drugs are often used to lower blood pressure in hypertensive crises, to lower controlled blood pressure during surgery, and sometimes to treat acute pulmonary edema.

Trimethaphan (Arfonad): Very short-term ganglion blockade. Intravenous infusion of 1 mg in 1 mL solution, blood pressure drops rapidly. When the infusion is stopped, blood pressure returns to normal after 5 minutes.

usually. Used to cause controlled hypotension during surgery or to treat acute pulmonary edema. 10 mL tube contains 500 mg of Arfonad, when used, dilute to 500 mL in isotonic saline solution to obtain 1 mg in 1 mL.

Mecamylamine (Inversin): Easily absorbed through the digestive tract, can be taken orally. The effect lasts 4 - 12 hours. Long-term use will gradually reduce the effect. Take 2.5 mg each time, twice a day. Gradually increase until the treatment effect is achieved, can take up to 30 mg per day. 2.5 mg and 10 mg tablets. High doses can stimulate the central nervous system and block the motor end of skeletal muscles.

- Nicotinic blockade of skeletal muscle

Cura and preparations (toxic, table B): Cura acts preferentially on the nicotinic system of skeletal muscles, blocking the flow of nerve impulses to the muscles at the motor end, thereby relaxing the muscles. When directly stimulated, the muscles still respond. Under the effect of cura, the muscles are not paralyzed at the same time, but in turn the ciliary muscles (causing ptosis), facial muscles, neck muscles, upper limb muscles, lower limb muscles, abdominal muscles, intercostal muscles and finally the diaphragm, causing the patient to stop breathing and die. Because of the short effect, if artificial respiration is performed, muscle function will be restored in the reverse order. In addition, cura also has a direct inhibitory effect on the respiratory center in the medulla oblongata and causes vasodilation, hypotension or tracheal constriction due to histamine release. Most of them contain quaternary amines, so they are difficult to penetrate the central nervous system and are not absorbed through the intestinal wall. According to the mechanism of action, they are divided into two types:

+ The type that competes with acetylcholine at the motor endplate, preventing the motor endplate from depolarizing, is called the antidepolarizing curare type, or the curarimimetic or pakicura type.

+The type that acts like acetylcholine, causing the motor plate to depolarize too strongly, (depolarisant) is called acetylcholine-like type, (acetylcholinomimetic) or leptocura.

3.2. ADRENERGIC STIMULANTS

These drugs have effects similar to adrenaline and noradrenaline, stimulating sympathetic postganglionic receptors, so they are also called sympathomimetic drugs.

Alpha and beta receptor agonists

Adrenaline (toxic, table A): Is a hormone of the adrenal medulla, obtained from animals or synthetically. Adrenaline acts on both a and b receptors.

On the cardiovascular system: Adrenaline makes the heart beat faster and stronger (effect b), thus increasing maximum blood pressure, suddenly increasing pressure in the aortic arch and carotid sinus, strengthening the vagus nerve center, thus slowing the heart rate and decreasing blood pressure. Adrenaline causes vasoconstriction in some areas (skin vessels, visceral vessels - receptor a) but causes vasodilation in other areas (skeletal muscle vessels, pulmonary vessels - receptor b ...) so the minimum blood pressure does not change or sometimes decreases slightly, blood pressure

Pharmacology - Tay Sai Gon College - 2

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