Drugs Acting On Central Nervous System PDF

0202‫‏‬ ‫ سرحان الزيادي‬.‫د‬ ]DRUGS ACTING ON CNS[ The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The central nervous system is so named because...

0202‫‏‬ ‫ سرحان الزيادي‬.‫د‬ ]DRUGS ACTING ON CNS[ The central nervous system (CNS) is the part of the nervous system consisting of the brain and spinal cord. The central nervous system is so named because it integrates information it receives from, and coordinates and influences the activity of, all parts of the bodies of bilaterally symmetric animals  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Drugs Acting On Central Nervous System I. Analgesics Analgesics are drugs that relieve pain due to multiple causes. Analgesics are classified into 2 main groups: Opioid (Narcotic) Analgesics Non-opioid Analgesics (analgesics- antipyretics) Are the most powerful analgesics Are mild analgesics and effective in certain types that can relieve any type of pain of pain as headache, toothache … except itching. Act mainly at the level of the cortex Act on the level of the thalamus and hypothalamus. Can produce addiction No addiction. Used to lower the elevated body temperature. Example: Morphine and codeine Example: NSAIDs e.g. salicylates, and paracetamol NARCOTIC ANALGESICS They are derived from opium alkaloids. Many alkaloids are isolated from opium, but few of them are used clinically. OPIUM ALKALOIDS I. Morphine Dose: 8-15mg by injection (subcutaneously or IM) as morphine hydrochloride or morphine sulfate.  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Pharmacological Actions of Morphine: (I) On C.N.S: A. Centers Depressed by Morphine: 1. Cortical pain center: 2. Respiratory center: 3. Cough center: 4. Inhibition of the polysynaptic spinal reflexes. 5. Inhibition of the vasomotor center in large doses. B. Centers stimulated by Morphine: 1. Vomiting center: Emetic chemoreceptor trigger zone (CTZ) in the medulla is stimulated by morphine leading to nausea and vomiting. 2. Occulomotor center: Morphine causes severe miosis 3. Stimulation of monosynaptic spinal reflexes (stretch reflex). 4. Release of antidiuretic hormone (ADH) form the posterior pituitary. 5. Stimulation of cardiovagal center: leading to slow and full pulse. Opioid Receptors: Several types of opioid receptors have been identified at various sites in the nervous system and other tissues. Mu (μ) receptors are responsible for: (1) Supraspinal analgesia (2) Euphoria, sedation. (3) Respiratory depression, (4) Physical dependence. (5) Constipation. (6) Miosis. Kappa (κ) receptors are responsible for: (1) Spinal analgesia. (2) Miosis and sedation. Delta () receptors: Supraspinal analgesia Tolerance: (failure of responsiveness to the usual dose of the drug) Tolerance develops to the analgesic and respiratory depressant actions of Morphine after 10-14 days.  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Therapeutic Uses of Morphine: (1) As a powerful analgesic in the treatment of severe pain (2) Pre-anaesthetic medication: 10-15 mg subcutaneously or IM one hour before the general anaesthesia. (3) to alleviate dyspnoea. (4) Certain cases of severe cough e.g. cancer of the bronchial tree. (5) Certain cases of severe diarrhea (loperamide) given orally after removing the poison causing the diarrhea from the intestine by a purgative. II. Codeine (Methyl Morphine) 1. It is less potent. 2. It produces constipation. 3. Nausea and vomiting are less. 4. Less addiction. Uses: 1. As cough depressant (for dry cough). 2. As analgesic with aspirin and paracetamol. SYNTHETIC MORPHINE DERIVATIVES 1. Heroin (Diacetyl Morphine) (semisynthetic) 2. Pethidine 3. Fentanyl 4. Methadone 5. Loperamide (Imodium) and diphenoxylate: are nonanalgesic opioids, used for antimotility effect on the gut. OPIOID ANTAGONISTS 1. Nalorphine : It has antagonist action on Mu receptors, with a partial agonist action on delta and Kappa receptors so it is considered as a partial antagonist. 2. Naloxone : It is a pure narcotic antagonist at all opioid receptor sites with no morphine like properties i.e. it is a pure antagonist. 3. Naltrexone: has a longer duration of action than naloxone and a single oral Therapeutic Uses: 1. Treatment of acute morphine poisoning (it stimulates respiration, improves miosis, vomiting and G.I spasm). 2. Diagnosis of opium addiction (precipitate withdrawal symptoms).  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Sedative–Hypnotic Drugs The major therapeutic use of sedative-hypnotic drugs is to cause sedation (with concomitant relief of anxiety) or to encourage sleep. Examples of Sedative-Hypnotic drugs: 1- Benzodiazepines 2- Buspirone 3- Zolpidem 4- Barbiturates I. BENZODIAZEPINES Benzodiazepines (BZs) are the most widely used anxiolytic drugs. Mechanism of Action: Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. BZs potentiate GABA-ergic inhibition at all levels of the CNS. BZs bind to specific, high affinity BZ receptors present in various parts of the CNS. These receptors are separate but adjacent to the receptor for GABA. The binding of BZ enhances the affinity of the GABA receptors for GABA neurotransmitter, resulting in a more frequent opening of adjacent chloride channels. The increased influx of Cl- into the neuron results in enhanced hyperpolarization and inhibition of neuronal firing. Pharmacological Actions: 1. Reduction of anxiety: At low doses, BZs are anxiolytic. 2. Sedation and induction of sleep: At higher doses, all BZs which are used to treat anxiety can produce hypnosis. 3. Muscle relaxation: BZs relax the spasticity of skeletal muscles, probably by increasing presynaptic inhibition in the spinal cord. Diazepam in particular, has a very pronounced depressant activity on skeletal muscles. 4. Anticonvulsant effect. Classification of Benzodiazepines  Short-acting; triazolam (3-8 hours).  Intermediate-acting; alprazolam (10-20 hours).  Long-acting; diazepam (1-3 days).  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ 2. ZOLPIDEM Mechanism of action: Zolpidem is a hypnotic that binds selectively to a subset of the BZs receptor family and facilitates GABA-mediated neuronal inhibition. 3. BARBITURATES Non-selective CNS depressants, which produce effects ranging from sedation and reduction of anxiety to hypnosis and unconsciousness. Barbiturates were in the past the mainstay of treatment used to sedate or to induce and maintain sleep. Today, they have been largely replaced by BZs. Classification: 1. Ultra-short acting: Thiopental Na is highly lipid soluble; it is an IV anesthetic that acts within seconds with duration of action of 20 minutes. (pre-anesthetic medication). 2. Short-acting: Pentobarbital and secobarbital act for 3-8 hours. (anesthesia) 3. Long-acting: Phenobarbital (more than 24 hours). Antiepileptic Mechanism of Action: Barbiturates facilitate the actions of GABA at multiple sites in the CNS but they do not bind to the same site of BZs on the GABA-receptor/chloride channel. They cause activation of GABAA receptors. This increases the duration of opening of the Cl- channel associated with the receptor, and the neuronal membrane is therefore hyperpolarized and less likely to fire. Therapeutic Uses: 1. Anaesthesia: Thiopental Na is used intravenously to induce anaesthesia. 2. As sedative-hypnotic agents: Barbiturates have been replaced by BZs. However, pentobarbital may still be used as sleeping pills. 3. Anticonvulsants: Emergency treatment of convulsions in status epilepticus by thiopental as the last approach. Phenobarbital is used in long term management of tonic- clonic seizures. 4. α2-Adrenoceptor agonists E X A M P L E S: Xylazine, detomidine and medetomidine  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Clinical applications 1. Sedative-hypnotics 2. muscle-relaxant 3. analgesic properties. 4. Chemical restraint 5. premedication in small and large animals. Mechanism of action The sedative, analgesic and muscle-relaxant properties of the α2-agonists are mediated at central α2- receptors. The primary mechanism involves a decrease in noradrenaline (norepinephrine) release and thereby inhibition of impulse transmission. Sedation has been attributed to depression of neurons in brain stem. CENTRAL NERVOUS SYSTEM STIMULANTS Stimulation of CNS can be produced in men by a large number of natural and synthetic substances. As a group, the CNS stimulants have few clinical uses, but some are important as drugs of abuse. Drugs which cause CNS stimulation fall into three broad categories: 1. Convulsants and respiratory stimulants. 2. Psychomotor stimulants. 3. Psychotomimetic drugs (hallucinogens). 1- CONVULSANTS and RESPIRATORY STIMULANTS They are also called analeptics and act mainly on brain stem and spinal cord. They mainly stimulate the respiratory and vasomotor centers in the brain stem but have little effect on the mental function. Examples of analeptics: 1- Nikethamide 2- Doxapram  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ 2. PSYCHOMOTOR STIMULANTS These drugs have marked effect on the mental function and behavior; they produce excitement, euphoria, reduced fatigue, and increased motor activity. Some are drugs of abuse. Examples: methylxanthines, amphetamines, and cocaine. Methylxanthines These include theophylline found in tea, theobromine found in cocoa, and caffeine. Caffeine, the most widely consumed stimulant in the world, is found in highest concentrations in coffee but is also present in tea, cola drinks, chocolate candy and cocoa. Mechanism of Action: Methylxanthines act by several mechanisms including: 1. Translocation of extracellular calcium. 2. Inhibition of phosphodiesterase leading to increases in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Therapeutic Uses: 1- Caffeine: In combination with salicylates to relief simple headache and in combination with ergotamine to relief migraine. To stimulate the depressed CNS in case of alcohol ingestion. 2- Theophylline: In cases of bronchial asthma, biliary colics, congestive heart failure and cardiac edema.  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Anti-Epileptic Drugs Anti-epileptic drugs Epilepsy is a recurrent, sudden, transient, excessive discharge of cerebral neurons without any immediate provoking cause resulting in abnormal movements and/or sensory perceptions (seizure). 1. Carbamazepine Carbamazepine is structurally related to the tricyclic anti-depressants. Mechanism of action 1. Use-dependent blockade of Na+ channels, which reduces cell excitability, is the main mechanism of action. 2. Suppresses repetitive neuronal firing. 3. Reduces propagation of abnormal impulses in brain. 4. Attenuates action and release of glutamate (excitatory neurotransmitter). 2. Phenytoin (diphenylhydantoin) Mechanism of action 1. Use-dependent blockade of Na+ channels, which reduces cell excitability, is the main mechanism of action 2. Blockade of L-type Ca2+ channels 3. Potentiation of GABA action at GABAA receptors. 3.Lamotrigine Mechanism of action 1. Use-dependent inhibition of neuronal Na+ channels (like carbamazepine and phenytoin) 2. It interferes with synthesis of glutamate and aspartate. 3. Reduces glutamate release, possibly through inhibition of voltagesensitive Ca+2 channels. 4.Sodium valproate Mechanism of action 1. Use-dependent blockade of Na+ channels. 2. Potentiation of GABA by enhanced synthesis and release as well as reduced degradation. 3. Attenuation of the excitatory action of glutamate.  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ 4. Inhibition of T-type Ca2+ channels 5. Phenobarbital and Primidone 6. Benzodiazepines General anesthetics General anaesthesia is a state of: 1. loss of sensation, 2. controllable reversible loss of consciousness and, 3. skeletal muscle relaxation. Four stages of anaesthesia are known: · Stage I (analgesia): loss of sensation but patient is still alert and speaking. · Stage II (Excitement): CNS excitation+ - BP (irregular) + - respiratory rate + release of subconscious emotions. · Stage III (surgical anaesthesia): regular respiration + relaxed skeletal muscles + progressive decrease in eye reflexes till eye movement stops and pupil is fixed · Stage IV (Medullary paralysis): fatal depression of RC and VMC. Classification of general anesthetic agents: 1. Inhaled volatile agents: They are hydrocarbons. They are suitable for maintaining the anesthetic state as long as the surgical procedure is going on. In the past, anaesthesia was induced and maintained by inhalation of a volatile agent alone. If this method is used, the patient passes through the previously mentioned stages (I-III) during induction and recovery of which the excitation stage (stage II) is undesirable. Nowadays, this is overcome by using a bolus of intravenous anesthetic for induction (see below), followed by an inhalation anesthetic for maintenance. In children, this is less problematic and anaesthesia is often both induced and maintained with an inhalational anaesthetic agent. 2. IV anesthetic drugs: General intravenous anaesthesia can be used for short surgical procedures. For longer procedures, an IV anesthetic agent is used for rapid induction followed by an inhalational agent. Pre-anaesthetic medications. These are drugs used to facilitate smooth induction of anaesthesia and help to lower the dose and side effects of anesthetic drugs. According to circumstances, pre-medication may involve any combination of the following drugs (i.e. balanced general anaesthesia):  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ 1. Benzodiazepines or barbiturates to induce sedation and to relieve anxiety. 2. H1 blockers (anti-allergic) and H2 blockers (to reduce gastric acidity). 3. Anti-emetic e.g. metoclopramide. 4. Opioid analgesics e.g. morphine or pethidine 5. An anticholinergic e.g. scopolamine for prevention of bradycardia and to decrease airway secretions. Mechanism of action of general anaesthetic agents 1. It is suggested that incorporation of the anaesthetic into cell membrane phospholipids alters cell membrane fluidity. 2. Anaesthetic agents may also enhance action of GABAA and glycine receptors and inhibit central actions of acetylcholine, serotonin, and glutamate. Note; Resumption of consciousness (reversal of anaesthesia) occurs when the intravenous anesthetic is redistributed out of CNS or metabolized, or when an inhalational anesthetic is redistributed out of CNS or exhaled. Residual neuromuscular blockade may need reversal with neostigmine Intravenous anaesthetics Examples: 1. Thiopental 2. Ketamine 3. Propofol Inhalational anesthetics Inhaled anesthetics are given with oxygen to avoid hypoxia during anaesthesia. Following induction with an intravenous anesthetic, an inhalational agent can be used to maintain anaesthesia. Example Halothane (Fluothane): an old but still used inhalational agent for mask induction in children, because it is the least irritant volatile agent. Enflurane: old and not recommended because of its powerful cardiac and respiratory depressant actions. Isoflurane has largely replaced halothane and enflurane because it offers the most rapid induction and recovery and has little post-anesthetic organ toxicity  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ Local anesthetics Definition: A local anesthetic is an agent that interrupts pain impulses in a specific region of the body without loss of patient consciousness. Chemical structure of local anesthetics Mechanism of action Local anesthetics block nerve conduction: 1. By interacting directly with specific receptors on neuronal Na+ channels, inhibiting Na+ ion influx. 2. By impairing propagation of the action potential in the axons. Factors affecting onset, intensity, and duration of neural blockade 1. Lipid solubility: a lipophilic local anesthetic is more potent because it is easier to cross nerve membranes. This property is determined by the aromatic portion of the molecule. 2. Protein binding: local anesthetics with a higher degree of protein binding have a prolonged duration of action. 3. The pKa: The pKa is the pH at which 50% of the local anesthetic is in the ionized form and 50% is in the unionized form. All local anesthetics are weak bases with pKa = 8-9.  Local anesthetics with pKa close to physiologic pH are associated with a greater fraction of the molecules existing in the unionized form = more penetration across nerve membranes = faster onset. (Small gap between pH and pKa)  Local infection (acidosis) increases the ionized drug fraction which means less drug will be available to penetrate across membranes and bind to intracellular local  ‫ سرحان الزيادي‬.‫د‬ ‫استاذ المادة‬ anesthetic receptors on Na+ channels = slower onset. (Increased gap between pH and pKa) 4. Dose: Increasing dose of the anaesthetric will increase the duration of the block. Techniques of administration 1. Surface administration: High concentrations (up to 10%) of drug in an oily vehicle can slowly penetrate the skin or mucous membranes to give a small localised area of anaesthesia. 2. Infiltration anaesthesia: A local injection of local anesthetic solution, sometimes with a vasoconstrictor, produces a local field of anaesthesia. The anesthetic effect produced is more efficient than surface anaesthesia. This technique is extensively used in dentistry. 3. Peripheral nerve block anaesthesia: Injection of solution around a nerve trunk. 4. Epidural anaesthesia: Injection or slow infusion via a cannula adjacent to, but outside the dura mater. This technique is used extensively in obstetrics. 5. Spinal anaesthesia: Injection into lumbar subarachnoid space, usually between the third and fourth lumbar vertebrae. Spinal and epidural anaesthesia can be used together, often using an opioid (fentanyl) alone or in combination with a local anesthetic. 6. Intravenous regional anaesthesia (Bier block): Local anaesthetic injected into a vein of a limb after application of a tourniquet. The resultant anaesthesia is produced by direct diffusion of the local anesthetic from the vessels into the nearby nerves. It is used for manipulation of fractures or surgery on wrist, hand and fingers.