Drugs Acting On The Central Nervous System PDF

f Unit (1) F Drugs acting on the central nervous system 1. 2. 3. Introduction: central nervous system stimulant Hallucinogen  4. antidepressant drugs 5. Sedative hypnotic 6. Antipsychot...

f Unit (1) F Drugs acting on the central nervous system 1. 2. 3. Introduction: central nervous system stimulant Hallucinogen  4. antidepressant drugs 5. Sedative hypnotic 6. Antipsychotic drugs 7. Antianxiety 8. alcohol 9. Drug used in anesthesia 10. Local anesthesia 11. Opioid analgesic, Narcotic analgesic 12. Non steroidal anti inflammatory drugs 13. Non narcotic analgesic 14. Gout 15. Skeletal muscle relaxant 16. Antiepileptic Drugs 17. Parkinson disease  Unit (1) Unit 1 Drugs acting on the central nervous system 8  Drugs acting on the central nervous system Drugs acting on the central nervous system Introduction: Central nervous system is the most important regulatory system in the body The brain functions continually as a switchboard for the human communication system also it has a role in emotion and mood. Central nervous system consists of:  Brain - Cerebrum , cerebellum - Thalamus and hypothalamus - Medullary oblongata …. Consist a vital centers as,, respiratory center,, vasomotor center ,,, control reflexes as swallowing coughing and emitting.  Spinal cord … collection of nerve axon travel in to brain (sensory nerves) From brain to body part (motor nerve) - Brain coordinates body function. - Control adaptation of body from: 1. sensory neurons or afferent 2. efferent neurons or motor 9 Unit (1) Neurotransmitter: Neurotransmitters are endogenous chemicals located and released in the brain to allow an impulse from one nerve cell to pass to another nerve cell. That transmits signals from a neuron to a target cell across a synapse Many drugs affecting CNS do so by acting on neurotransmitter concentration and activity Drugs can modify the affect of neurotransmitters at the synapse by blocking, mimicking, or increasing the activity of the neurotransmitter. Nerve cells communicate messages by secreting neurotransmitters. Neurotransmitters can excite or inhibit neurons (nerve cells). Some common neurotransmitters are acetylcholine, norepinephrine, dopamine, serotonin and gamma aminobutyric acid (GABA). Acetylcholine and norepinephrine are excitatory neurotransmitters while dopamine, serotonin, and GABA are inhibitory. Each neurotransmitter can directly or indirectly influence neurons in a specific portion of the brain, thereby affecting behavior. 10  Drugs acting on the central nervous system Figure 1:1 neurotransmitter Types of neurotransmitters on CNS: - acetylcholine - noradrenalin - dopamine - serotonin - histamine - 5-HT ( 5-hydoxy tryptamine) - GABA 11 Unit (1) Blood Brain Barrier: The blood–brain barrier (BBB) is a separation of circulating blood from the brain this barrier protect the brain by restrict the diffusion of drugs into the brain , only lipid soluble drugs pass through BBB to reach the brain …. Drugs must be small in size not ionic, lipid soluble to cross this barrier. In general drugs affect the central nervous system classified: 1. Either stimulant Ex xanthenes Antidepressant Hallucination 2. Or CNS depressant General and local anesthesia Hypnotic and sedative Tranquilizer and antipsychotic Muscle relaxant Antiepileptic Antiparkinson Narcotic  From this classification we can find that neurotransmitter have a major role in treatment of many CNS diseases 12  Drugs acting on the central nervous system 1st nervous system stimulants 1) central nervous system stimulant: (Stimulants psychostimulants) are drugs which induce temporary improvements in either mental or physical functions or both and promote CNS function. Examples of these kinds of effects may include enhanced alertness, wakefulness,,, stimulants are also occasionally referred to as "uppers". Depressants or "downers", which decrease mental and/or physical function, are considered to be their functional opposites. Stimulants are widely used throughout the world as prescription medicines and as drugs of abuse. Uses of CNS stimulant: Stimulants are used for therapeutic purposes in the treatment of a number of indications, including the following:  To counteract lethargy and fatigue throughout the day while at work or while doing other activities.  To reduce sleepiness and to keep the person awake when necessary, as well as to treat narcolepsy.( brain's inability to regulate sleep-wake cycles normally)  To decrease appetite and promote weight loss, as well as to treat obesity.  To improve concentration and focus while at work or school, especially for those with intentional disorders such as ADHD.( Amphetamine)  Occasionally, they are also used off label to treat clinical depression,  Bronchodilator in asthma ( Theophylline)  Caffeine added to analgesic preparations 13 Unit (1) Types of CNS stimulant: 1) Amphetamines and related substances  Dextramphetamine ( Dexedrine)® is a major member  source: synthetic  effect: Sympathomemetic Central stimulant Reduce appetite Cause tolerance  Mechanism of action: amphetamine increases the levels of norepinephrine and dopamine in the brain via reuptake inhibition;  Uses:- and numerous studies have demonstrated the effectiveness of drugs in controlling symptoms associated with /ADHD. - To decrease appetite and promote weight loss, as well as to treat obesity  Side effect: 1. Aamphetamines are prime candidates for abuse tolerance and dependence. 2. Insomnia. 3. Hypertension. 4. Dry mouth. 14  Drugs acting on the central nervous system 2) xanthenes derivative - Most important stimulant that affect the brain cortex - Most used alkaloids - Caffeine, Aminophylline (Theophylline), Theobromine - Source : tea leaves , coca , coffee - Mechanism of action: block action of enzyme phospodiesterase thus increase the effect of catecholamine ( NA, Adrenaline) - The xanthine derivatives have several pharmacological effects. One, they directly relax the smooth muscle of the bronchi and pulmonary blood vessels. By such dilation of the bronchi, more oxygen can be drawn into the lungs most powerful → theophylline. Two, they stimulate the central nervous system and produce diuresis (they increase the production of urine) by direct action on the kidney most potent → theobromine. Third, stimulate CNS and wakefulness … most powerful → caffeine and least theophylline There are several examples of xanthenes derivatives:  Caffeine is a stimulant that has been long used as a morning "wakefulness”. Caffeine is found in some headache remedies products promoted to prevent drowsiness, and in some products designed to suppress appetite (in these preparations caffeine acts to stimulate the person)., it is possible for a person to develop a psychological dependence on the drug. Withdrawal of the drug results in some persons' having mild withdrawal symptoms (for example, headaches). 15 Unit (1) Figure 1:2 caffeine toxicity  Aminophylline (Theophylline). This drug is used in the treatment of bronchial asthma. It is given intravenously to provide rapid effect as vasodilators. problem ---- it increases heart rate, dosage forms (elixir, tablets, capsules) 16  Drugs acting on the central nervous system  Theobromine - The side effects 1. Usually associated with the use of the drug are nausea, vomiting, and nervousness 2. Tachycardia 3) Cocaine: From coca leaves Cause dependence Local anesthetic Sympathomimetic 4) Others: Ginseng , nicotine, ammonia ----------------------------------------------------------------------- 2 Hallucinogen These classes of psychoactive drugs have in common that they can cause subjective changes in perception, thought, emotion and consciousness. Strychnine Cannabis ( THC) LSD from ergot 17 Unit (1) 3 antidepressant drugs Antidepressant  Antidepressants are drugs used for the treatment of depression  Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behavior, feelings  Depressed people may feel sad, anxious, , hopeless, worried, , guilty, irritable, , or restless. They may lose interest in activities that once were pleasurable, experience loss of appetite, have problems concentrating, remembering details, or making decisions, and may attempt suicide. Insomnia, excessive sleeping, fatigue, loss of energy.  Depressed mood is not necessarily a psychiatric disorder. It may be a normal reaction to certain life events,.  However more sever depressed mood is a primary or associated feature of certain psychiatric syndromes such as clinical depression.  The cause of depression is believed to be a reduction in neurotransmitter norepinephrine , 5-HT and serotonin at the junction between nerve cell in the brain.  Many of drugs treat depression increase the amount of these substances in the brain Classification of antidepressant:  Minor depression does not usually require drug  Sever depression however may be helped by antidepressant drug  Antidepressant may have to be taken for many months  They can be withdrawn gradually after prolong treatment without relapse occurring 18  Drugs acting on the central nervous system Figure 1:3 action of antidepressants 1. Tricyclic antidepressants TCA - So called because of the characteristic three- ring nucleolus - Action : when excitatory neurotransmitter in the brain are released they are normally rapidly taken up again into the cell. Tricyclic antidepressants typically block the reuptake of norepinephrine and serotonin at the nerve ending in the brain which thus increase the amount of these substances available for receptor uptake - Effect and uses: 1. To treat several types of depression …. It may take several weeks before the depression itself is relieved 19 Unit (1) 2. Imipramine … is used for nocturnal enuresis (bed wetting) in children  Side effect: - Anticholinergic effect dry mouth, blurred vision, - CNS problem drowsiness, dizziness, tremors, - Sexual problems, skin rash, - And weight gain, increase appetite. - Postural hypotension and arrythmiacis - Toxicity occurs at about ten times normal dosages; these drugs are often lethal in overdoses, as they may cause a fatal arrhythmia. - However,tricyclic antidepressants are still used because of their effectiveness, especially in severe cases of major depression,  Interaction: - Not given with MAOI - Not given with alcohol - Not given to patient with cardiac disease  The Tricyclics include: - Amitriptyline (Elavil, Endep)® - Clomipramine (Anafranil)® - Doxepin (Adapin, Sinequan) ®… from TCA with weaker antidepressant and major anxiolytic effect - Imipramine (Tofranil)® - Nortriptyline ( Aventyl)® 2. Monoamine oxidase inhibitors: - Action Monoamine oxidase inhibitors (MAOIs) Irreversibly inhibit the enzyme monoamine oxidase, which 20  Drugs acting on the central nervous system breaks down the neurotransmitters serotonin, and norepinephrine in the brain and lead to accumulation to these substances - Uses: The main use of MAOI is in typical depression the long list of possible adverse effect limits their usefulness  Side effect MAOI - Can produce a potentially lethal hypertensive reaction if taken with foods that contain excessively high levels of tyramine, such as mature cheese, cured meats or yeast extracts - Other side effects of MAOI include: postural hypotension, heart attack, stroke, and palpitation. - Insomnia nervousness headache - Dry mouth, urinary retention  A new generation of MAOIs has been introduced; moclobemide (Manerix)®, known as a reversible inhibitor of monoamine oxidase (Arima)®, which is as effective as SSRIs and tricyclic antidepressants, in depressive disorders with less side effect - Monoamine Oxidase inhibitors:  Isocarboxazid (Marplan)®  Phenelzine (Nardil)®  Selegiline (Eldepryl, Emsam)®  Tranylcypromine (Parnate)® 3. Selective serotonin reuptake inhibitors: - Selective serotonin reuptake inhibitors, SSRIs are thought to prevent the reuptake of serotonin (also known as 5- hydroxytryptamine, or 5-HT) by the presynaptic neuron, 21 Unit (1) thus initially maintaining higher levels of 5-HT and serotonin in the synapse. - Their advantage lies in the lack of many side effect of the former groups - SSRI side effects include: nausea, diarrhea, increased blood pressure, agitation, headaches, anxiety, nervousness, emotional liability, insomnia, drug interactions,, anorexia, tremors, sexual dysfunction, decreased libido,, drowsiness, GI irregularities, muscle weakness, - Not cardiotoxic , not cause postural hypotension, - No anticholinergic effect ,no weight gain  SSRI antidepressants includes: - Citalopram (Celexa)® - Paroxetine (Paxil,)® - Fluoxetine (Prozac)® - Sertraline (Zoloft)® Lithium carbonate:  Lithium remains the standard treatment for bipolar disorder and is often used in conjunction with other medications. Figure 1: Bipolar 22  Drugs acting on the central nervous system  Action: Lithium ions interfere with ion transport processes, lithium is treated in the body in similar way to sodium, its believed to modify neurotransmission in the brain  Side effect: Lithium is potentially toxic drug, must monitor blood level  Lithium's potential side effects include thirst, tremors, light-headedness  nausea, diarrhea.( take with meal)  Cardiac arrythmiacis , hypotension  Thyroid dysfunction  Long term use is associated with kidney failure.  Toxicity with overdose: weakness, drowsiness, confusion, coma  Lithium has narrow therapeutic window  Dose : 600mg – 1200 mg / day  This therapeutic dose very close to toxic dose 23 Unit (1) Figure 1:4 24  Drugs acting on the central nervous system 2nd Nervous System Depressant Sedative hypnotic Insomnia: is a sleep disorder in which there is an inability to fall asleep or to stay asleep as long as desired, can cause feeling of anxiety, inability to concentrate Hypnotic: drugs whose primary function is to induce sleep and to be used in the treatment of insomnia  Hypnotic medications also have a number of side effects such as daytime fatigue, and cognitive impairments.  Benzodiazepine hypnotic lack evidence of long-term effectiveness due to tolerance that develops in 2 – 3 weeks. The risks include dependence,  Many sedative hypnotic alter the normal sleep cycle , and don’t produce natural sleep, many centrally acting drugs and alcohol do in fact suppress the REM (rapid eye movement) sleep state with dreaming, increase heart rate  Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. Preferably they should be prescribed for only a few days at the lowest effective dose. Sedative: anxiolytic agent should reduce anxiety and exert calming effect and relaxation, reduce the physical activity.  Whereas only low doses are needed to provide a peaceful and calming sedative effect 25 Unit (1) Figure 1:5 sleep cycle  Classification of sedative hypnotic  Benzodiazepines (e.g.,diazepam (Valium®), midazolam (Versed)®, clonazepam (Klonopin)®  Barbiturates (amobarbital)®, pentobarbital (Nembutal)®, thiopental (Pentothal®)  Miscellaneous agents (e.g. paraldehyde (Paral)®, meprobamate (Miltown)®, ethchlorvynol (Placidyl)® Barbiturates:  A group of drug that derived from barbituric acid  Barbiturates sedative-hypnotic drugs produce a dose- dependent sequence of CNS depression  With increasing dosage:  Calming or drowsiness {sedation} 26  Drugs acting on the central nervous system  Sleep {pharmacological hypnosis}  Unconsciousness Coma  Surgical anesthesia  Fatal respiratory/cardiovascular depression  Action: Barbiturates activate inhibitory GABA an inhibiting neurotransmitter.  Increase effect of GABA reduce CNS activity and promote sleep  Therapeutic uses: 1. Sedative in anxiety, hypnotic, induce sleep in insomnia 2. Induction agent in anesthesia( thiopental) 3. Anticonvulsant effect in epilepsy ( phenobaritone)  Adverse Effects:  They have addiction potential, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, & for epilepsy,  Drowsiness lethargy, incoordination, memory problem.  Significant depression of myocardial contractility occurs in barbiturate poisoning.  Barbiturates depress respiratory drive centrally ,at doses somewhat (three times) higher than required for pharmacological hypnosis  Acutely, barbiturates combine with cytochrome P-450 and produce stimulation of metabolism of a number of drugs and endogenous agents (such as steroids) 27 Unit (1)  Treatment of barbiturate toxicity---- Respiratory establish, osmotic diuretic Dialysis, alkalization of urine ?  Preparation: 1. Ultra short acting (5–10 minutes) for induction of anesthesia Ex. Thiopental 2. Short acting (2-4 hours) for difficult falling in sleep Ex. Secobarbital, hexobarbitone 3. Intermediate acting (4-6 hours) for difficult maintenance in sleep Ex. Pentobarbital 4. Long acting…..(6 -12 hours) mainly used anticonvulsant Ex. phenobarbitone Benzodiazepines :  Action: Benzodiazepines enhance GABA an inhibiting neurotransmitter.  Increase effect of GABA reduce CNS activity and promote sleep 28  Drugs acting on the central nervous system  Effect:  With increasing doses, benzodiazepines can progressive cause sedation, then hypnosis and then stupor.  Benzodiazepines do not cause general anesthesia since awareness persists.  These agents have anti-anxiety / sedative-hypnotic properties.  Some benzodiazepines (clonazepam are effective muscle relaxants, whereas most others are not.  Benzodiazepines have proven far safer than barbiturates for pharmacological hypnosis and both safer and more effective in management of generalized anxiety disorder.  Tolerance and abuse liability to barbiturates occurs more often than that observed with benzodiazepines  Barbiturate use may be accompanied by significant drug- drug interaction. 29 Unit (1) Figure 1:6  Uses: a. Hypnotic, sedative b. Anxiolytic, minor tranquilizer c. Anticonvulsant …. clonazepam d. Centrally acting Muscle relaxant e. Used in irritable bowel syndrome …. chlordiazepoxide  Adverse Effects:  If used as preanesthetic medication, benzodiazepines decrease blood pressure and increase heart rate.  Respiratory System : At pharmacological hypnotic doses, benzodiazepines do not affect respiration in normal subjects.  Severely benzodiazepine-intoxicated patients may require assistance in breathing if other CNS depressant drugs have been taken  CNS Drowsiness, lethargy hypotonia, dysarthria, dizziness, behavior disturbances including hyperactivity, irritability, difficulty in concentration.  Alcohol and antidepressant may increase these drugs effect  Antidote: Flumazenil is a benzodiazepam’s antagonist in case of toxicity  Preparation:  There are a very little to choose between the member of this group in efficacy , their main deference being in their duration of action 30  Drugs acting on the central nervous system  Diazepam (Valium)® …. 24h long acting  Alprazolam (Xanax)®  Chlordiazepoxide (Librium)®  Clonazepam (Rivotril)®  Flurazepam (Dalmane)®  Triazolam (Halcion)®  Lorazepam ( Ativan)® Chloralhydrate: - Chloral hydrate is a hypnotic /sedative - given orally - In liver its converted to active metabolite (trichloroethanol) - May cause excessive CNS depression , gastric irritation, unplesant test Phenothiazine: - Promethazine. Herbal medicine: Melissa officinalis (lemon balm) and Valeriana officinalis (valerian) have been used both traditionally and contemporaneously as mild sedatives, anxiolytics and hypnotics. Recent research has suggested that both may attenuate stress. As the two herbs are most often sold in combination with each other. Antihistamine: Numerous "antihistamines" as well are widely utilized to treat insomnia. Over-the-counter sleep aids usually contain many agents that block the histamine H1 receptor are also 31 Unit (1) widely considered to have therapeutic limitations, including the development of next-day carryover sedation, Antipsychotic drugs Psychosis is a generic psychiatric term for a mental state involving the loss of contact with reality complete breakdown of personality, causing the detioration of normal social functioning. A psychotic episode may involve hallucinations, delusions, paranoia. It is treated by the prescription of anti- psychotic medications, psychotherapy, and in extreme cases, periods of hospitalization. The term donate a variety of mental disorder - "mania" - Paronia - Schizophrenia - bipolar disorder( manic depression) Neurosis is a general term referring to mental distress that, unlike psychosis, the problem in neurosis the thoughts or behaviors that significantly impair, but do not prevent, normal daily living. Disorders associated with the term have included - obsession, - chronic anxiety - phobias, 32  Drugs acting on the central nervous system Neurosis is commonly treated, by anxiolytic drugs Antipsychotic drugs: Also called Neurolyptic (major tranqulizer) Typical antipsychotic:  primarily used to manage psychosis (including delusions, hallucinations, or disordered thought), particularly in schizophrenia and bipolar disorder  Action All antipsychotic drugs tend to block the dopamine pathways of the brain. Because. Excess release of dopamine in the brain has been linked to psychotic experiences.  Effect these drugs suppress psychosis, schizophrenia, psychotic behavior, delusion, hallucination agitation …. They exert their effect on mental process , emotional and behaviors Figure 1:7 action of antipsychotic  Adverse effects: A number of adverse effects have been observed, including extrapyramidal effects on motor control – including akathisia (constant discomfort causing 33 Unit (1) restlessness), tremor, and abnormal muscle contractions, an involuntary movement disorder known as tardive dyskinesia,  Withdrawal symptoms from antipsychotics may emerge during dosage reduction and discontinuation, recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse A drug groups: 1st phenothiazine  Effects and uses: 1. The phenothiazine structure occurs in various neurolptic drugs, e.g. chlorpromazine 2. And antihistaminic drugs, e.g. promethazine. 3. Antiemetic properties 4. Chloropromazine used as antihiccup 5. They have anticholinergic effect (dry mouth, urinary retention) 6. Produce some sedative effect 7. α- adrenergic receptor blocker so decrease BP 8. Because drugs decrease dopamine may increase prolactin so used in milk production  Pharmacokinetics: most of these drugs given orally and metabolized extensively in liver  Adverse effect 1. extrapyramidal effects on motor control because of increase dopamine 2. hypotension , bradycardia 3. constipation, urinary retention , dry mouth, 4. Drowsiness ,confusion 34  Drugs acting on the central nervous system 5. jaundice / photosensitivity  Drugs:  Chlorpromazine (Largactil)® … sedative & antiemetic  Fluphenazine (Prolixin)® – Available in (long-acting) form injection for schizophrenia  Perphenazine (Trilafon)®  Prochlorperazine (Compazine)® useful in vomiting and vertigo  Thioridazine (Mellaril)®  Trifluoperazine (Stelazine)®  Promazine (saprine)®  Triflupromazine (Vesprin)®  Promethazine (Phenergan)® for allergy  Pimozide (Orap)® 2nd Butyrophenones:  Is a chemical compound; some of its derivatives (called commonly butyrophenones) are used to treat various psychiatric disorders such as schizophrenia, as well as acting as antiemetic  The group of drugs has action rather similar to those of phenothiaine they are less sedative but are liable to produce extrapyramidal side effect  Has a fewer autonomic effect Drugs:  Haloperidol (Haldol)® the most widely used classical antipsychotic drug in this class mainly used in manic and highly agitated patient  Droperidol (Droleptan)® often used for neurolept analgesic anesthesia and sedation in intensive-care treatment 35 Unit (1) 3rd Thioxanthenes: - Several of its derivatives are used as typical antipsychotics in the treatment of schizophrenia and other psychoses. has antiemetic effect - The therapeutic efficacy of these drugs is related to their ability to antagonize the Dopamine receptors in the brain but more selective blocker , don’t inhibit acetylcholine , norepinehrine and histamine so less side effect - These drugs rather similar to phenothiazine but less sedative - Side effect: extrapyramidal , drowsiness  Drugs: - Flupenthixol (Depixol, Fluanxol)® - Thiothixene (Navane)® - Zuclopenthixol (Cisordinol, Clopixol, Acuphase)® Atypical antipsychotic: - Were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects (and extrapyramidal symptoms in particular) than typical medications - These drugs block serotonin receptor without effect in dopamine level, more effective with less side effect  Drugs: - Clozapine (Clozaril)® – Requires complete blood counts every one to four weeks due to the risk of agranulocytosis. 36  Drugs acting on the central nervous system - Olanzapine (Zyprexa)® – Used to treat psychotic disorders including schizophrenia, acute manic episodes, and maintenance of bipolar disorder - Sulpride: 37 Unit (1) Antianxiety Also known as minor tranquilizers an anxiolytic is a drug that inhibits anxiety. Anxiolytic medications have been used for the treatment of anxiety and its related psychological and physical symptoms.  Neurosis is a class of functional mental disorders involving distress but neither delusions nor hallucinations, whereby behavior is not outside socially acceptable norms. It is also known as psychoneurosis or neurotic disorder.There are many forms of neurosis: obsessive–compulsive disorder, anxiety neurosis, hysteria (in which anxiety may be discharged through a physical symptom), and a nearly endless variety of phobias as well as obsessions.  symptoms...anxiety, sadness or depression, anger, irritability, mental confusion, low sense of self-worth, etc., behavioral symptoms lethargy, etc., cognitive problems such as unpleasant or disturbing thoughts, socio-culturally inappropriate behaviors,  clinically , anxiety arise when the balance between certain chemicals in the brain is distributed, activation of sympathetic nervous system  this can be treated by anxiolytic drugs  anxiolytic high potential of abuse, tolerance , physical and psychological dependence  if they are stopped suddenly withdrawal symptoms including excessive anxiety, restlessness insomnia and seizure  Beta-receptor blockers such as propranolol, although not anxiolytics, can be used to combat the somatic symptoms of anxiety. 38  Drugs acting on the central nervous system The preparations: 1st Benzodiazepines: - Benzodiazepines are prescribed for short-term relief of severe and disabling anxiety. Benzodiazepines may also be indicated to cover the latent periods associated with the medications prescribed to treat an underlying anxiety disorder. - They are used to treat a wide variety of conditions and symptoms and are usually a first choice when short-term CNS sedation is needed. - Longer-term uses include treatment for severe anxiety. - Mechanism of action: Benzodiazepines enhance GABA an inhibiting neurotransmitter. - Uses: treat anxiety. phobia neurosis Benzodiazepines exert their anxiolytic properties at moderate dosage. At higher dosage hypnotic properties occur.  Insomnia.  Psychosomatic disorder (irritable bowel syndrome)  Anticonvulsant  Muscle relaxant  Preoperative medication  Side effect: 1. There is a risk of a benzodiazepine withdrawal and rebound syndrome after continuous usage for longer than two weeks, and tolerance and dependence may occur if patients stay under this treatment for longer. 2. Drowsiness , dizziness , forgetfulness , depression , confusion 39 Unit (1) 3. Ataxia 4. Respiratory depression  Special precaution: - People who need to drive or operate - Mental depression - Interaction with other CNS depressant and alcohol  The preparations:  Chlordiazepoxide (Librium)®  Clonazepam (Klonopin, Rivotril)®  Diazepam (Valium)®  Lorazepam (Ativan)®  Oxazepam (Serax)®  Alprazolam (Xanax)®  Temazepam ( restoril)® 2nd Meprobamate Which is used as an anxiolytic drug. It was the best- selling minor tranquilizer for a time, but has largely been replaced by the benzodiazepines, due to their wider therapeutic index (lower toxicity) and lower incidence of serious side effects 40  Drugs acting on the central nervous system Alcohol Ethanol: Effect: a. CNS depressant, impaired judgment , affect memory and emotion b. Body react with excitement, sedation and anesthesia c. Peripheral vasodilatation, flushing and sweetening d. Euphoria e. Vasoconstriction of coronary arteries, arrythmiacis f. Tolerance and physical dependence Uses of ethanol: a. Antiseptic 70% b. Co-solvant c. Preservative d. Irritation, rubifacient e. Cooling effect Drug interaction: a. Increase effect of CNS depressant as (sedative and hypnotic) b. Suppress metabolism of Phenobarbital and warfarine c. Chronic alcoholism increase metabolism of drugs Acute toxicity (poisoning) Acute alcohol poisoning" is a related medical term used to indicate a dangerously high concentration of alcohol in the blood, (overdose) 41 Unit (1) Symptoms of Alcohol Poisoning  Severe confusion, unpredictable behavior and stupor  Vomiting..  Slowed or irregular breathing. Cold clammy or pale or bluish skin.  Common symptoms of alcohol intoxication include slurred speech, euphoria, impaired balance, loss of muscle coordination (ataxia), flushed face, dehydration, reddened eyes, and erratic behavior.  Sufficiently high levels of blood-borne alcohol will cause coma and death from the depressive effects of alcohol upon the central nervous high enough to induce coma or respiratory depression. is considered a medical emergency. “alcohol intoxication”.  Alcoholic breath  Cerebral edema Management: Acute alcohol poisoning is a medical emergency due to the risk of death from respiratory depression and/or inhalation of vomit if emesis occurs while the patient is unconscious and unresponsive. Emergency treatment for acute alcohol poisoning strives to stabilize the patient and maintain a patent airway and respiration, while waiting for the alcohol to metabolize: Also:  Treat hypoglycemia (low blood sugar) with 50ml of 50% dextrose solution and saline flush, as ethanol induced hypoglycemia is unresponsive to glucagon.  Administer the diuretic as Mannitol / IV fluid 42  Drugs acting on the central nervous system  Apply haemodialysis if the blood concentration is dangerously high (>400 mg%), and especially if there is metabolic acidosis.  Provide oxygen therapy as needed via nasal cannula or non- rebreather mask.  Additional medication may be indicated for treatment of nausea, tremor, and anxiety. Symptoms of chronic Alcoholism:  Difficulty with interpersonal relationships, problems at work or school, and insomnia Alcohol abuse is also an important cause of chronic fatigue.  poor judgment; chronic anxiety, irritability,.  Alcohol's effects on the liver include elevated liver function tests, prolonged use leads to cirrhosis and failure of the liver. Jaundice and ascities.  Alcohol also causes impairment in a person's critical thinking. And they seem very inattentive to what is going on around them. Social skills are significantly impaired in people suffering from alcoholism due to the neurotoxic effects of alcohol on the brain,  Alcohol abuse causes an increased risk of brain damage and other long lasting alterations to the brain.  Memory loss, neglect of personal appearance and responsibility  Gastritis, ulceration  Malnutrition Treatment of chronic alcoholism: Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. It blocks the processing of alcohol in the body by inhibiting 43 Unit (1) acetaldehyde dehydrogenase thus causing an unpleasant reaction when alcohol is consumed.. Action: alcohol dehydrogenas Ethanol acetaldehyde acetaldehyde dehydrogenas Acetaldehyde acetic acid → H2O + O2 + ATP Disulfiram suppress the second stage metabolism (inhibit aldehyde dehydrogenase) thus acetaldehyde will accumulate which lead to symptoms of nausea, vomiting, hypotension , which the patient cannot tolerate Methanol:  Wood alcohol , methyl alcohol , CH3OH alcohol dehydrogenase  methanol formaldehyde ⤍ formic acid ⤍ CO2  Formic acid effect ( methanol toxicity) a. Cornea toxicity …. blindness b. Acidosis c. Bradycardia …. Death due to cessation in respiration Management of methanol toxicity: 1. NaHCO3 IV … to manage acidosis 2. Blood dialysis 3. Give antidote the ethanol Mechanism: ethanol compete for alcohol dehydrogenase which responsible for metabolism of methanol to formic acid, it’s essential to saturate the enzyme with less toxic ethanol 44  Drugs acting on the central nervous system Drug used in anesthesia Anesthetic drugs divided into: 1. General anesthesia 2. Local anesthesia General Anesthesia|: A medically induced coma and loss of protective reflexes resulting from the administration of one or more general anesthetic agents. A variety of medications may be administered, with the overall aim of ensuring loss of consciousness, analgesia, relaxation of skeletal muscles,. The optimal combination of these agents for any given patient because no single anesthetic agent capable of achieving all of these desirable effect Types of general anesthesia: Anesthetic agents may be administered by various routes, including inhalation, injection Preanaesthetic medication: Anesthetic premedication consists of a drug or combination of drugs that serve to complement or otherwise improve the quality of the anesthetic. 1. hypnotic, anxiolytic, sedative to manage preoperative anxiety, most effective is benzodiazepines and phenothiazine groups 45 Unit (1) ex: - Diazepam temazepam ….. potent anxiolytic - Chloropromazine …. It has a central sedative effect - Promazine & promethazine 2. Administer an antiemetic agent such as prochloroperazine to reduce the incidence of postoperative nausea and vomiting, also chloropromazine 3. Drug used to decrease oral secretion Atropine Injection is given before anesthesia to decrease mucus secretions, such as mucous and saliva. Which occur if using some drugs like ether During anesthesia and surgery, atropine is used to help keep the heart beat normal. because increase heart rate and blood pressure. 4. Analgesic which may provide useful postoperative pain relieve ,morphine and its derivative usually used 5. Muscle relaxant : to relax muscle sufficiently to make surgery possible Ex tubocurarine. Stages of anesthesia There are four stages of anesthesia. Stage 1 Stage 1 Anesthesia, also known as the "induction. During this stage, the patient progresses from to analgesia with amnesia. Patients can carry on a conversation at this time. Stage 2 46  Drugs acting on the central nervous system Anesthesia, also known as the "excitement stage", is the period following loss of consciousness Stage 3 "Surgical anesthesia". During this stage, the skeletal muscles relax, Stage 4 Anesthesia, also known as "overdose", this results in a cessation of respiration and potential cardiovascular collapse. This stage is lethal without cardiovascular and respiratory support. Types of anesthesia: 1st Induction or IV anesthesia Most induction general anesthetics induced, by (intravenous). Onset of anesthesia is faster with intravenous injection than with inhalation, taking about 10–20 seconds to induce total unconsciousness Commonly used intravenous induction agents include: propofol, - Iintravenously administered hypnotic/ agent. Its uses include the induction and maintenance of general anesthesia,. - Chemically, propofol has largely replaced sodium thiopental (Pentothal)® for induction of anesthesia because recovery from propofol is more rapid and "clear" when compared with thiopental. Propofol is not considered an analgesic, so opioids such as morphine may be combined with propofol to alleviate pain. 47 Unit (1) - Propofol has been referred to as "milk of amnesia" because of the milk-like appearance of its intravenous preparation. Thiopental sodium, - The drug is barbiturates, and its action is to produce sleep , when given IV the patient will loose consciousness in 30 seconds - Action on CNS , its very poor analgesic a good hypnotic , its chief use in anesthesia is the production of pleasant induction for the patient prior to administration of other more suitable for maintenance Etomidate, - Very short acting induction agent Ketamine. - Primarily for the induction IV and maintenance of general anesthesia, - Usually in combination with muscle relaxant - Widely used in children because not affect the respiratory tract - Ketamine has a wide range of effects in humans, including analgesia, anesthesia, hallucinations, elevated blood pressure, and bronchodilation - Ketamine has also been found to descending pain and has analgesic effect Diazepam - This can be used as induction agent given IV - Its an irritant cause pain when given IV - Its more effective as sedative in premedication 48  Drugs acting on the central nervous system 2nd Maintenance or inhalational anesthesia The duration of action of intravenous induction agents is in general 5 to 10 minutes, after which time spontaneous recovery of consciousness will occur. In order to prolong anesthesia for the required duration (usually the duration of surgery), anesthesia must be maintained. Usually this is achieved by allowing the patient to breathe a carefully controlled mixture of oxygen, nitrous oxide, and a volatile anesthetic agent or by having a carefully controlled infusion of medication, usually propofol, through an intravenous catheter These drugs either: 1. Volatile liquid … chloroform, ether, halothane 2. Or gases: nitrous oxide, cyclopropane Diethyl ether: - first used - Ether survived as a viable agent for many years because it,  is readily made in pure form  is a volatile liquid, therefore easily vaporized  is potent,  supported respiration and the circulation so safe drug - Problem explosive and flammable mixtures with oxygen, & increase respiratory secretions 49 Unit (1) Chloroform: - Apart from its pleasant odor and nonflammability, it had major problems,  Severe cardiovascular depression  Hepatotoxicity. Cyclopropane: - Highly explosive and flammable agent Nitrous oxide , laughing gas - Its neither irritating nor flammable - Its an efficient analgesic and its possible to carry out minor painful procedures under gas analgesic without loss of consciousness - Combine with O2 or other anesthetic - Fast onset, short acting , return to conscious fast A variety of other newer halogenated agent revolutionized anesthetic practice Halothane - Volatile liquid with a musty smell - Potent , non inflammable - Usually administered by accurate vaporizer in combination with nitrous oxide or oxygen - Halothane affect the cardiovascular system, cause full in BP and pulse rate which could be counteracted by IV atropine - Recently has come in to some disrepute for postoperative liver failure Enflurane: 50  Drugs acting on the central nervous system - Suspected cardiotoxicity and respiratory depression, Isoflurane, - The same characteristic as Enflurane , but not produce myocardial depression, induction and recovery are rapid - unlike halothane, neither enflurane nor isoflurane has a toxic effect on liver Desflurane: Sevoflurane: - Is currently the most commonly used agent for inhalational induction, because it is less irritating to the tracheobronchial tree than other volatile anesthetic agents. Local anesthesia 51 Unit (1) A local anesthetic (LA) is a drug that causes reversible local anesthesia, generally for the aim of having a local analgesic effect, that is, inducing absence of pain sensation, They block both sensory and motor nerves They do not interfere with consciousness Usually used in minor surgical procedures for example.. Dental treatment, stitching cuts, they can also injected in space around the spinal cord to numb the lower half of the body Synthetic local anesthetics are structurally related to cocaine. They differ from cocaine mainly in that they have no abuse potential and do not act on the sympathoadrenergic system, i.e. they do not produce hypertension or local vasoconstriction, Local anesthetics vary in their pharmacological properties and they are used in various techniques of local anesthesia such as: Admenestration:  Surface anesthesia - application of local anesthetic spray, solution or cream to the skin or a mucous membrane. The effect is short lasting and is limited to the area of contact..  subcutaneous injection of a local anesthetic in an area bordering on the field to be anesthetized  Peripheral nerve block - injection of local anesthetic in the vicinity of a peripheral nerve to anesthetize that nerve's area of innervations.  Epidural anesthesia - a local anesthetic is injected into the epidural space where it acts primarily on the spinal nerve roots 52  Drugs acting on the central nervous system  Spinal anesthesia - a local anesthetic is injected into the cerebrospinal fluid, usually at the lumbar spine (in the lower back), where it acts on spinal nerve roots and part of the spinal cord. The resulting anesthesia usually extends from the legs to the abdomen or chest.  Direct to mucous membrane ( eye drop)  Infusion ( IV) slowly , blood circulation of a limb is interrupted using a tourniquet Vasoconstrictor and local anesthesia: In order to restrict the anesthetic to site of injection it is often given together with vasoconstrictor (adrenaline), which cuts down the blood supply at the site of injection and prevent the drug being carried away , this prolong the action and minimized the like hood of side effect Mechanism of action: All local anesthetics are membrane stabilizing drugs; they reversibly decrease the rate of depolarization and repolarization of excitable membranes Local anesthetic drugs act mainly by inhibiting sodium influx through sodium-specific ion channels in the neuronal cell membrane. They inhibit the initiation and propagation of nerve impulse, in consequence conduction is blocked in at afferent nerve ending, sensory and motor nerve fiber Side effect: 53 Unit (1)  The local adverse effects of anesthetic (numbness) and paresthesia (tingling, feeling of "pins and needles", skin becomes itchy and red  General systemic adverse effects are due to high dose or the drugs inter the blood stream - Tremor, nervousness, convulsion, respiratory depression, distribution of heart rhythm or blood pressure - Nausea vomiting or abdominal pain - Sudden cardiovascular collapse and respiratory depression - Allergic reaction, rash or asthma Types of local anesthesia: Surface applied local anesthesia Benzocaine is a local anesthetic commonly used as a topical pain reliever or in cough drops. It is the active ingredient in many over-the-counter anesthetic ointments such as products for oral ulcers. May used in rectal suppositories Cocaine - is alkaloid obtained from the leaves of the coca plant. - It is topical surface applied anesthetic ( eye drops). - It is addictive - it has sympathomimetic properties , vasoconstrictive effect , so no need to add adrenaline - it should not be injected , can be dangerous may cause CNS stimulant and sympathomimetic 54  Drugs acting on the central nervous system Local anesthesia given by injection: Procaine: - Is a local anesthetic drug. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it is also used in dentistry. The trade name (Novocain)®, - Not absorbed from mucus membrane and has to be given by injection Lidocaine or lignocaine: - Trade name xylocaine® - Is a common local anesthetic - Its rather more powerful than procaine , and is more stable and longer acting - Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery. - The duration of anesthesia 15 – 45 min , if adrenaline added the effect will last for 2 hrs - And antiarrhythmic drug. Bupivacaine: - Is a local anesthetic drug. - Trade names, Marcain® - More prolong action than lidocaine lasts for 3 – 6 hrs - Its widely used for epidural anesthesia in child birth to relieve labor pain without interfering with uterine contraction 55 Unit (1) Figure 1:7 Management and complication of local anesthesia Opioid analgesic 56  Drugs acting on the central nervous system Narcotic analgesic An opioid is any chemical that resembles morphine which has opium like action, also called narcotic Opioids are among the world's oldest known drugs; all the opioid from the opium poppy capsule ( P a p a v e r s o m n i f e r u m ) The analgesic (painkiller) effects of opioids are due to decreased perception of pain, decreased reaction to pain as well as increased pain tolerance They are of great importance in medicine as pain is a common and distressing feature of many diseases Since the pain is not a disease but a symptom, long term relief depending on treatment of underlying causes Nearly all opioids are potentially drugs of dependence Types of analgesic  Narcotic analgesic – related to morphine and more powerful  Non narcotic analgesic – related to aspirin less powerful  Local anesthesia Mechanism of action Opioids work by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract. Opioid block the transmission of pain signals 57 Unit (1) The receptors in these organ systems mediate both the beneficial effects and the side effects of opioids. Opioids act like endorphine Endorphins ("endogenous morphine") are endogenous opioid that function as neurotransmitters, and they resemble the opiates in their abilities to produce analgesia and a feeling of well-being. Endorphins that prevent nerve cells from releasing more pain signals, so increase the pain threshold endorphin has the highest affinity for the opioid receptor Opioid:  Natural opioids natural alkaloids found in the resin of the opium poppy. - Codeine - Morphine - Thebaine - Narcotine - papaverine  The semi-synthetic substances that are directly derived from the opium poppy are considered to be opiates as well, - Hydromorphone - Diamorhine (heroin)  Synthetic derivatives - Dextropropoxyphen (dolostop)® - Fentanyl 58  Drugs acting on the central nervous system - Pethidine (meperidine)® - Pentazocine—agonist/antagonist - Methadone Classification of opioid The pharmacodynamic response to an opioid depends upon the receptor to which it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist, or partial agonist For example, - Agonists as morphine are mediated by activation of the receptor; respiratory depression and physical dependence and sedation and spinal analgesia according to receptor binding affinities of the opioid). For example, the opiate alkaloid morphine exhibits high-affinity binding to -opioid receptor, and Diamorphine - Partial agonist , stimulation and blocking of receptor ex pentazocin - Antagonist... block the receptor Naloxone , reverse the opioid effect and used to treat the poisoning 59 Unit (1) Figure 1:9 Receptor binding affinity of opioids Pharmacological effect of opioid and uses - Opioids have been used to treat acute pain moderate to sever pain (such as post-operative pain). They also used in palliative care to alleviate the severe, terminal conditions such as cancer (pain is present but tolerated) - Decrease GI motility, used in sever diarrhea - Acts on CNS to reduce anxiety because has sedative effect - Suppress cough center in modularly oblongata , used as cough suppressant (codeine) Adverse effects Common adverse reactions in patients taking opioids for pain relief include: 1. Nausea and vomiting, drowsiness, , dry mouth, miosis, 2. Constipation. urinary retention, 3. Dose-related respiratory depression (especially with more potent opioids), 4. Confusion, hallucinations, delirium, dizziness and restlessness 5. Bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, 6. Urticaria, itching and flushing (due to histamine release,) 7. Physical and emotional dependence (the most serious) Opioid antagonists - used in treatment of opioid overdose - used in treatment of opiate induced respiratory depression - Lethal dose.. 200 mg - drugs 60  Drugs acting on the central nervous system  Naloxone or nallorphine  Naltrexone Example of opioids Morphine - Is a potent most powerful opiate analgesic drug that is used to relieve severe pain. - Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although, tolerance. - Given orally ,SC IM , IV - Dose 4 – 10 mg - Metabolized in liver to codeine. Codeine - or 3-methylmorphine - Is a natural opiate used for its analgesic, antitussive, antidiarrheal, , anxiolytic, , sedative and hypnotic properties. -.Codeine is the second-most predominant alkaloid in opium, at up to three percent. - Combined with aspirin and panadol to give synergistic effect in pain - (Revacod)® codine + panadol - Less dependence than morphine Heroin - also known as diamorphine - Heroin itself is an active drug, but it is also converted into morphine in the body. - Faster action , more addiction. 61 Unit (1) Methadone - Is a synthetic opioid. It is used medically as an analgesic., and thus has many of the same effects. Methadone is also used in managing severe chronic pain, owing to its long duration of action, extremely powerful effects, and very low cost. - Methadone is mainly used in the treatment of opioid dependence methadone acts on the same opioid receptors as these drugs. It has cross-tolerance (tolerance to similar drugs) with other opioids including heroin and morphine, and offers very similar effects, but a longer duration of effect. Oral doses of methadone can stabilize patients by mitigating or making more tolerable; opioid withdrawal syndrome. Pethedine: - Relive pain in labor, not cause depression of infants respiration Fentanyl - Intraoperative analgesic Tramadol - Trade name tramal® - Analgesic , low addiction liability Naloxone and nallorphine Antidote of morphine reverses respiratory depression 62  Drugs acting on the central nervous system Non steroidal anti inflammatory drugs  Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs  Are a class of drugs that provide analgesic and antipyretic (fever-reducing) effects, and, anti-inflammatory effects.  The term nonsteroidal distinguishes these drugs from steroids,  NSAIDs are unusual in that they are non-narcotic and thus are used as a non-addictive alternative to narcotics.  The most prominent members of this group of drugs are aspirin, ibuprofen, and naproxen, all of which are available over the counter in most countries. Mechanism of action NSAIDs work by inhibiting the production of prostaglandins 63 Unit (1) Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2 ) COX catalyzes the formation of prostaglandins from arachidonic acid COX-1 has a role in. the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum internal bleeding can result. The discovery of COX-2 led to research to development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.  Reduce fever by affect the hypothalamus  Acetaminophen is not considered an NSAID because it has little anti-inflammatory Medical uses NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.  Rheumatoid arthritis  Acute gout  Dysmenorrheal (menstrual pain) 64  Drugs acting on the central nervous system  bone pain  Headache and migraine  Postoperative pain  Mild-to-moderate pain due to inflammation and tissue injury  Pyrexia (fever)  Aspirin, the only NSAID able to inhibition of platelet aggregation. This is useful in the management of arterial thrombosis and prevention of adverse cardiovascular events. Adverse effects 1. GIT effect These effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding,, limiting the use of NSAID therapy. 2. NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (hematourea, albuminurea) 3. Not given in asthma 4. Bleeding disorder (blood dyscracias) 5. Tinnitus 6. NSAIDs are not recommended during pregnancy, particularly during the third trimester. 7. COX-2 inhibitors and traditional anti-inflammatory, increase the risk of myocardial infarction and stroke. Interactions: Warfarine and digoxin need precaution if given with aspirin because competition in the plasma protein The drugs: 65 Unit (1) Aspirin  Also known as acetylsalicylic acid is a salicylate drug,  Often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever the dose 300 – 600 mg,  And as an anti-inflammatory medication. Dose 900 mg  Aspirin also has an antiplatelet effect, aspirin is also used long-term, at low doses, to help prevent heart attacks, strokes, in dose 100 mg  Aspirin may be effective at preventing certain types of cancer  The main undesirable side effects of aspirin taken by mouth are gastrointestinal ulcers, stomach bleeding, and tinnitus, especially in higher doses.  In children, aspirin is no longer indicated, because of the risk of Reye's syndrome.  contra indicated in : children , pregnant , patients with asthma , tinnitus , ulcer , hepatic renal dysfunction ,  in the market ( buffarin)® aspirin + antacid to decrease toxicity  if toxicity by aspirin give NaHCO3 for alkalization of urine? Ibuprofen:  is a nonsteroidal anti-inflammatory drug (NSAID) used for pain relief, fever reduction,. . Originally marketed as Brufen,® ibuprofen is available under a variety of popular trademarks, including, Advil®  Avoid in peptic ulcer patient  Doses 200 -400 – 600 mg for pain , t.d.s or q.d.s 66  Drugs acting on the central nervous system  Avoid in peptic ulcer ,,,, low incidence of side effect Indomethacin  Is a non-steroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling.,  Trade names. indocid®  Dosage form , oral 50 – 100 mg tab , and suppositories Naproxen:  Is a nonsteroidal anti-inflammatory drug (NSAID) and is commonly used for relief of a wide variety of pain specially dental pain, fever, inflammations, and stiffness  Trade name proxen® , nopain® Diclofenac:  Is a nonsteroidal anti-inflammatory drug (NSAID) taken or applied to reduce inflammation and as an analgesic reducing pain in certain conditions,  Has a variety of trade names. Voltarine®, diclogesic®, tratul®, olfen®, rofenac®, votre®  It may be supplied as either the sodium or potassium salt,.  Avoid in peptic ulcer patient  Dose 50 – 100 mg tab (acid-resistant formulations),,, supp,,,, injection (75) ,,,, emulgel ,,,, powder for oral solution (50 mg),,,,,, slow- and controlled-release forms 67 Unit (1) (75, 100 or 150 mg) ,,,,, 12.5 mg diclofenac for children one year and above Mefenamic acid  Used mainly in dysmenorrheal and dental pain  ( ponstan)® Piroxicam ,,,, ( Felden)® Selective COX-2 inhibitors (Coxibs) Meloxicam ,,,,,, ( Mobic)® Rofecoxib (withdrawn from market) because of the cardiovascular effect Figure 1:9 COX pathways 68  Drugs acting on the central nervous system Figure 1:10 Mechanism of action of NSAIDS / Glucocortecoids Non Narcotic analgesic Paracetamol 69 Unit (1) Paracetamol, or acetaminophen is a widely used over- the-counter analgesic (pain reliever) and antipyretic (fever reducer). Also classified Non narcotic analgesic Uses Paracetamol is classified as a mild analgesic. It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In combination with opioid analgesics, paracetamol can also be used in the management of more severe pain such as post- surgical pain and providing palliative care in advanced cancer patients. Analgesic mixtures - Paracetamol + caffeine ( panadol extra)® - Paracetamol+ aspirin - Paracetamol + codeine ( revacod)® Action affects pain receptor in CNS not the prostaglandin Effect it is not generally classified as an NSAID because it exhibits only weak anti-inflammatory activity. - Analgesic and antipyretic. Pharmacokinetics The onset of analgesia is approximately 11– 29.5 minutes after oral administration of paracetamoland its half-life is 1–4 hours. Paracetamol is the active metabolite of phenacetin, 70  Drugs acting on the central nervous system Doses: generally safe for use at recommended doses - Adult (1,000 mg per single dose and up to 4,000 mg per day for adults), - Children..3 – 12 months 60 – 120 mg - 1 – 5 years 120 – 250 mg - 6 – 12 years 250 – 500 mg Adverse effect unknown at normal dose but acute overdoses of paracetamol can cause potentially fatal liver damage. The risk may be heightened by chronic alcohol abuse;. Paracetamol toxicity is the foremost cause of acute liver failure ( above 10 gm)  Not affect gastric mucosa , used in ulcer  Not cause Ray’s syndrome so suitable for children , and infants  Safe in pregnancy Trade names ,,,, ( panadol)® ( Tylenol)® ( revanin)® Gout  Inflammatory disease  It is caused by elevated levels of uric acid in the blood. The uric acid crystallizes, and the crystals deposit in joints, tendons and surrownding tissues. 71 Unit (1)  Phagocytes attack the crystals and cause inflammation , pain and swelling  Usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. at the base of the big toe is the most commonly affected (approximately 50% of cases). However, it may also present a s u r a t e n e p h r o p a t h y.  Figure 1:11 Gout  Normal uric acid 1- 7 mg  Gout was historically known as "the disease of kings" or "rich man's disease". Treatment of gout:  The initial aim of treatment is to settle the symptoms of an acute attack Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicines improves symptoms 72  Drugs acting on the central nervous system  Repeated attacks can be prevented by different drugs used to reduce the serum uric acid levels.( prophylactic) Levels of uric acid are usually lowered via lifestyle changes, and in those with frequent attacks, allopurinol or probenecid provide long-term prevention. 1st drugs that reduce inflammation in acute attack:  NSAIDs NSAIDs are the usual first-line treatment for gout, and They are not recommended, however, in those with gastrointestinal bleeding, renal failure, or heart failure While indomethacin has been the most commonly used NSAID, or, ibuprofen,.  Colchicine Source: alkaloid from (colchicum autumnale) Uses: 1. For relive acute attack and relive pain associated with gout, inhibit some action of inflammatory cells in gout 2. Prevent attack of Mediterranean fever Side effect: diarrhea, nausea, vomiting, abdominal pain Teratogenic and carcinogenic  Steroids Glucocorticoids have been found as effective as NSAIDs 2nd prophylactic drugs 73 Unit (1) They are not usually recommended until one to two weeks after an acute attack has resolved  uricosuric Action are substances that increase the excretion of uric acid in the urine, thus reducing the concentration of uric acid in blood plasma. In general, this effect is achieved by action on the proximal tubule of the kidney. Uses: Uricosurics are often used in the treatment of gout, By decreasing plasma uric acid levels, Drugs: probenecid drug interactions is very important when using uricosuric drugs in the presence of other medications. Also used as adjunct to antibiotic therapy because its inhibit renal tubular secretion of most penicillin and cephalosporin Sulphinpyrozone  allopurinol Allopurinol (Zyloric,)® - Uses used primarily to treat hyperuricemia (excess uric acid in blood plasma), including chronic gout , which is administered orally. - Action: allopurinol inhibit enzyme xanthine oxidase that is responsible for uric acid synthesis so decrease uric acid concentration xanthine oxidase Allopurinol alloxanthine xanthine oxidase hypoxanthine xanthine uric acid 74  Drugs acting on the central nervous system Figure 1: 11 Action of Allopurinol - Side effect little GI upset 75 Unit (1) Figure 1: 13 Gut treatment Skeletal muscle relaxant Pathway for stimulation of skeletal muscle: Brain ⟶ spinal cord ⟶ somatic neuron ⟶ synaps (neuromuscular junction) ⟶ skeletal muscle Neuromuscular junction  skeletal muscles are voluntary muscles  connects the nervous system to the muscular system via synapses between efferent nerve fibers and muscle fibers,. As an action potential reaches the end of a motor neuron, open allowing calcium to enter the neuron. and subsequent neurotransmitter release from the motor neuron into the synaptic cleft., motor neurons release acetylcholine (ACh),, which diffuses through the synapse and binds nicotinic 76  Drugs acting on the central nervous system acetylcholine receptors on the plasma membrane of the muscle fiber, The binding of ACh to the receptor can depolarize the muscle fiber (open ion channel), causing a muscle contraction.  Muscle fiber containing actin and myosin ( skeletal muscle protein necessary for muscle contraction) to produce contraction  Ach is destroyed by acetylcholine esterase and the contraction is terminated ⟶ muscle relaxation Figure 1 : 14 Pathway for stimulation of skeletal muscle Skeletal muscle relaxant  Muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and to relax muscles in surgery Types of skeletal muscle relaxant The term "muscle relaxant" is used to refer to three major therapeutic groups: 77 Unit (1) 1. Neuromuscular blockers. Neuromuscular blockers act by interfering with transmission at the neuromuscular end plate 2. Centrally acting drugs (CNS) activity. They are. Spasmolytics, muscle relaxants, are used to alleviate musculoskeletal pain and spasms 3. Direct acting drugs 1st Neuromuscular blockers , or peripherally acting drugs: Figure 1:15 Neuromuscular blockers.  Action: neuromuscular blockers function by blocking nicotinic receptor at the end plate of the neuromuscular junction.,so blocking the transmission of nerve impulses from nerve to muscle  Normal end plate function can be blocked by two mechanisms. Nondepolarizing agents, such as tubocurarine, block the agonist, acetylcholine, from binding to nicotinic receptors. Alternatively, depolarizing agents, such as succinylcholine, are nicotinic receptor agonists which 78  Drugs acting on the central nervous system mimic Ach, block muscle contraction by depolarizing to such an extent that it desensitizes the receptor and it can no longer initiate an action potential and cause muscle contraction.  Uses: a. Paralyze patient to facilitate intubation of the trachea for endotracheal intubation b. To relax muscle sufficiently to made surgery possible  Adverse effects may include drowsiness, headaches and migraines, motor coordination impairment, and/or upset stomach. Drugs: 1. Tubocurarine:  Tubocurarine (is a skeletal muscle relaxant)  Tubocurare is a naturally occurring quaternary amonium compound alkaloid obtained from the bark of. Curare plant , had been used as a source of arrow poison that produce death by skeletal muscle paralysis  Action: in the category of non-depolarizing neuromuscular-blocking drugs,  Uses: used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation. And clinically to facilitate endotracheal intubation.  Tubocurarine is classified as a long-duration, antagonist for Nicotinic acetylcholine receptor It is the active agent of curare. 79 Unit (1)  Its effect reversed by Neostigmine , that inhibit acetylcholine esterase ⟶so increase Ach conc , ⟶ so competition in receptor  Side effect: hypotention Respiratory paralysis Histamine release 2. Succinylcholine:  Also known as suxamethonium or succinylcholine,  Is a nicotinic acetylcholine receptor agonist, Suxamethonium acts as a depolarizing neuromuscular blocker.  Used to induce muscle relaxation and short-term paralysis, usually to facilitate tracheal intubation. , also in endoscopy  At first it cause contraction then paralysis  Not reversed by Neostigmine  side effect: muscle pain is common post operative 3. Gallamine - Gallamine is a non-depolarizing muscle relaxant. - It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. - Not cause histamine release. - Gallamine is commonly used to stabilize muscle contractions during surgical procedures. 2nd centrally acting skeletal muscle relaxant: Action: damp down the passage of the nerve signals from the brain and spinal cord that cause muscle to contract 80  Drugs acting on the central nervous system Effect: reduce nervous stimulation allows the muscle to contract Uses: painful muscle spasm Side effect: most spasmolytic agents have the side effects of sedation, drowsiness and may cause dependence with long- term use. Several of these agents also have abuse potential, and their prescription is strictly controlled Drugs: - benzodiazepines, such as diazepam While it can be used in patients with muscle spasm of almost any origin, it produces sedation in most individuals at the doses required to reduce muscle tone. ( 10 mg x 3/ day) - Baclofen is considered to be at least as effective as diazepam in reducing spasticity, and causes much less sedation. - Orphenandrine: ( Norgesic)® relieve muscle spasm , not cause sedation - Tizanidine ( sirdalud)® - Mephenisin: not used because toxicity - Batulinum toxin 3rd direct acting skeletal muscle relaxant:  Action: reduce the sensitivity of muscle to nerve signals by preventing actin and myosin stimulation , by reduce the release the calcium in the muscle  Uses:. It is the only specific and effective treatment for malignant hyperthermia,( a rare, life-threatening disorder triggered by general anesthesia.characterestic by massive calcium release in skeletal muscle , it’s a genetic disorder) 81 Unit (1) It is also used in the management of spinal cord injury Drug: Dantrolene sodium / problem of liver toxicity Antiepileptic Drugs  Seizure = convulsion = epilepsy  Epilepsy is a common and diverse set of chronic neurological disorders characterized by sudden attack of alter consciousness motor activity, or sensory impairment (seizures).  Also involuntary muscle contraction and autonomic function  It is a recurrent paroxysmal behavioral spell generally caused by an excessive disorderly discharge of cortical nerve cells of brain and can range from clinically undetectable (electrographic seizures) to convulsions.  In many cases a cause cannot be identified; however, factors that are associated include brain trauma, strokes, brain cancer, intracranial infection fever, and drug or alcohol misuse among others.  Epileptic seizures result from abnormal, excessive signals in the brain occur are normally finely coordinated to produce 82  Drugs acting on the central nervous system smooth movement of arms and legs and those signals can become paroxysmal and chaotic , and trigger the disorderly muscle activity and mental  Seizure are labeled Epilepsy if they are recurrent Types of epilepsy: Seizure types are organized firstly according to whether the source of the seizure within the brain is localized (partial or focal onset seizures) or distributed (generalized seizures). 1st Generalized seizures Bilateral symmetrical abnormal brain discharge through both hemisphere of brain Are divided according to the effect on the body but all involve loss of consciousness. 1. Tonic-clonic (grand mal): last for 2-5 minutes Many patients with generalized tonic-clonic seizures have vision, taste, smell, or sensory changes before the seizure. This is called an aura. The seizures usually involve muscle rigidity ( clonic ), followed by violent muscle contractions ( tonic), and loss of alertness (consciousness).Other symptoms that occur during the seizure may include:  Biting the cheek or tongue ,Clenched teeth or jaw ,Loss of urine or stool control (incontinence) ,difficulty breathing , blue skin color 83  Unit (1) After the seizure, the person may have:  Normal breathing ,Sleepiness that lasts for 1 hour or longer Loss of memory (amnesia) regarding events surrounding the seizure episode Manegment :  Prevent injury  Cushion head  Loosening tight clothing  Don’t try to open the mouth or force anything between the teeth  medication 2. absence (petit mal), last 10 – 30 seconds Involves a brief, sudden loss of consciousness. Absence seizures are more common in children than adults. Someone having an absence seizure may look like he or she is staring into space for a few seconds, no convulsion, no falling. Absence seizures appear mild. Absence seizures usually can be controlled with anti-seizure medications 3. myoclonic, People with disorder experience muscle twitching or jerking. cause sudden, quick, small jerks of the arms, shoulder, or (less often) the legs 4. Atonic seizures 2nd Partial seizures  Partial seizures (also called localized seizures) are seizures which affect only a part of the brain at onset. The brain is divided into two hemispheres,. the seizure is generated in and affects just one part of the brain – the whole hemisphere or part of a lobe. Symptoms will vary 84  Drugs acting on the central nervous system according to where the seizure occurs, symptoms may include a wave-like sensation in the head; in numbness or tingling;, visual disturbance or hallucination.  Partial seizures are split into two main categories; simple partial seizures and complex partial seizures  In simple partial seizures a small part of one of the lobes may be affected and the person remains conscious  A complex partial seizure affects a larger part of the hemisphere and the person may lose consciousness Status epilepticus Is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous, unremitting seizure lasting longer than 5 minutes or recurrent seizures without regaining consciousness between seizures for greater than 5 minutes. Treatment is, however, generally started after the seizure has lasted five minutes. It is always considered a medical emergency. There is some evidence that five minutes is sufficient to damage neurons and that seizures are unlikely to self-terminate by that time. Warning : patient with epilepsy should be warned against driving vehicles , swimming and working under conditions where fit could produce disaster Anticonvulsant The anticonvulsants (also commonly known as antiepileptic drugs) are a group of drugs used in 85 Unit (1)  the treatment of epileptic seizures.  and for the treatment of neuropathic pain. The goal of an anticonvulsant is to suppress the start a seizure. An effective anticonvulsant would prevent the spread of the seizure within the brain drugs function to help reduce this area of irritability and thus prevent epileptic form seizures. While the term 'anticonvulsant' is a fair description the use for Convulsive non-epileptic seizures Action : these drugs block initiation of electrical discharge in the brain to prevent spread of the abnormal electrical discharge. drug used in seizure disorder tonic clonic and absence seizure myoclonic partial seizure ethosuxamide seizure carbamazepine valproic acid valproic acid phenytoin clonazepam clonazepam valproic acid Drugs : Phenytoin:  Stucture From Hydantoin group  Trade name ( Epanutin)®  Uses : Phenytoin sodium is a most important antiepileptic drug. It is useful to treat partial seizures and generalized tonic-clonic seizures but not absence seizures or myoclonic seizures. has advantage of not producing sedation or drowsiness. 86  Drugs acting on the central nervous system  Action Phenytoin is believed to protect against seizures by use- and voltage-dependent block of voltage-gated sodium channels. so that block accumulates of charged sodium and activation, such as occurs during a seizure discharge. Thus phenytoin is able inhibit pathological hyperexcitability in epileptogenic neuron  Pharmacokinetics: well absorbed orally. extensive 1st pass effect  Adverse effect - Acute toxicity within 2 weeks: nystagmus. At toxic doses, patients experience sedation, ataxia, and include rash and severe allergic reactions. - Chronic effect ( within 20 years) - causes a reduction in folic acid levels, predisposing patients to megaloblastic anemia - Phenytoin has induced gingival enlargement (overgrowth of the gums) - hirsutism, - osteomalacia - for pregnancy: Phenytoin is a known teratogen Carbamazepine  Carbamazepine (Tegretol)® is an anticonvulsant and mood-stabilizing  Uses - drug used primarily in the treatment of epilepsy partial seizures and generalized tonic-clonic seizures but not absence seizures or myoclonic seizures - And bipolar disorder, - as well as Trigeminal neuralgia  Mechanism of action: decrease level of Na+ inside of nerve cell, decrease hyperexcitability of epileptogenic neuron  Adverse effect: 87 Unit (1) - Common adverse effects may include drowsiness, headaches and migraines, motor coordination impairment, - And/or upset stomach nausea and vomiting - Liver dysfunction. jaundice and bone marrow depression Valproic acid  (Valproic acid , Valproate), an acidic chemical compound, brand names, (Depakene,)®  Uses: has found clinical use as an anticonvulsant drug, primarily in the treatment of epilepsy, used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, myoclonic epilepsy, i.e. all types of seizures. It is also used to treat migraine headaches.  Action: Its mechanism of action includes enhanced neurotransmission of GABA Valproic acid also blocks sodium channels, These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.  Adverse effect: - its potential for sudden and severe, possibly fatal, liver toxicity, especially in those just starting the medication,espesially in young patient - Common side effects are dyspepsia nausea vomiting , or weight gain ,and tremor - Teratogenic , not used for pregnancy Ethosuximide:  Ethosuximide is a succinimide anticonvulsant, used mainly in absence seizures. Trade name ( Zarontin)® 88  Drugs acting on the central nervous system  Uses: Ethosuximide is considered the first choice drug for treating absence seizures because it lacks the hepatotoxicity of the alternative drug as valproic acid  Action: The mechanism by which ethosuximide affects neuronal excitability includes block of T-type Ca2+ channels in the thalamus T current believed to play role in absence  Adverse effect: - GI distress nausea and vomiting - some drowsiness and dizziness , lethargy Phenobarbital:  Phenobarbital is a long-acting barbiturate  Uses: and the most widely used anticonvulsant worldwide, It also has sedative and hypnotic properties, but as with other barbiturates, it has been superseded by the benzodiazepines for these indications. The WHO recommends its use as first-line for partial and generalized tonic–clonic seizures (grand mal)  Phenobarbital is supplied in various forms: in tablets, added to analgesic enfant preparations  Action: increase GABA  Side effect:- Sedation and hypnosis are the principal side effects of phenobarbital. - Tolerance develops with chronic use - Increase liver enzyme Primidone: - Primidone is an anticonvulsant, the active metabolites of which, phenobarbital 89 Unit (1) - In the body converted to phenobarbital - Has same effect and properties to phenobarbital Benzodiazepines: - Anticonvulsant - Action Increase GABA levels - May be administered IV to stop seizure in progress (Status epilepticus ) - Adverse effect: sedation - Examples:  Diazepam (Valium)®….. for grand mal and status epilepticus  Clonazepam (Rivotril)® status epilepticu, myoclonic, and absence seizure that not affected by ethosuximide New antiepileptic drugs:  Felbamate (febatol)®. It was originally developed to treat epilepsy,( partial seizure) Risk of aplastic anemia and liver failure, reserved for patient not respond to other drugs.  Gabapentin (Neurontin)® is a pharmaceutical drug, specifically a GABA analog Used in patient over 12 years of age in combination with other anticonvulsant  Lamotrigine ( lamictal)® Interfere with sodium ions to decrease neuron excitability Used in combination with others 90  Drugs acting on the central nervous system Side effect: dizziness, ataxia, sleepiness rash visual disturbance Parkinson disease  Parkinson's disease is a degenerative disorder of the central nervous system.  The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in a region of the midbrain; the cause of this cell death is unknown.  Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, thinking and behavioral problems may arise, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other symptoms include sensory, sleep and emotional problems.  Parkinson's disease is more common in older people, with most cases occurring after the age of 50.  Causes: Parkinson's disease in most people is idiopathic, (having no specific known cause) although some atypical cases have a genetic origin. Many risk in people exposed to certain pesticides and a reduced risk in tobacco smokers. Viral infection of brain , brain tumor , and narrowing blood vessel in the brain  Other causes include the side effect of certain drugs (antipsychotic) 91 Unit (1)  Pathophsiology: its caused by imbalance between chemicals in the brain , Dopamine and acetylcholine ,these chemicals are responsible for transmission of nerve signals in the part of brain that coordinate movement (basal ganglia), they have opposing actions and are normally finely balanced.  In Parkinson there is a reduction in the action of dopamine, so that the effect of acetylcholine is increased and imbalance is created. Figure 1:16 Neurotransmitter imbalance in parkinson Drug therapy: Drugs can relieve symptoms of Parkinson by restore the balance in the brain between the dopamine and acetylcholine They full into two main groups: 1. Those that act by reducing the effect of acetylcholine (anticholinergic) 2. Those that act by increase level of dopamine 1st Anticholinergic Agents for Parkinson's Disease  Examples 92  Drugs acting on the central nervous system benztropine Benhexoln (artanne)® Orphenandrine ⟶ a muscle relaxant  How It Works Anticholinergic medicines block nerve impulses (cholinergic nerve impulses) that help control the muscles of the arms, legs, and body. They also restrict the action of acetylcholine that helps regulate muscle movement,  For normal motor or muscle control, the effects of acetylcholine and dopamine need to be carefully balanced. When dopamine levels are low (as they are in people who have Parkinson's disease), a chemical imbalance results, causing symptoms such as tremor and rigid muscles. Anticholinergic medicines decrease levels of acetylcholine to achieve a closer balance with dopamine levels.  Used there is some evidence that anticholinergics work well to control tremor in Parkinson's disease, less affect rigidity  Toxicity of anticholinergic: 1. CNS toxicity: drowsiness, confusion, delusion, hallucination 2. anticholinergic side effect: dry mouth, constipation, glaucoma , tachycardia 2nd Dopamine agonists  Several dopamine agonists that bind to dopaminergic post- synaptic receptors in the brain have similar effects to levodopa  These were initially used , and as a complementary therapy to levodopa;  Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea and constipation. 93 Unit (1)  Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling  Uses of this group: 1. As these drugs decrease prolactin level , so used  in prolactinemia  in mother wants to stop breast feeding  treat infertility because of high prolactin level 2. Parkinson when levodopa is ineffective  Dopamine agonists include  bromocriptine,  pergolide, ( Dopergine)®  cabergoline, ( Dostinex)® 3rd Amantadine  Antiviral  Causes the release of dopamine from neuronal storage site and inhibit reuptake  Works best in early stages of disease, often used in combination with other antiparkinson drugs  Used to treat extrapyramidal reaction assosiated with prolong use of phenothiazine 4th selegiline:  Is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia.  In normal clinical doses it is a selective irreversible MAO- B inhibitor. 94  Drugs acting on the central nervous system  Used alone early in disease to slow progression  Used with lvodopa to prolong effect of levodopa 5th Levodopa  Levodopa has been the most widely used treatment for over 30 years.  It is not possible to restore the deficiency in the brain by giving dopamine , as this substance will not enter the brain therefore levodopa is used  (L-DOPA)® is converted into dopamine in the brain dopaminergic neurons in brain by dopa decarboxylase  Since motor symptoms are produced by a lack of dopamine in the brain  Only 5–10% of (L-DOPA)® crosses the blood–brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness.  Carbidopa are peripheral dopa decarboxylase inhibitors which help to prevent the metabolism of Levodopa before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa. Existing preparations are carbidopa/levodopa (sinemet)®  Therapeutic: Levodopa is the drug of choice in treatment of parkinson , its useful in treatment of rigidity but less effective in tremor  Side effect: - Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias - Nausea vomiting …. So give the drug with meal - Postural hypotension - Cardiac arrhythmia 95 Unit (1) - Constipation - Lower prolactin level  Drug interactions: Not given with MAO inhibitor Not given with Halothane Figure 1: 17 96  Drugs acting on the central nervous system f Unit (2) F Antihistamine 18.  Unit (2) Antihistamine  97 Unit (1) 98  Drugs acting on the central nervous system Antihistamine Allergy:  Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment.  Allergic diseases are strongly familial (genetic)  A substance that causes a reaction is called an allergen..  Allergic reactions are distinctive because of excessive activation of certain white blood cells called mast cells and basophils by a type of antibody called Immunoglobulin E (IgE). This reaction results in an inflammatory response  Types of allergies: Mild allergies like hay fever are very common in the human population and cause symptoms such as red eyes ( conjunctivitis), itchiness, and runny nose, eczema, hives ( urticaria) , or an asthma attack. - In some people, severe allergies to environmental or dietary allergens or to medication may result in life- threatening reactions called anaphylaxis.  Causes of allergies (allergins) Food allergies,/ and reactions to the venom of stinging insects such as wasps and bees are often associated with these severe reactions/ medications, / pollens ,/ dust mite ,/ latex gloves,/ animal fur  Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhea, itchy skin, and swelling of the skin during hives. respiratory (asthmatic) reactions, or rhinitis Insect stings, antibiotics, and certain medicines produce a systemic allergic response that is also called anaphylaxis; multiple organ systems can be affected, 99 Unit (1) including the digestive system, the respiratory system, and the circulatory system. Depending on the rate of severity, it can cause cutaneous reactions, bronchoconstriction, edema, hypotension, coma, and even death. This type of reaction can be triggered suddenly, or the onset can be delayed. The severity of this type of allergic response often requires injections of epinephrine, Figure 2: 1 Histamine release  Pathophysiology : In the early stages of allergy, causes a response in a type of immune cell of B cells , whose role is production of antibodies known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage, are sensitized to the allergen. 100  Drugs acting on the central nervous system  If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Activated mast cells undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects Figure 2:2  Inflammatory response: such as vasodilatation, mucous secretion, nerve stimulation, and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis. 101 Unit (1)  Histamine Histamine is a small molecule derived from the decarboxylation of the amino acid histidine Figure 2:3 Antihistamine Histamine Receptors and Receptor Antagonists: Tow histamine rece