CNS Pharmacology PresentationBy Daniel-1.pptx

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1. PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM By: Daniel M 29 June 2021 1

2. Outline Sedative – hypnotic( anexiolytics )drugs Pharmacology of epilepsy Psychotropic and antiparkinson drugs Pharmacology of pain Classification of analgesics General & local anesthetics 29 June 2021 2 By Daniel M

3. Introduction CNS drugs are agents that act on brain and spinal cord . Most of the time they are widely used for medical and non medical purpose Medical application includes: Sedative – hypnotic & anxiolytics drugs Treatment of psychiatric disorders Suppression of seizure Relief of pain Production of anesthesia Non medicals include; Stimulant, Depressant, Euphoriant and other as a mind altering drugs 29 June 2021 3 By Daniel M

4. Sedatives-hypnotics And Anxiolytics A sedative drug- decreases activity, moderates excitement, relax and calms the recipient Insomnia : refers to difficulty of falling asleep or staying asleep or having non-refreshing sleep. Drugs used for induction and maintenance of sleep known as “ hypnotics ”. Anxiety: is an unpleasant state of tension, apprehension, or uneasiness a fear that seems to arise from a sometimes unknown source . Drugs used for anxiety called “antianxiety agents” or “anxiolytics” - 29 June 2021 4 By Daniel M

5. Classes of anxiolytic and hypnotic drugs Barbiturates ( e.g. phenobarbitone ). Benzodiazepines. 5- HT1A receptor agonist (e.g. buspirone ). β - blockers (e.g. propranolol ). Miscellaneous drugs (chloral hydrate, paraldehyde, and diphenhydramine). 29 June 2021 5 By Daniel M

6. BARBITURATES MoA Facilitate the actions of GABA At high concentrations , the barbiturates may also be GABA mimetic and inhibit excitatory neurotransmission Drugs Long acting: Phenobarbitone Short acting: butobarbitone and pentobarbitone Ultrashort : Thiopentone , methohexitone 29 June 2021 6 By Daniel M

7. Clinical indications Daytime sedation Hypnotic effects Preoperative sedation and anesthesia Relief of anxiety Anticonvulsant effects All of this properties usually resides on the same drugs. But the dosage differentiate 29 June 2021 BTs BDZs Euphoria -> sedation ->hypnosis -> general anesthesia -> coma -> death 7 By Daniel M

8. Barbiturates may interact with many other drugs: Are enzyme inducer Hydantoins , such as phenytoin , Monoamine oxidase inhibitors (MAOIs) reduce the metabolism of phenobarbital , resulting in increased toxic effects. Adverse effects Drowsiness, lethargy, headache, depression, mild bradycardia, hypotension, hypoventilation, severe respiratory depression, nausea and vomiting, epigastric pain, allergic reactions. Patients develop tolerance to barbiturates more quickly than to benzodiazepines 29 June 2021 Drug interactions 8 By Daniel M

9. Precautions During lactation Patients with a history of drug abuse or mental illness Patients with liver or kidney disease Treatment of poisoning Artificial respiration Purging the stomach of its contents if the drug has been recently taken Hemodialysis may be necessary if large quantities have been taken Alkalinization of the urine often aids in their elimination No specific barbiturate antagonist is available 29 June 2021 9 By Daniel M

10. BENZODIAZEPINES Drugs Hypnotic Diazepam , Flurazepam , Nitrazepam , Alprazolam, Temazepam , Triazolam Antianxiety Diazepam , Chlordiazepoxide , Oxazepm , Lorazepam , Alprazolam Anticonvulsant Diazepam , Lorazepam , Clonazepam, Clobzam 29 June 2021 10 By Daniel M

11. MOA Enhance the response to GABA and facilitate the opening of GABA activated chloride channel Benzodiazepines are unable to produce effect in the absence of GABA 29 June 2021 11 By Daniel M

12. Pharmacological use 29 June 2021 Reduction of anxiety and aggression Sedation and induction of sleep Anticonvulsant effect BZD are selective anticonvulsant against GABA mediated convulsion Treating alcohol withdrawal symptoms 12 By Daniel M

13. BDZ are safest alternative. Why BZDs are preferable to barbiturates ? 1.BZDs have high therapeutic index 2.Hypnotic doses do not affect respiration or CVS 3.Cause less distortion on sleep architecture 4.Do not affect disposition of other drugs 5.Have relatively low abuse liability 6.Presence of BZD antagonist ( flumazenil : GABA receptor blocker) as antidote 29 June 2021 13 By Daniel M

14. Side effects of BZDs Drowsiness, confusion, amnesia and impaired coordination Long lasting hangover effects Withdrawal syndromes Development of dependence Contraindications In patients with known hypersensitivity, psychoses , acute narrow-angle glaucoma, and shock Also in patients in a coma or with acute alcoholic intoxication P regnancy and lactation 29 June 2021 14 By Daniel M

15. Nonbenzodiazepines - nonbarbiturates ZOLPIDEM AND ZALEPLON Structurally unrelated to the benzodiazepines but bind to benzodiazepine receptors and facilitate GABA-mediated inhibition. BUSPIRONE Its clinically relevant effects are mediated through interactions at the serotonin 5-HT1A receptor, where it acts as a partial agonist. No rebound anxiety or withdrawal signs on abrupt discontinuance 29 June 2021 15 By Daniel M

16. ß-ADRENOCEPTOR BLOCKING AGENTS Can prevent the autonomic responses associated with anxiety. Eg . tremors, sweating, tachycardia, and palpitations. ANTIDEPRESSANTS Eg : Tricyclic antidepressants like amitriptiline and Selective serotonin reuptake inhibitors (SSRIs) like fluxetine U sed in the treatment of several anxiety disorders like general anxiety, obsessive- compulsive disorder, and several phobias 29 June 2021 16 By Daniel M

17. ANTICONVULSANTS Seizure Described as an abnormal disturbance ( hyperexcitability ) in the electrical activity in one or more areas of the brain Etiology Seizure disorders are generally categorized as idiopathic (no known cause) or acquired Acquired seizure disorders can be due to H igh fever, electrolyte imbalances, uremia, hypoglycemia, hypoxia, brain tumors, and some drug withdrawal reactions 29 June 2021 17 By Daniel M

18. Epilepsy Is a chronic, usually life-long disorder characterized by recurrent seizures and usually, episodes of unconsciousness and/or amnesia Causes Examples of the known causes of epilepsy include brain injury at birth, head injuries, and inborn errors of metabolism . In most instances, the cause of the seizure disorder is not known (idiopathic epilepsy) The particular symptoms produced depend on the function of the region of the brain that is affected 29 June 2021 18 By Daniel M

19. Seizure classification May be classified as partial (focal) or generalized. NB: Patients often exhibit more than one type Partial or focal seizures Arise from a localized area in the brain and cause specific symptoms . Often due to structural abnormalities such as scars, tumors or inflammation It can spread to the entire brain and cause a generalized seizure. 29 June 2021 19 By Daniel M

20. 2.Generalized seizures Involves the whole brain Generalized tonic clonic seizures/grand mal There is alternate contraction (tonic phase) and relaxation ( clonic phase) of whole body muscles Involves a loss of consciousness Myoclonic seizures involve sudden, forceful contractions involving the musculatu re of the trunk, neck, and extremities . Atonic seizures( akinetic epilepsy) Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges 29 June 2021 20 By Daniel M

21. Absence seizures/ petit mal Momentary loss of consciousness, patient freezes and stares in one direction Seizures typically last a few seconds , occur many times a day , and may go unnoticed by others . Status epilepticus A n emergency situation characterized by continual seizure activity with no interruptions M ay cause permanent brain damage or death 29 June 2021 21 By Daniel M

22. Anticonvulsants by Their Proposed Mechanism Type I Enhancing sodium channel inactivation Phenytoin , Carbamazepine , Oxcarbazepine , Lamotrigine , Felbamatea Type II Multiple actions: enhance GABAergic inhibition, reduce T-calcium currents, and possibly block sodium channels Valproic acid, Benzodiazepines, Phenobarbital, Primidone 29 June 2021 22 By Daniel M

23. Type III Block T-calcium currents only Ethosuximide , Trimethadione Type IV Only enhances GABAergic inhibition Vigabatrin Non-categorized Has no known effect on sodium channel, GABAergic inhibition, or T-calcium currents Gabapentin 29 June 2021 23 By Daniel M

24. Principles of anticonvulsant therapy Increase dose of suitable agent until desired effect is achieved or until toxicity prevents further increase Follow serum drug levels A second drug may be added if maximal doses of the initial drug fail. The initial drug should then be tapered and discontinued Abrupt discontinuance of an anticonvulsant may induce status epilepticus . ( Always taper doses ) 29 June 2021 24 By Daniel M

25. Inform female patients of association with birth defects Anticonvulsants are additive with other CNS depressants Phenobarbital is considered safest during pregnancy Therapeutic goal in epilepsy treatment is complete seizure control without excessive side effects Overall, only about 40 to 60% of patients become totally seizure free with available drugs 29 June 2021 25 By Daniel M

26. PHENOBARBITAL MOA Enhances GABA mediated chloride influx Pharmacokinetics Slow onset (>30 min) Very long half life (>50 hrs) Metabolized by P450 enzymes in liver Indications Generalized seizures in pediatric patients Less often in adults 29 June 2021 26 By Daniel M

27. Adverse effects CNS depression, drowsiness, nausea, vomiting, constipation, bradycardia, hypoventilation, skin rash, headache, fever, and diarrhea. Some of these adverse effects may be reduced or eliminated as therapy continues or with slight dose reduction Drug interactions Stimulates P450 enzymes, additive with CNS depressants 29 June 2021 27 By Daniel M

28. DIAZEPAM AND LORAZEPAM Enhances GABA mediated chloride influx Pharmacokinetics Rapid onset(<5minutes) Metabolized in liver Has longer half life Indication Status epilepticus ( not for chronic seizure ) Drug interactions Additive with CNS depressants 29 June 2021 28 By Daniel M

29. PHENYTOIN MOA Blocks sodium channels Pharmacokinetics Oral absorption is slow but usually complete is highly bound (about 90% ) to plasma proteins Slow onset, long half life, metabolized in liver Has zero-order (or saturation) kinetics in its metabolism …..????? Indications All types of seizure except absence seizures 29 June 2021 29 By Daniel M

30. Adverse effects- mostly result from overdose Nystagmus (involuntary eye mov’t ), ataxia, other CNS depressants, bone marrow suppression, gingival hyperplasia , hepatotoxicity, GI disturnances , hirsutism IV administration may cause CNS depression, severe hypotension, arrhythmias, and hyperkinesis Teratogenic Drug interactions Many drugs alter metabolism and protein binding of phenytoin and vice versa 29 June 2021 30 By Daniel M

31. Carbamazepine Blocks sodium channels Pharmacokinetics PO Induces its auto inducer by stimulating P450 enzyme in liver Indications All types of seizure except absence seizures Trigeminal neuralgia , manic depression , schizophrenia unresponsive to antipsychotics 29 June 2021 31 By Daniel M

32. Adverse effects Drowsiness, agranulocytosis or aplastic anemia ( monitor blood counts), vertigo, diplopia, nausea, vomiting Teratogenic Drug interactions Do not administer to patients with MAOIs (potentiation may be lethal ) C ontraindicated in patients with bone marrow depression or hepatic or renal impairment and during pregnancy 29 June 2021 32 By Daniel M

33. Valproic acid MOA Also inhibition of GABA transaminase Blockade of T-type calcium channel Pharmacokinetics PO/IV W ell absorbed from the gastrointestinal tract and is highly bound (~90%) to plasma protein Metabolized in liver Inhibit P450 enzymes 29 June 2021 33 By Daniel M

34. Indications All seizure types particularly disorders of combined seizure types Manic episodes in bipolar disorders M igraines Adverse effects Severe/fatal hepatotoxicity ( due to toxic metabolites ), particlularly in small children Thrombocytopenia, hyperammonemia , alopecia Teratogenicity 29 June 2021 34 By Daniel M

35. Ethosuxemide MOA Blocks T-calcium channels in thalamic neurons Pharmacokinetics PO Metabolized in liver, not protein bound Indications Only absence seizures Adverse effects Headache, nausea, dizziness, vomiting, fatigue, ataxia, blurred vision, confusion, rashes, hepatotoxicity, blood dyscrasias , lupus like syndrome 29 June 2021 35 By Daniel M

36. Treatment of febrile seizures Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug; diazepam is also effective. 29 June 2021 36 By Daniel M

37. Table 7. Drugs for specific types of seizures Seizure Type Drugs used for treatment Effective and well tolerated Effective but less tolerated Newer Alternatives Partial Seizures Simple Partial Complex partial Carbamazepine Phenytoin Valproic acid Clorazepate Phenobarbitone Primidone Gabapentin Lamotrigine Topiramate Tiagabine Same as simple partial Same as simple partial Same as simple partial Generalized seizures Tonic-clonic (grand mal) Carbamazepine Phenytoin Valproic acid Phenobarbitone Primidone Lamotrigine Topiramate Absence (petit mal) Ethosuximide Valproic acid Clonazepam Lamotrigine Myoclonic Valproic acid Clonazepam - Lamotrigine Topiramate 29 June 2021 37 By Daniel M

38. DRUGS FOR PARKINSON DISEASE Disorder of muscle movement , characterized by: T remors , muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural abnormalities It is correlated with destruction of dopaminergic neurons in the substantia nigra result in decreased dopamine activity in the basal ganglia Imbalance between the excitatory cholinergic neurons and inhibitory dopaminergic neurons Therapy is aimed at restoring dopamine in the basal ganglia and antagonizing effect of cholinergic neurons 29 June 2021 38 By Daniel M

39. MOA It is actively transported into the CNS and is converted to dopamine in the brain Pharmacokinetics A bsorbed rapidly from the small intestine (when empty of food) Peripherally metabolism of levodopa result side effects that include nausea, vomiting, and cardiac arrhythmias and fluctuations in motor response. In addition to that large dose of levodopa is required But combining with carbidopa inhibit peripheral metabolism 29 June 2021 Levodopa and carbidopa Levodopa 39 By Daniel M

40. Carbidopa MOA Enhances the effects of levodopa on the CNS when coadministered by inhibiting a dopa decarboxylase in the peripheral tissues and GIT D oes not cross the blood-brain barrier 29 June 2021 40 By Daniel M

41. Catechol-O- methyltransferase (COMT) inhibitors 29 June 2021 Drugs:- Entacapone or tolcapone Selectively and reversibly inhibit COMT and lead to decreased plasma concentrations of 3-O-methyldopa which competes with levodopa for active transport into the CNS Tolcapone has longer duration and is only the COMT inhibitor cross BBB , but it is hepatotoxic 41 By Daniel M

42. Adverse effects Peripheral effects: Anorexia, nausea, and vomiting occur because of stimulation of the CTZ of the medulla. Hypotension , tachycardia and hypertension depending on dose Mydriasis Saliva and urine are a brownish color because of the melanin pigment produced from catecholamine oxidation . CNS effects Visual and auditory hallucinations Abnormal involuntary movements ( dyskinesias ) may occur. Mood changes, depression, psychosis, and anxiety. 29 June 2021 42 By Daniel M

43. Vit B6 increases the peripheral breakdown of levodopa Concomitant administration of levodopa and monoamine oxidase (MAO) inhibitors, can produce a hypertensive crisis caused by enhanced catecholamine production 29 June 2021 Drug interactions 43 By Daniel M

44. MOA At low to moderate doses , it selectively inhibits MAO Type B which metabolizes dopamine (increase level in the brain) Has little potential for causing hypertensive crises At higher dose , it inhibit MAO Type A ( which metabolizes norepinephrine and serotonin ) Risk for severe hypertension Selegiline is metabolized to methamphetamine and amphetamine , whose stimulating properties may produce insomnia if the drug is administered later than mid afternoon. 29 June 2021 Monoamine oxidase inhibitors Selegiline 44 By Daniel M

45. Rasagiline An irreversible and selective inhibitor of brain (MAO) Type B, has five times the potency of selegiline Unlike selegiline , it is not metabolized to an amphetamine It enhances the actions of levodopa when administered together. 29 June 2021 45 By Daniel M

46. Dopamine-receptor agonists Ergot derivative :- Bromocriptine Nonergot drugs:- ropinirole , pramipexole and rotigotine . Durations of action longer than that of levodopa Effective in patients with advanced Parkinson's disease Side effects Bromocriptine Confusion , delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent. In psychiatric illness , bromocriptine and levodopa may cause the mental condition to worsen . In patients with peripheral vascular disease , a worsening of the vasospasm occurs 29 June 2021 46 By Daniel M

47. I s effective in the treatment of influenza Also has an antiparkinsonism action MOA I ncreases the release of dopamine , blocking cholinergic receptors, and inhibiting the N-methyl-D-aspartate (NMDA) type of glutamate receptors If dopamine release is already at a maximum , amantadine has no effect Amantadine is less efficacious than levodopa, and tolerance develops more readily. 29 June 2021 Others : Amantadine 47 By Daniel M

48. Antimuscarinic agents B enztropine , T rihexyphenidyl , Procyclidine , and B iperiden Are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. All of these drugs can induce mood changes and produce xerostomia (dryness of the mouth) and visual problems 29 June 2021 48 By Daniel M

49. ANTIPSYCHOTIC AGENTS Antipsychotics/neuroleptic drugs/major tranquilizers - are a group of drugs used mainly for treating schizophrenia . Schizophrenia: is a chronic psychotic illness Psychotic illness is characterized by delusion, hallucinations, thought disorder, social withdrawal, etc Etiology The cause remains unclear Probably reflects a dysfunction of the mesolimbic or mesocortical dopaminergic neurons. 29 June 2021 49 By Daniel M

50. Schizophrenia The main clinical features are: Positive symptoms ; mostly do to hyperactivity of dopamine receptor like Delusions : fixed false beliefs Hallucinations , usually in the form of voices Abnormal behaviors, such as aggressive behaviors. Negative symptoms : W ithdrawal from social contacts F lattening of emotional responses. The goals of treatment Are to reduce symptoms, decrease psychotic relapses, and improve patient functioning and social outcomes. 29 June 2021 50 By Daniel M

51. Antipsychotic agents are classified into:- Traditional/typical neuroleptics /first generation /conventional Chlorpromazine, thioridazine , haloperidol Antipsychotic effects is due to competitive blockage of dopamine receptors No one drug is clinically more effective than another Atypical neurolopitics /second generation C lozapine , R isperidone Produce activity to blockade of both serotonin and dopamine (and, perhaps, other ) receptors Have fewer extrapyramidal adverse effects than the older 29 June 2021 51 By Daniel M

52. Mechanism of action All of the older and most of the newer neuroleptic drugs block dopamine receptors Most of the newer atypical agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT) However, many of antipsychotic agents also block cholinergic , adrenergic , and histaminergic receptors Negative symptoms are responsive to many atypical agents to some extent but, not responsive to typical ones. All of the neuroleptics can reduce positive symptoms 29 June 2021 52 By Daniel M

53. Therapeutic Uses of antipsychotics Treatment of schizophrenia Prevention of severe nausea and vomiting Older neuroleptics (most commonly prochlorperazine For treatment of chronic pain with severe anxiety Neuroleptics are used in combination with narcotic analgesics Chlorpromazine is used to treat intractable hiccups The antipsychotic effects usually take several days to weeks to occur Their therapeutic index is high 29 June 2021 53 By Daniel M

54. Extrapyramidal side effects occur with chronic treatment dystonias (sustained contraction of muscles leading to twisting distorted postures) akathisia (motor restlessness), and tardive dyskinesia (involuntary movements of the tongue, lips, neck, trunk, and limbs) The atypical neuroleptics exhibit a lower incidence of these symptoms. 29 June 2021 54 By Daniel M

55. Neuroleptics can also aggravate preexisting epilepsy , and they should be used with caution in patients with epilepsy chlorpromazine and clozapine are contraindicated in patients with seizure disorders High incidence of agranulocytosis with clozapine may limit its use to patients who are resistant to other drugs. Weight gain commonly occurs with atypical neuroleptics 29 June 2021 55 By Daniel M

56. Antipsychotic Drugs: Relative Potency and Incidence of Side Effects Incidence of Side Effects Drug Equivalent oral dose (mg) Extrapyramidal effects Sedation Orthostatic hypotension Anticholinergic effects Conventional agents Low potency Chlorpromazine Thioridazine Moderate potency Triflupromazine Perphenazine Loxapine High potency Haloperidol Fluphenazine 100 100 25 10 10 2 2 Moderate Low Moderate Moderate Moderate High High High High High Moderate Moderate Low Low High High Moderate Low Low Low Low Moderate High Moderate Low Low Low Low Atypical Agents Clozapine Risperidone 50 4 Very low Very low High Low Moderate Low High None 29 June 2021 56 By Daniel M

57. Pharmacology of drugs used to treat pain Introduction Pain : is an unpleasant sensory and emotional experience that is associated with actual or potential tissue damage. Neurotransmitters involved in pain pathways include acetylcholine, histamine, polypeptides such as bradykinin, prostaglandin(PG) , and substance P Classification of pain Acute pain: short duration and lasts less than 3 to 6 months. E.g. postoperative pain and traumatic pain. Chronic pain:- lasts longer than 6 months e.g. AIDS pain 29 June 2021 57 By Daniel M

58. ANALGESIC DRUG: Can be broadly classified as Non narcotic analgesics The narcotic analgesics NON NARCOTIC ANALGESICS Can be divided into the salicylates , nonsalicylates (acetaminophen), and the nonsteroidal anti-inflammatory drugs ( NSAIDs ) They do not cause physical dependency 29 June 2021 58 By Daniel M

59. Aspirin (acetylsalicylic acid), magnesium salicylate, sodium salicylate etc Have analgesic (relieves pain);, antipyretic and anti-inflammatory effects MOA Irreversible inhibition of COX enzyme, which use for the synthesis of prostaglandin PGs increase the sensitivity of peripheral pain receptors Maximum dose is 8g/d 29 June 2021 SALICYLATES 59 By Daniel M

60. Therapeutic use For mild to moderate pain :- prostaglandin is a chemical mediator that sensitizes nerve cells to pain To reduce elevated body temperature by stimulating the hypothalamus, producing dilation of the peripheral blood vessels and increased sweating ; because prostaglandin E increases body temperature, To treat inflammatory disorders by inhibiting the PG synthesis and release To reduce cardiovascular risk(only aspirin) by blood flow during MI and to prevent recurrence of MI, stroke , & also in patients undergoing certain revascularization procedures. . 29 June 2021 60 By Daniel M

61. 29 June 2021 Adverse effects Gastric upset , heartburn, nausea, vomiting, anorexia, and gastrointestinal bleeding Allergic reactions like Rash, angioedema, bronchospasm, and anaphylactic reactions. Salicylate produces salicylism ( tinnitis , dizziness, fever, headache, hyperventilation). Mild salicylism is reversible with reduction of the dosage Dose-dependent effects of salicylate. 61 By Daniel M

62. Contraindications Known hypersensitivity to the salicylates or the NSAIDs During pregnancy particularly third trimester Breast-feeding In those with bleeding disorders or bleeding tendencies;- prolong bleeding time Children or teenagers with influenza or chickenpox should not take the salicylates , particularly aspirin If taken by such patients, they cause Reye’s syndrome (a life threatening condition characterized by vomiting and lethargy , fulminating hepatitis with cerebral edema . progressing to coma ) Postpartum hemorrhage Anemia Labor duration 29 June 2021 62 By Daniel M

63. ACETAMINOPHEN The major drug classified as a nonsalicylate is acetaminophen Has analgesic and antipyretic activity but no anti inflammatory action MOA Work by inhibiting prostaglandin synthesis in CNS and in the peripheral nervous system in some unknown way. It reduces fever by acting directly on the heat-regulating center in the hypothalamus. 29 June 2021 63 By Daniel M

64. Adverse effects Occur with chronic use or when the recommended dosage is exceeded (>4,000 mg/day) Include skin eruptions, hemolytic anemia, hypoglycemia, jaundice (yellow discoloration of the skin), and hepatic failure (seen when chronic alcohol, phenytoin, barbiturates, carbamazepine, and isoniazid are combined with acetaminophen ) Death can occur due to liver failure Contraindications Hypersensitivity to acetaminophen Used cautiously during pregnancy and lactation 29 June 2021 64 By Daniel M

65. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) The chemical and physiologic effects are similar to salicylates Have analgesic, antipyretic , and anti-inflammatory effects Thought to act by inhibiting prostaglandin synthesis by inhibiting the action of the enzyme cyclooxygenase COX-1- the enzyme that helps to maintain the stomach lining; and COX-2 - the enzyme that triggers pain and inflammation. 29 June 2021 65 By Daniel M

66. There are two types of NSAIDs: The nonselective NSAIDs Eg diclofenac, ibuprofen, indomethacin, naproxen, piroxicam, and . Selective NSAIDs- eg celecoxib Therapeutic uses NSAIDs have a variety of uses Generally, they can be used for Relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and other musculoskeletal disorders Mild to moderate pain relief Fever reduction 29 June 2021 66 By Daniel M

67. Adverse effects Vomiting, diarrhea, constipation, epigastric pain, intestinal ulceration, stomatitis etc Dizziness, anxiety, lightheadedness, vertigo, headache etc Congestive heart failure, BP change, hematuria Visual disturbances Aplastic anemia etc Rash, erythema etc Contraindications Hypersensitivity to aspirin NSAIDs. During the third trimester of pregnancy and lactation . 29 June 2021 67 By Daniel M

68. NARCOTIC ANALGESICS Obtained from the juice of the opium poppy Are controlled substances used to treat severe or chronic malignant pain Produce effects that mimic the action of endogenous peptide neurotransmitters enkephalins, endorphins, and dynorphins. Opoid receptors Mu:- Activation includes analgesia, respiratory depression, euphoria ,miosis and constipation. Kappa :- activation produces analgesia, sedation, and dysphoria ( a state of disatisfaction ). Delta :- Are responsible for producing spinal/supraspinal analgesia 29 June 2021 68 By Daniel M

69. Pure opioid agonists: E.G. Morphine, pethidine, codeine, methadone, dextropropoxyphene Agonist-antagonists opioids —e.g. Pentazocine, nalbuphine, butorphanol, and buprenorphine) In individuals who have not recently received opioids show agonist activity and are used to relieve pain. In the patient with opioid dependence, they may produce withdrawal symptoms. Pure opioid antagonists —naloxone, naltrexone. Antagonize mu and kappa receptors and are used for reversal of respiratory and CNS depression. 29 June 2021 Classification of drugs that act at opioid receptors 69 By Daniel M

70. Major use of the narcotic analgesic is to relieve or manage moderate to severe acute and chronic pain As an adjunct during anesthesia To lessen anxiety and sedate the patient before surgery Management of opiate dependence ( levomethadyl and methadone) Treatment of severe diarrhea and intestinal cramping decreases the motility & can cause constipation Relief of severe, persistent cough (codeine, although the drug’s use has declined) : suppresses the cough reflex 29 June 2021 Therapeutic uses 70 By Daniel M

71. Morphine: Produces analgesia, sedation, euphoria, respiratory depression, cough suppression, and decreased bowel motility. Mechanism of analgesic action Mimics endogenous opioid peptides (mu and kappa receptors). Undergoes first-pass metabolism in the liver Therapeutic use Relief of pain (moderate to severe) preoperatively for sedation and anti-anxiety 29 June 2021 71 By Daniel M

72. Adverse effects Respiratory depression, constipation, orthostatic hypotension, urinary retention, cough suppression, emesis, increased intracranial pressure (ICP), sedation, euphoria/ dysphoria , and miosis Abuse liability Toxicity :- Coma, respiratory depression and pinpoint pupils—provide support and give antagonist (IV naloxone). Tolerance Occur in CNS actions and respiratory depression , but minimally in terms of miosis and the effects on GI motility. Cross-tolerance occurs b/n individual opioid analgesics. 29 June 2021 72 By Daniel M

73. Opioid antagonists Naloxone and naltrexone Competitively block the effects of opoid receptors Naloxone (IM, SC or IV) the drug of choice for managing an opoid overdose Naltrexone is administered orally Opioid dependence Tolerance and physical dependence occur rapidly for opioids even in 3 days Withdrawal from chronic use Increased respiration, perspiration, mydriasis etc Managed by opoids like levomethadyl and methadone 29 June 2021 73 By Daniel M

74. Anesthesia 29 June 2021 74 By Daniel M

75. ANESTHETICS Anesthesia is a loss of feeling or sensation The anesthetics can be divided into three groups general anesthetics, local anesthetics, and topical anesthetics. I. General anesthetics produce unconsciousness and lack of responsiveness to painful stimuli MOA- general anesthetics enhance the effects of GABA No single agent is perfect. Hence a combination is used. 29 June 2021 75 By Daniel M

76. General anesthetics can be classified as: inhalational anesthetics and Intravenous anesthetics Inhalational anesthetics Most often used for long term maintenance of the anesthetic state They have brief and pleasant induction, minimal adverse effects, large margin of safety Are also reversible, because most are rapidly eliminated from the body by exhalation. Gases : such as nitrous oxide, cyclopropane , or ethylene) Volatile liquids : such as halothane , enflurane, isoflurane, desflurane, and sevoflurane 29 June 2021 76 By Daniel M

77. Adverse effects: as a group Respiratory and cardiac depression Sensitization of heart to catecholamine eg Halothane Aspiration of gastric contents Hepatotoxicity ( especially with halothane) and renal toxicity with methoxyflurane Toxicity to operating room personnel 29 June 2021 77 By Daniel M

78. Intravenous anesthetics Are typically used when the patient requires general anesthesia for just a short period such as during outpatient surgery also used to promote rapid induction of anesthesia or to supplement inhalation anesthetics These include: Short acting barbiturates E.g. Sodium salt of thiopental, methohexital Benzodiazepines :- e.g. diazepam, midazolam Propofol : - sedative-hypnotic, induction of anesthesia, antiemetic Others – ketamine,, etomidate, opioids ( e.g. fentanyl) 29 June 2021 78 By Daniel M

79. II . Local anesthetics Produce regional anesthesia/block pain conduction by nerves without generalized depression of the CNS MOA :- Block sodium channel in axonal membranes Coadministration of alpha adrenoceptor agonists will decrease absorption into the systemic circulation, prolonging effects and possibly decreasing toxicity Duration of action: Short acting : Procaine, chloroprocaine Intermediate acting : lidocaine, mepivicaine , prilocaine Long acting : Tetracaine, bupivacaine, etidocaine, ropivacaine, levobupivacaine 29 June 2021 79 By Daniel M

80. Given IM or SC Take care to avoid IV injection Therapeutic use used to prevent and relieve pain from medical procedures, disease, or injury May also be used for severe pain that topical anesthetics or analgesics can’t relieve Adverse effects CNS depression, cardiovascular depression, allergic reaction ( more commonly with ester types), depressed uterine contractility 29 June 2021 80 By Daniel M

81. E.g.: lidocaine and tetracaine Applied directly to intact skin or mucous membranes All topical anesthetics are used to prevent or relieve minor pain . Therapeutic use Relieve or prevent pain, especially minor burn pain , before an injection is given , numb mucosal surfaces before a tube, such as a urinary catheter, is inserted, alleviate sore throat or mouth pain when used in a spray or solution Adverse effects These drugs may cause topical skin reactions e.g. irritation III. Topical anesthetics 29 June 2021 81 By Daniel M

82. Thank you ! Questions or comments? 29 June 2021 82 By Daniel M