PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM B.pptx

PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM

1. PHARMACOLOGY OF THE CENTRAL NERVOUS SYSTEM

2. Outline Sedative – hypnotic( anexiolytics ) drugs Pharmacotherapy of epilepsy Psychotropic and antiparkinson drugs Pharmacotherapy of pain C lassification of analgesics Treatment of pain with narcotic and non-narcotic Pharmacotherapy of rheumatic arthritis Treatment of acute & chronic gout General & local anesthetics

3. Neurotransmitter Postsynaptic effect Acetylcholine involved in arousal, short term memory, learning and movement Norepinephrine involved in arousal, wakefulness, mood and cardiovascular regulation Dopamine Involved in emotion, reward systems, motor control, hormone release and stimulate CTZ Serotonin Feeding behavior, control of body temperature, modulation of sensory pathways including nociception (pain sensation), regulation of mood and emotion, and sleep/wakefulness, control vomiting

4. Neurotransmitter Postsynaptic effect GABA Increases Cl - influx into the postsynaptic neuron, resulting in hyperpolarization, mediates the majority of inhibitory postsynaptic potentials Glycine Increases Cl - influx into the postsynaptic neuron, resulting in hyperpolarization Glutamate mediates excitatory Na+ influx in to the postsynaptic neuron Substance p mediates nociception (pain) within the spinal cord Met- enkephalin mediates analgesia as well as other central nervous systemic effects 4

5. Sedatives-hypnotics And Anxiolytics Introduction Anxiety: is an unpleasant state of tension, apprehension, or uneasiness a fear that seems to arise from a sometimes unknown source. Insomnia : refers to difficulty of falling asleep or staying asleep or having non-refreshing sleep. -A sedative drug- decreases activity, moderates excitement, relax and calms the recipient -Drugs used for induction and maintenance of sleep known as “hypnotics”. -Drugs used for anxiety called “antianxiety agents” or “anxiolytics” The same drugs are used for both purposes. 5

6. Classes of anxiolytic and hypnotic drugs: Benzodiazepines. 5- HT1A receptor agonist (e.g. buspirone ). Barbiturates ( phenobarbitone ). β - adrenoceptor antagonists (e.g. propranolol ). Miscellaneous drugs (chloral hydrate, paraldehyde, and diphenhydramine ).

7. 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 Mainly used in anesthesia & treatment of epilepsy Low doses Depress the sensory and motor cortex in the brain, causing drowsiness.

8. High doses May cause respiratory depression and death because of their ability to depress all levels of the CNS Clinical indications Daytime sedation (for short periods only) Hypnotic effects for patients with insomnia Preoperative sedation and anesthesia Relief of anxiety Anticonvulsant effects Patients develop tolerance to barbiturates more quickly than to benzodiazepines

9. Drug interactions 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, Vertigo, nausea and vomiting, diarrhea, epigastric pain, allergic reactions. Withdrawal reaction may be severe enough to cause death 9

10. 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

11. BENZODIAZEPINES 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 Drugs Hypnotics Diazepam,Flurazepam,Nitrazepam , Alprazolam,Temazepam,Triazolam Antianxiety Diazepam,Chlordiazepoxide , Oxazepm , Lorazepam , Alprazolam Anticonvulsant Diazepam,Lorazepam,Clonazepam,Clobzam

12. All benzodiazepines are metabolized in the liver and excreted primarily in urine Pharmacological use Reduction of anxiety and aggression Sedation and induction of sleep Reduction of muscle tone and coordination Anticonvulsant effect -BZD are selective anticonvulsant against GABAA mediated convulsion Treating alcohol withdrawal symptoms

13. … 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

14. Side effects of BZDs •Drowsiness, confusion, amnesia and impaired coordination •Long lasting hangover effects •Withdrawal syndromes •Development of dependence ☼Sedative / hypnotics should not be used for longer duration Contraindications In patients with known hypersensitivity, psychoses, acute narrow-angle glaucoma, and shock Also in patients in a coma or with acute alcoholic intoxication pregnancy and lactation

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

16. 16 ETHANOL CNS depressant, producing anxiolytic, sedative and hypnotic effects. But its toxic potential outweighs its benefits Treating alcohol withdrawal Treatment of choice for alcohol withdrawal are the benzodiazepines. Carbamazepine is effective in treating convulsive episodes during withdrawal. Drugs used in alcoholic people to stop drinking Disulfiram:- inhibit aldehyde dehydrogenase –leads to accumulation of acetaldehyde in the blood results flushing, tachycardia, hyperventilation, and nausea Drugs causes disulfiram like reactions metronidazole , griseofulvin

17. ß-ADRENOCEPTOR BLOCKING AGENTS can prevent the autonomic responses associated with anxiety. Eg . tremors, sweating, tachycardia, and palpitations. ANTIDEPRESSANTS Eg : Tricyclic antidepressants and Selective serotonin reuptake inhibitors (SSRIs) used in the treatment of several anxiety disorders like general anxiety, obsessive- compulsive disorder, and several phobias 17

18. 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 high fever, electrolyte imbalances, uremia, hypoglycemia, hypoxia, brain tumors, and some drug withdrawal reactions 18

19. 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 19

20. 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. 20

21. Generalized seizures 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 musculature of the trunk, neck, and extremities. Atonic seizures( akinetic epilepsy) •Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges 21

22. 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 an emergency situation characterized by continual seizure activity with no interruptions may cause permanent brain damage or death 22

23. Categorization of 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 23

24. 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 24

25. 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) 25

26. 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 26

27. 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 27

28. 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 28

29. DIAZEPAM AND LORAZEPAM MOA 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

30. 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 30

31. Adverse effects 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 31

32. Carbamazepine MOA Blocks sodium channels Pharmacokinetics PO Induces its own metabolism by stimulating P450 enzyme in liver Indications All types of seizure except absence seizures Trigeminal neuralgia, manic depression, schizophrenia unresponsive to antipsychotics 32

33. 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) 33

34. Valproic acid MOA Also inhibition of GABA transaminase Blockade of T-type calcium channel Pharmacokinetics PO/IV well absorbed from the gastrointestinal tract and is highly bound (~90%) to plasma protein Metabolized in liver Inhibit P450 enzymes 34

35. Indications All seizure types particularly disorders of combined seizure types Manic episodes in bipolar disorders migraines Adverse effects Severe/fatal hepatotoxicity ( due to toxic metabolites), particlularly in small children Thrombocytopenia, hyperammonemia , alopecia Teratogenicity 35

36. 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 36

37. 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. 37

38. 38 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

39. DRUGS FOR PARKINSON DISEASE Parkinson disease:- disorder of muscle movement, characterized by: tremors, 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 All anti Parkinson's drugs produce psychotic symptoms 39

40. Levodopa and carbidopa Levodopa MOA It is actively transported into the CNS and is converted to dopamine in the brain Pharmacokinetics absorbed 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 40

41. 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. 41

42. Drug interactions 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 Carbidopa MOA Enhances the effects of levodopa on the CNS when coadministered by inhibiting a dopa decarboxylase in the peripheral tissues and GIT does not cross the blood-brain barrier 42

43. Monoamine oxidase inhibitors Selegiline 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. 43

44. 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 Catechol -O- methyltransferase (COMT) inhibitors 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 Adverse effects :- diarrhea, postural hypotension, nausea, anorexia, hallucinations, and sleep disorders. 44

45. 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 45

46. Others Amantadine is effective in the treatment of influenza Also has an antiparkinsonism action MOA increases the release of dopamine, blockading cholinergic receptors, and inhibiting the N-methyl-D- aspartate (NMDA) type of glutamate receptors Action at NMDA receptors as the primary action at therapeutic concentrations If dopamine release is already at a maximum, amantadine has no effect 46

47. The drug may cause restlessness, agitation, confusion, and hallucinations, and at high doses, it may induce acute toxic psychosis Orthostatic hypotension, urinary retention, peripheral edema, and dry mouth also may occur. Amantadine is less efficacious than levodopa , and tolerance develops more readily. Antimuscarinic agents benztropine , trihexyphenidyl , procyclidine , and biperiden 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 47

48. ANTIPSYCHOTIC AGENTS Antipsychotics/ neuroleptic drugs/major tranquilizers - are a group of drugs used mainly for treating schizophrenia. Psychotic illness is characterized by delusion, hallucinations, thought disorder, social withdrawal, etc Schizophrenia: is a chronic psychotic illness Etiology The cause remains unclear Probably reflects a dysfunction of the mesolimbic or mesocortical dopaminergic neurons. 48

49. Schizophrenia The main clinical features Positive symptoms Delusions Hallucinations, usually in the form of voices Abnormal behaviors, such as aggressive behaviors. Negative symptoms: withdrawal from social contacts flattening of emotional responses. The goals of treatment are to reduce symptoms, decrease psychotic relapses, and improve patient functioning and social outcomes. 49

50. 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 clozapine , risperidone Produce activity to blockade of both serotonin and dopamine (and, perhaps, other) receptors Have fewer extrapyramidal adverse effects than the older 50

51. 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 Side effects of these agents, are often a result of actions at these other receptors. All of the neuroleptics can reduce positive symptoms Negative symptoms are responsive to many atypical agents to some extent but, not responsive to typical ones. 51

52. 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 52

53. 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. 53

54. 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 54

55. 55 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

56. 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 Pain stimuli are detected by physiological receptors (nociceptors) Neurotransmitters involved in pain pathways include acetylcholine, histamine, polypeptides such as bradykinin , prostaglandin(PG) , and substance P. Acute pain: short duration and lasts less than 3 to 6 months. Eg postoperative pain and traumatic pain. Chronic pain:- lasts longer than 6 months eg . AIDS pain 56

57. ANALGESIC DRUG: Can be broadly classified as Non narcotic analgesics The narcotic analgesics NON NARCOTIC ANALGESICS Unlike narcotic analgesics, do not cause physical dependency Can be divided into the salicylates , nonsalicylates (acetaminophen), and the nonsteroidal anti-inflammatory drugs (NSAIDs) 57

58. SALICYLATES aspirin (acetylsalicylic acid), magnesium salicylate , sodium salicylate etc Have analgesic (relieves pain), antipyretic (reduces elevated body temperature), and anti-inflammatory effects MOA Irreversible inhibition of cyclooxygenase enzyme, which use for the synthesis of prostaglandin PGs increase the sensitivity of peripheral pain receptors Aspirin can be given orally and rectally Maximum dose is 8g/d 58

59. Therapeutic use For mild to moderate pain To reduce elevated body temperature To treat inflammatory disorders To reduce cardiovascular risk(only aspirin) 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 drug dosage . 59

60. Contraindications Known hypersensitivity to the salicylates or the NSAIDs During pregnancy particularly third trimester Breast-feeding In those with bleeding disorders or bleeding tendencies 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, progressing to coma) 60

61. ACETAMINOPHEN The major drug classified as a nonsalicylate is acetaminophen Has analgesic and antipyretic activity but no anti inflammatory action MOA Reducing pain- 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. 61

62. 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), hepatotoxicity and hepatic failure (seen in chronic alcohol) Death can occur due to liver failure Contraindications Hypersensitivity to acetaminophen Used cautiously during pregnancy and lactation 62

63. 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 cyclooxygenase-1 (COX-1) - the enzyme that helps to maintain the stomach lining; and cyclooxygenase-2 (COX-2) - the enzyme that triggers pain and inflammation. 63

64. There are two types of NSAIDs: The nonselective NSAIDs Eg diclofenac , ibuprofen, indomethacin , naproxen, piroxicam , and sulindac . 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 64

65. 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. 65

66. NARCOTIC ANALGESICS Opoid is any drug, natural or synthetic, with actions like morphine Are controlled substances used to treat moderate to severe pain. Enkephalins , endorphins, and dynorphins endogenous opoids . Opoid receptors Mu Activation includes analgesia, respiratory depression, euphoria , miosis and constipation. Kappa activation produces analgesia, sedation, and dysphoria ( a state of disatisfaction ). 66

67. Delta are responsible for producing spinal/ supraspinal analgesia Classification of Drugs That Act at Opioid Receptors Pure opioid agonists Eg codeine, methadone, dextropropoxyphene Agonist-antagonists opioids —eg . pentazocine , nalbuphine , butorphanol , and buprenorphine ) when administered alone, produce analgesia, but given to a person taking opioids , produce an antagonistic effect. Pure opioid antagonists — Naloxone , naltrexone . Antagonize mu and kappa receptors and are used for reversal of respiratory and CNS depression. 67

68. Therapeutic uses 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 Relief of severe, persistent cough (codeine, although the drug’s use has declined) 68

69. 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 69

70. 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. 70

71. 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 71

72. Rheumatoid Arthritis Is the most common chronic systemic inflammatory disease characterized by involvement of joints. Chronic inflammation of the synovial tissue lining the joint capsule results in the proliferation of this tissue which invades the cartilage and eventually the bone surface Erosion of bone and cartilage  destruction of the joint. 72

73. Drug therapy of RA There is no curative agent available for RA NSAID Alleviate the pain and inflammation of RA Do not halt the loss of bone associated with RA Are first line agents Disease modifying antirheumatic drugs (DMARD) Slow the progression of joint erosion usually employed in combination with NSAIDs and sometimes other DMARDs Methotrexate , Chlorambucil , Cyclophosphamide , Adalimumab 73

74. Methotrexate inhibits dihydrofolate reductase and other folate -dependent enzymes in cells Also used as an anticancer, psoriatic arthritis, systemic lupus erythematosus and as immunosuppressive Commonly cause mucosal ulceration and nausea. Chlorambucil and Cyclophosphamide cross-links DNA to prevent cell replication. Adalimumab is a recombinant human anti-TNF monoclonal antibody, because TNF-  plays central role in RA inflammatory process indicated for treatment of moderate to severe RA Others - Hydroxychloroquine , D- Penicillamine 74

75. Gout Metabolic disorder characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage. Usually associated with high serum levels of uric acid Hyperuricemia can lead to deposition of sodium urate crystals in tissues, especially the joints and kidney. Urate crystals’ phagocytosis by synoviocytes cause inflammation Colchicine , NSAIDs, Uricosuric Agents, Allopurinol 75

76. Uricosuric Agents : Probenecid and sulfinpyrazone Decrease net reabsorption of UA Cause GI irritation Maintain large urine volume to minimize the possibility of stone formation. Allopurinol is a purine analog and inhibits xanthine oxidase as result inhibits formation of uric acid Used in gouty patients with renal functional impairment Acute attacks of gouty arthritis occur early in treatment ( coadminister colchicine or indomethacin) GI intolerance (nausea, vomiting, and diarrhea ) 76

77. Colchicine Inhibits leukocyte migration and phagocytosis and inhibits formation of leukotriene B4 Traditionally used to alleviate the inflammation of acute gouty arthritis but largely replaced by NSAIDs [except aspirin] Now used in prophylaxis of recurrent episodes of gouty arthritis. Frequent diarrhea may occur NSAIDs Inhibit urate crystal phagocytosis + the PG synthesis Indomethacin is commonly used as replacement for colchicine 77

78. Treating acute gout treated with indomethacin to decrease movement of granulocytes into the affected area Aspirin is contraindicated, because it competes with uric acid for excretion Intra- articular administration of glucocorticoids (when only one or two joints are affected) Treating chronic gout Uricosuric drugs that increase the excretion of uric acid are first-line agents for patients with gout associated with reduced urinary excretion of UA Allopurinol preferred in patients with excessive uric acid synthesis, previous histories of uric acid stones, or renal insufficiency 78

79. Anesthesia

80. 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. 80

81. General anesthetics can be classified as: inhalational anesthetics and Intravenous anesthetics Inhalational anesthetics Most often used for long term maintenance of the anesthetic state gases : such as nitrous oxide, cyclopropane , or ethylene) volatile liquids : such as halothane , enflurane , isoflurane , desflurane , and sevoflurane Minimum Alveolar Concentration(MAC) Is minimum concentration of the drug in the alveolar air that will produce immobility in 50% of patients exposed to a painful stimuli. is index of inhalation anesthetic potency 81

82. Adverse effects : as a group Respiratory and cardiac depression Sensitization of heart to catecholamine Malignant hyperthermia Aspiration of gastric contents Hepatotoxicity ( especially with halothane) and renal toxicity with methoxyflurane Toxicity to operating room personnel 82

83. Intravenous anesthetics Are generally employed to induce anesthesia, to provide supplemental anesthesia, or to permit anesthesia for short operative procedures These include Short acting barbiturates Eg Sodium salt of thiopental Bezodiazepines :- to produce unconciousness and amnesia, pre operative sedation, induction of anesthesia eg diazepam, midazolam Propofol : - sedative-hypnotic, induction of anesthesia, antiemetic Others – ketamine,, etomidate , opioids ( eg fentanyl) 83

84. 84 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 General groups: Short : Procaine, chloroprocaine Intermediate : lidocaine , mepivicaine , prilocaine Long acting : Tetracaine , bupivacaine , etidocaine , ropivacaine , levobupivacaine

85. Local anesthetics can be esters or amides Amides L i docaine , Bup i vacaine , Levobup i vacaine , Rop i vacaine , Mep i vacaine , Et i docaine , Pr i locaine Metabolized by liver amidases Esters Procaine, Chloroprocaine , Tetracaine , Benzocaine , Cocaine (the first local anesthetic that has largely been replaced by synthetic agents) Metabolized by plasma and tissue esterases 85

86. 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 86

87. III. Topical anesthetics Eg : 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 eg irritation 87