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1. CNS Pharmacology

2. Neurotransmitters in CNS Can be inhibitory or excitatory Inhibitory: GABA, Glycine Excitatory: Glutamate, both Aspartate , Ach, NE, DA, 5-HT

3. Sedative-Hypnotic drugs cont… Sedative vs. Hypnotic Sedative - Tranquilizers Depress the CNS to sedate or relax, producing a calming effect Hypnotic Depress the CNS enough to cause sleep Sedative-Hypnotic Produce calming effect at lower dose and sleep at higher dose Barbiturates and Benzodiazepines

4. Sedative-Hypnotic drugs Barbiturates P otentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel openings C lassified by duration of action Ultra short-acting ( T hiopental Na) - Duration of 20 min or less Short-acting ( Secobarbital , pentobarbital) - DOA - 3 - 4 hrs Intermediate-acting ( Amobarbital , aprobarbital & butabarbital ) - 6- 8 hrs Long-acting(Phenobarbital , mephobarbital ) - 10 - 16 hrs

5. Sedative-Hypnotic drugs Barbiturates cont… Depression of CNS At low doses - Produce sedation (calming effect, reducing excitement) At higher doses - Hypnosis , followed by anesthesia (loss of feeling or sensation), and finally, coma and death No analgesic properties - May even exacerbate pain Chronic use leads to tolerance Respiratory depression Suppress hypoxic and chemoreceptor response to CO 2 Enzyme inducers - ↓ Action of other drugs

6. Sedative-Hypnotic drugs Barbiturates cont… Therapeutic uses Anesthesia : Thiopental are used IV Anticonvulsant: Phenobarbital T onic- clonic seizures, status epilepticus , and eclampsia Drug of choice for treatment of young children with recurrent febrile seizures Can depress cognitive performance in children - Used cautiously Anxiety - Mild sedatives to for anxiety , nervous tension and insomnia A s hypnotics, they suppress REM sleep Most have been replaced by the benzodiazepines

7. Sedative-Hypnotic drugs Barbiturates cont… Adverse effects Drowsiness , impaired concentration, mental and physical sluggishness D epressant effects synergize with ethanol D rug hangover, nausea, dizziness Physical dependence: Abrupt withdrawal cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest Withdrawal is much more severe than that associated with opiates and can result in death

8. Sedative-Hypnotic drugs Benzodiazepines Potentate effect of GABA by ↑ the frequency of Cl channel opening Classifications Short acting agents - Triazolam Intermediate acting agents - Alprazolam , Lorazepam , Oxazepam , Temazepam , Chlordiazepoxide Long acting agents - Diazepam , Flurazepam

9. Sedative-Hypnotic drugs Benzodiazepines cont… Reduction of anxiety - At low doses Sedative and hypnotic actions: All have some sedative properties and some produce hypnosis at higher doses Anterograde amnesia - Temporary impairment of memory I mpairs a person's ability to learn and form new memories Anticonvulsant: Several of the benzodiazepines S ome are used to treat s tatus epilepticus and other seizure disorders Muscle relaxant: At high doses

10. Sedative-Hypnotic drugs Benzodiazepines cont… Therapeutic uses Anxiety disorders Muscular disorders: Muscle spasms - Diazepam Amnesia – Short acting ones Seizures – Clonazepam , diazepam and lorazepam Sleep disorders – F lurazepam , temazepam , triazolam

11. Sedative-Hypnotic drugs Benzodiazepines cont… Adverse effects Drowsiness, confusion, ataxia, cognitive impairment, tolerance, dependence (Psychological and physical dependence) and withdrawal symptoms Precautions – Avoid in pregnancy Liver disease, acute narrow-angle glaucoma. Alcohol and other CNS depressants L ess dangerous than older anxiolytic and hypnotic drugs

12. Epilepsy G roup of disorders characterized by excessive excitability of neurons within the CNS I nitiated by synchronous, high-frequency discharge from group of hyperexcitable neurons ( focus) S ymptoms depend on location of focus

13. Epilepsy cont… Sudden, transient disturbance of brain function, manifested by involuntary motor, sensory, autonomic, or psychic phenomena, often accompanied by alteration or loss of consciousness May range from mild twitching to loss of consciousness and uncontrollable convulsions A seizure may occur after a metabolic, traumatic, anoxic, or infectious insult to the brain Idiopathic cause (>75%), drugs, brain tumor

14. Epilepsy cont… Pathogenesis Enhanced excitatory NT glutamate ↓ I nhibitory gamma amino butyric acid ( GABA) Classification of seizures B ased upon nature not the cause of seizures 1. Partial (local) seizure 2. Generalized seizure 3. Status epilepticus

15. Epilepsy cont… 1. Partial (local) seizures Are seizures localized to certain areas of the brain only Further classified as Simple partial - No loss of consciousness Complex partial - Simple partial seizure followed by loss of consciousness Secondary generalized seizures - Partial onset which evolves to generalized tonic- clonic seizures

16. Epilepsy cont… 2 . Generalized seizures Affects wider areas of the brain & are associated with loss of consciousness Involves both hemispheres of the brain Could be classified into different groups Absence seizures Myoclonic seizures Clonic seizures Tonic seizures Tonic- clonic seizures

17. Epilepsy cont… 3. Status epileptics Is any recurrent or continuous seizure activity lasting longer than 30 minutes in which period the patient doesn’t regain consciousness I s a medical emergency Because it can lead to brain damage & death

18. Anti-epileptic drugs Treatments for epilepsy No effective preventions or cures known Surgical methods T o remove the epileptogenic part of the brain Seizure inhibiting drugs

19. Anti-epileptic drugs Class of drugs for epilepsy Type I antiepileptics - Inhibit Na+ channels Phenytoin , Carbamazepine , lamotrigine , felbamate , oxycarbazepine Type II antiepileptics – Multiple action I nhibit Ca++ or Na + channels or promote GABA activity Valporic acid, benzodiazepines, primidone , Phenobarbital Type III antiepileptics - Ca ++ channel inhibitors Ethosuximide , trimethadione Type IV - GABA promoters Vigabatrin , tiagabine , gabapentine

20. Anti-epileptic drugs Phenytoin Is one of the Na+ channel inhibitor antiepileptic drugs Limited water solubility, slow , incomplete and variable absorption Equal efficacy as phenobarbital but with lesser CNS depressant effect It is highly plasma protein bound

21. Anti-epileptic drugs Phenytoin cont… Adverse effects Acute toxicity - Results of over dosage Nystagmus , ataxia, vertigo, diplopia Chronic toxicity - Related to long term use Behavioral changes Gingival Hyperplasia (overgrowth of the gums) Enlargement of lips & nose Coarsening of facial features Hirsutism (excessive hairiness )

22. Anti-epileptic drugs Carbamazepine I s highly efficacious & well tolerated, Na+ channel blocker Has fewer long term side effects than other anti-epileptics Metabolized in the liver by the CYP450 enzymes E nzyme inducer & can induce its own metabolizing enzyme as well as enzymes of other drugs SEs : Drowsiness, headache, dizziness & incordination Allergic reactions, rare but sever aplastic anemia Most SEs occur at first therapy & tolerance develops T oxicity is low as compared to phenytoin

23. Anti-epileptic drugs Ethosuximide Drug of choice for Absence seizure Not effective in other seizure types Blocks Ca ++ currents (T-currents) in the thalamus SEs GI complaints - Most common CNS effects - Drowsiness & lethargy Potentially fatal bone marrow toxicity and skin reactions (both rare)

24. Anti-epileptic drugs GABA transmission enhancers 1 . Phenobarbital Is the only barbiturate with selective anticonvulsant effect Bind at allosteric site on GABA receptor & ↑ duration of opening of Cl channel Inducer of microsomal enzymes → D rug interactions Toxic effects S edation ( t olerance develops), nystagmus , ataxia at higher dose, osteomalacia , folate and vitamin K deficiency

25. Anti-epileptic drugs GABA transmission enhancers cont… 2. Benzodiazepines Clonazepam , lorazepam & clorazepate Bind to another site on GABA receptor & increase frequency of opening of the Cl - channel Are well absorbed from the GIT Metabolized by CYP450 enzymes to active metabolites Toxicities Lethargy, drowsiness, CNS sedation

26. Anti-epileptic drugs GABA transmission enhancers cont… 3. Gabapentin - Developed as GABA analogue ↑ release of GABA from gabanergic neurons by unknown mechanism 4. Vigabatrin Irreversible inhibitor of GABA transaminase enzyme which metabolizes GABA 5. Tiagabine ↓ GABA uptake by neuronal and extraneuronal tissues so as to increase GABA at the synapse

27. Anti-epileptic drugs GABA transmission enhancers cont… 6. Valporic Acid Effective in the treatment of multiple seizure types Works by multiple mechanisms Blocks both Na + & Ca++ channels and ↑ GABA activity Drug interactions: Inhibits metabolism of phenobarbital , Carbamazepine & phenytoin Side effects Fatal hepatic failure (most serious SE), reversible hair loss, ↑ in body weight, transient GI disturbances

28. Anti-epileptic drugs Magnesium sulphate CNS depressant Block transmission of neuromuscular signals by ↓ Ach Vasodilation ↓ Cerebral edema (Protect BBB) SE – Respiratory depression and loss of deep tendon reflexes  

29. Anti-psychotics D rugs that primarily affect psyche (mental process) & useful in psychiatric disorders Also called Psychotropic drugs Neuroleptics Major tranquillizers

30. Anti-psychotics Schizophrenia Is a group of heterogeneous, chronic psychiatric disorders It is one particular kind of psychosis It is characterized by two clinical symptoms Positive symptoms - Delusion hallucination & thought disorders Commonly occur in acute phase of the illness Usually respond to antipsychotic drug therapy Negative symptoms - Apathy, social withdrawal & lack of drive & enthusiasm Occur in chronic phase of illness and is resistant to drug therapy

31. Anti-psychotics Schizophrenia cont… Pathogenesis Genetic & environmental factors (Maternal virus infection) Neurochemical abnormalities - DA & glutamate Abnormality of DA activity in mesolimbic-mesocortical pathway of DA 5-HT & other NTs might also be involved

32. Anti-psychotics cont… Classification based on chemical structure 1.Phenothiazine derivatives with A liphatic side chain - Chlorpromazine (CPZ), triflupromaizne Piperidine side chain - Thioridazine , mesoridazine , piperacetazine P iperazine ring side chain - Fluphenazine , trifluoperazine 2. Butyrophenones - Haloperidol, trifluperidol , penfluperidol 3. Thioxanthenes - Chlorprothixene , flupenthixol 4. Atypical Neuroleptics - Clozapine , risperidone , olanzapine , ziprasidone , aripiprazole 5. Miscellaneous - Reserpine

33. Anti-psychotics cont… C an also be grouped into two groups 1 st generation ('typical') antipsychotics 2 nd generation ('atypical') antipsychotics Grouping is based on Receptor profile Incidence of extrapyramidal side effects (less in atypical group) Efficacy in 'treatment-resistant' patients ( atypicals are more efficacious) Efficacy against negative symptoms ( atypicals are more efficacious)

34. Anti-psychotics Mechanism of action A ll effective antipsychotic drugs block D 2 receptors D egree of blockade to other actions on different receptors considerably varies Clozapine - 5-HT 2A > α 1 > D 2 > D 1 Haloperidol - D 2 > α 1 > D 4 > 5-HT 2A > D 1 >H 1 Antipsychotic action has shown good correlation with the capacity to bind to D 2 receptor N o clear correlation with D 1 , D 3 & D 4 binding Activities on other NT receptors - Determine their SE

35. Anti-psychotics Pharmacological action ANS - Varying degree of α - blocking activity Weak anticholinergic & antihistamine property Local anesthetic – CPZ but causes irritation CVS - Postural hypotension, ↓ BP, ↑ HR Endocrine effects ↑ prolactin secretion by blocking inhibitory effect of DA Galactorrhea , gynacomasteia

36. Anti-psychotics Uses of anti-psychotics Schizophrenia - the main use Anxiety Should not be used for simple anxiety b/c of autonomic & extraipyramdal side effects Those not responding to BDZs or having psychiatric base As antiemetic - Control drug & disease induced vomiting At dose much lower than those needed for psychosis I neffective in motion sickness Other uses - Potentiate hypnotics, analgesics & anesthetics

37. Anti-psychotics Adverse effects of anti-psychotics CNS effects Drowsiness , lethargy, mental confusion Increased appetite & weight gain (not with haloperidol) Aggravation of seizures in epileptics High dose cause seizure - Clozapine & olanzapine CVS effects Postural hypotension (not with haloperidol) Palpitation

38. Anti-psychotics Adverse effects of anti-psychotics Anticholinergic effects - Dry mouth, blurred vision, constipation Endocrine effects – Hyperprolactinemia Galactorrhea , gynacomasteia Atypical - Free of such endocrine problems Extrapyramidal (EP) disturbances Pseudo parkinsonism, acute muscular dystonia , a kathisia , t ardive dyskinesia

39. Parkinson’s disease (PD) D isorder of movement that occurs mainly in the elderly individuals O ccur s for a variety of possible reasons Exposure to certain toxins (manganese dust, carbon- disulfide) Drug induced parkinsonism - Reserpine , haloperidol, chlorpromazine & other antipsychotics that block D 2 Post encephalitic parkinsonism - After viral infection Idiopathic parkinsonism - Unknown cause

40. Parkinson’s disease cont… The basal ganglia are responsible for controlling automatic movements of body by action of DA DA level in brain’s substantia nigra normally fall with ageing L evel has to fall to 1/5th of normal for signs of PD to emerge In PD, there is extensive destruction of dopaminergic neurons of Substantia nigra Leads to DA deficiency

41. Parkinson’s disease cont… S hortage of DA & excess of Ach (imbalance)

42. Parkinson’s disease cont… Cardinal Features of PD Bradykinesia Is an extreme slowness of movement Is the most disabling feature b/c it affects all motor systems Muscular rigidity: increased muscle tone which leads to movement resistance Resting tremor: involuntary movements of limbs at rest Impaired postural balance

43. Parkinson’s disease cont… Treatment Strategy: Restore balance between DA and Ach Activating DA receptors Blocking Ach receptors Overview of Drugs Employed Dopaminergic drugs Anticholinergic drugs

44. Parkinson’s disease Classification of drugs 1. Drugs affecting brain dopaminergic system a. Dopamine precursors: levodopa b. Peripheral decarboxylase inhibitors: carbidopa & benserazide c. Dopaminergic agonists: bromocriptine , pergolide , ropinirole , cabergoline & pramipexole d. MAO-B inhibitors : Selgiline e. COMT inhibitors: Entacapone , tolcopone f. Dopamine facilitator : Amantidine

45. Parkinson’s disease Classification of drugs cont… 2. Drugs affecting brain cholinergic system a. Anticholinergics : Benzotropine , benzhexol , Procyclidine , biperiden b. Antihistamines: promethazine

46. Parkinson’s disease Levodopa (L-DOPA) First-line treatment for PD Is the immediate metabolic precursor of dopamine Prodrug for DA and can cross BBB while DA does not More than 95% of oral dose is decarboxylated in periphery tissue mainly in gut & liver to dopamine DA in periphery cause SE Peripheral DOPA decarboxylase inhibitor ( carbidopa or benserazide ) ↓metabolism in periphery

47. Parkinson’s disease Levodopa (L-DOPA) cont… Adverse effects Dyskinesia (involuntary writhing movements) O n / off phenomenon Effectively improves mobility with marked dyskinesia (on - period) Rigidity & akinesia at the end of the dosing interval (off - period) Nausea & anorexia – Tolerance develops Postural hypotension, cardiac arrthymias & excerbation of angina - β adrenergic action Psychological effects - Schizophrenia-like syndrome

48. Parkinson’s disease Dopamine receptor agonists Lower incidence of on /off phenomenon & dyskinesias D o not require enzymatic conversion to active metabolite S electively affec t certain DA receptors (primarily D 2 ) Used for patients who have largely lost the capacity to synthesis, store & release dopamine from levodopa Have longer duration of action than that of levodopa Effective as monotherapy or as adjuncts to carbidopa

49. Parkinson’s disease Dopamine receptor agonists cont… Bromocriptine (Ergot derivative) Potent D 2 agonist & partial D 1 agonist /antagonist High dose is needed if used alone Used only in late case as supplement to levodopa Low dose - For treatment of hyperprolactinemia Pergolide - M ore effective than bromocriptine and allow the levodopa dose to be reduced Pramipexole - S cavenge hydrogen peroxide ( neuroprotective )

50. Parkinson’s disease Dopamine receptor agonists cont… A dverse effects Anorexia , nausea & vomiting , c onstipation, dyspepsia, symptoms of reflux esophagitis Postural hypotension and c ardiac arrhythmias D yskinesias Confusion, hallucinations, delusions & other psychiatric reactions

51. Parkinson’s disease MAO-B i nhibitors MAO-B - The predominant form of MAO in striatum Responsible for most of oxidative metabolism of DA in the brain Selegiline (deprenyl) A t low to moderate doses ( < 10mg/day), it is selective & irreversible MAO-B inhibitor It does not affect metabolism of peripheral catecholamines At dose > 10mg/day , MAO-A can be inhibited Used a s adjunctive therapy for patients with declining or fluctuating response to levodopa

52. Parkinson’s disease COMT i nhibitors T olcapone (long duration) & entacapone (short duration) Inhibition of DOPA decarboxylase is associated with activation of other levodopa metabolism pathways : such as metabolism of L-DOPA by COMT Addition of COMT inhibitors to carbidopa / levodopa combination delays ’’on/off’’ phenomenon of the L-DOPA therapy

53. Parkinson’s disease Muscarinic receptor antagonists Benzatropine , b iperiden , o rphenadrine , p rocyclidine ↓ the unbalanced cholinergic activity in striatum The only drugs effective in drug induced ( phenothiazines – anti-psychotics) parkinsonism – Benzatropine Start from small dose & gradually ↑ until benefit occurs or SE limit further increment

54. 54 Antidepressant drugs

55. Depression Depression is defined as disorders of mood which occurs for more than 6 weeks of time It is characterized by different symptoms Lack of interest in normal activities Insomnia, anorexia, low self esteem Fatigue & inability to concentrate Mental slowing, indecisiveness Lack of energy & libido Pessimism, feelings of guilt, ugliness

56. Monoamine theory The theory states that depression is caused by a functional deficit of monoamine transmitters (NE &/or 5-HT) at certain sites in the brain So, most of the antidepressant drugs work by facilitating adrenergic & serotonergic neurotransmission in the CNS Inhibiting reuptake of NE & serotonin (5-HT) Inhibiting metabolism of NE & 5-HT Increasing release of NE & 5-HT

57. Classification of antidepressants T ricyclic antidepressants ( TCAs ) S elective serotonin reuptake inhibitors (SSRI s ) Monoamine oxidase inhibitors (MAOIs) Miscellaneous ('atypical') antidepressants

58. I. T ricyclic or heterocyclic antidepressants ( TCAs ) Were mainstays of depression treatment in earlier times But now TCAs are not 1 st line therapy for depression due to their prominent side effects They can be classified into two based on their mechanism A. NE & 5-HT reuptake inhibitors – Predominantly 5-HT Imipramine Amitriptline Trimipramine Dothiepin Doxepin Clomipramine B. Predominantly NE reuptake inhibitors Amoxapine Desipramine Nortriptyline Reboxetine

59. Mechanism of TCAs TCAs work by blocking reuptake of NE & 5-HT ↑these NTs concentration in the synaptic cleft Reuptake inhibition by the TCAs occurs within short period after administration but therapeutic effect occurs after 2-3 weeks of drug taking This delay of therapeutic effect has been hypothesized to be due to On the 1 st few weeks of treatment the increased NTs activate presynaptic autoreceptors ( α 2 , 5-HT 1A & 5-HT 1D ) Activation of these receptors leads to decreased release of the NTs But after 2-3 weeks these receptors are desensitized & NE & 5-HT are released well

60. After long term administration of TCAs (2-3 wks) The drug desensitize presynaptic auto receptors ( α 2 , 5-HT 1A & 5-HT 1D ) ↑concentration of NTs in synaptic cleft Increased sensitivity of postsynaptic receptors Hence, the net effect after long term therapy is enhanced noradrenergic & serotonergic transmission

61. Pharmacological actions of TCAs Well absorbed from the GIT Are highly lipid soluble & bound to plasma proteins They block several receptors other than their effect to inhibit 5-HT & NE reuptake including Muscarinic receptors Histamine receptors α -1 adrenergic receptors D2 receptors (only Amoxapine) So the capacity of TCAs to inhibit multiple receptors is the source for Most of their side effects & drug interactions

62. Side effects Due to muscarinic receptor antagonism Dry mouth, constipation, urinary retention, blurred vision, tachycardia Due to histamine receptor antagonism Sedation, weight gain Due to α 1-antagonism Orthostatic hypotension Due to D2 antagonism (only for Amoxapine) Extrapyramidal effects, gynacomasteia, lactation TCAs can also cause life threatening seizures, sexual dysfunction

63. Drug interactions TCAs compete for binding sites of plasma proteins & displaced by phenytoin, aspirin & phenothiazines Serious but rare interaction occurs b/n TCAs & MAOIs Both are important for treatment of depression But coadministeration of a drug from each class leads to Hyperpyrexia, convulsions, coma So, in TCAs resistant patients, it is advisable to discontinue the TCAs drug for 2-3 weeks before initiation of a MAOI therapy TCAs can also potentiate sedative effects of alcohol & patients should be cautioned about this interaction

64. II. S elective serotonin reuptake inhibitors (SSRI s ) Includes: Fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, maprotiline, trazodone & nefazodone This class of antidepressants Has little/no affinity for cholinergic, adrenergic & histaminergic receptors Don’t affect cardiac function, so they are well tolerated by patients with cardiac problems

65. SSRIs MOA: inhibit reuptake of 5-HT into the neuron & increase 5-HT concentration in the synapse 1 st line drugs for management of depression Due to their relative safety & acceptability No seizure precipitating propensity & not inhibit cardiac conduction They don’t cause weight gain

66. For TCAs & SSRIs onset of action is slow, so: Treatment should be given for at least 4-6 weeks before concluding that the drug is ineffective for the particular individual If there is a partial response, treatment should be continued for several more weeks before increasing the dose Treatment should continue for at least 4 months following subsidence of depression

67. Side effects Anxiety/agitation Insomnia Nausea Loose stools Sexual dysfunctions Decreased libido, delayed ejaculation, anorgasmia Drug interaction – If combined with MAOIs, cause 5-HT syndrome – Overstimulation of 5-HT receptor in brain stem and spinal cord Confusion, elevated or dysphoric mood, tremor, myoclonus , incoordination , hyperthermia, and cardiovascular collapse

68. Fluoxetine Prototype of the SSRIs Given in the morning to prevent night time insomnia Has slow elimination from the body after discontinuing the drug So we should weight 4-6 weeks of time before administering a drug which could interact with it such as MAOIs Is potent inhibitor of CYP2D6 enzyme So it can increase the concentration of drugs metabolized by this enzyme Note: from all SSRIs, Citalopram has the least effect on the CYP450 enzymes & has the most favorable profile regarding drug-drug interactions

69. III. Monoamine oxidase inhibitors (MAOIs) Two types of MAO enzymes MAO-A: metabolizes NE, 5-HT, DA & tyramine MAO-B: metabolizes DA So, there are two types of MAOIs Non selective MAOI Tranylcypromine, phenelzine & isocarboxide Older, irreversible, long-acting drugs Selective MAO-A inhibitor Moclobemide, clorgyline Newer, r eversible & short acting agents

70. MAOIs are as effective as TCAs & SSRIs as antidepressant However, at least two forms of life threatening toxicities have been associated with their long term use Hepatotoxicity Dietary tyramine induced hypertensive crises For these reasons MAOIs are not considered as 1 st line therapy for depression So, they are used for resistant type of depression Note: MAO-A inhibition is responsible for the antidepressant effect of both the non selective & selective inhibitors

71. Adverse effects Hepatotoxicity Drug-food interactions Tremors, Sexual dysfunction Dry mouth, fatigue & weight gain Note: When switching from SSRIs to MAOIs, we should allow drug free 3-4 weeks before starting the MAOIs therapy A drug free period of 2 weeks is required before switching to SSRIs To allow for regeneration of tissue MAO & elimination of MAOIs

72. IV. Miscellaneous ('atypical') antidepressants Venlafaxine Inhibits the reuptake of both NE & 5-HT Doesn’t have significant effects at muscarinic, histaminic or α -adrenergic receptors Has minimal effects on CYP450 enzymes Has similar side effects as the SSRIs Mirtazapine Enhances NE & 5-HT neurotransmission (promotes their release) by blocking presynaptic α 2 receptors Doesn’t inhibit neuronal reuptake of 5-HT & NE Doesn’t have significant effect on CYP450 enzymes SEs: weight gain, sedation( should be given at bed time)

73. Bupropion Weak inhibitor of DA & NE reuptake But is MOA as antidepressant isn’t well known It doesn’t inhibit other receptors such as: Muscarinic Histamine Adrenergic receptors It inhibits the CYP2D6 enzyme Unlike the SSRIs & Venlafaxine, Bupropion doesn’t cause sexual dysfunction Side effects Restlessness, insomnia Risk of seizures So it is contraindicated in patients with history of seizure

74. Analgesic drugs Drugs eliminate pain by ↓ transmission of nociceptive impulses and pain perception Opioids ↓ the underlying cause of the pain Nonopioid analgesics - NSAIDs Miscellaneous Anti-depressants, adrenergic agonist, transcutaneous electrical nerve stimulation, physical and massage therapy, acupuncture, meditation, behavior modification

75. Analgesic drugs Opioid (Narcotic) analgesics All compounds related to or derived from opium Opium - Extract of the juice of the poppy Papaver somniferum Opioid receptors – Three receptors µ (Mu)-receptors - Responsible for the analgesic and major SE Clinically used opioids relatively selective for µ ↑ Dose - Interact with additional receptor subtypes  ( Delta) – Analgesia, peripheral effects, tolerance  ( Kappa) – analgesia, psychomimetic , dysphoria Inhibit adenyl cyclase or Ca++ channel or activate K+ channel Inhibit nociceptive transmission

76. Analgesic drugs Opioid analgesics cont… Class of opioid analgesics Strong agonists Phenanthrenes - Morphine, hydromorphone, h eroin , oxymorphone Phenylheptylamines – M ethadone Phenylpiperidines - M eperidine , f entanyl , sufentanil, alfentanil, remifentanil , pethidine Morphinans - Levorphanol

77. Analgesic drugs Opioid analgesics cont… Class of opioid analgesics Mild to moderate agonists Phenanthrenes - Codeine, oxycodone, dihydrocodeine, hydocodon Phenylheptylamines - Propoxyphene Phenylpiperidines - Diphenoxylate → D ifenoxin , Loperamide Opioids with mixed receptor action Phenanthrenes - Nalbuphine , Buprenorphine Morphinan s – Butorphanol Benzomorphans - Pentazocine

78. Analgesic drugs Opioid analgesics cont… Class of opioid analgesics Antagonists - N aloxone, naltrexone, nalmefene Anti- tussives - Dextromethorphan , Codeine, Levopropoxyphene Miscellaneous - Tramadol

79. Analgesic drugs Opioid analgesics Therapeutic uses Severe, constant pain Acute pulmonary edema ↓ A nxiety , ↓ c ardiac preload and a fterload Cough suppression D extromethorphan, codeine, levopropoxyphene Diarrhea – D iphenoxylate , Loperamide Pre- anaesthetic medication

80. Analgesic drugs Opioid analgesics cont… Adverse effects Respiratory depression Sedation Constipation Miosis Euphoria and physical dependence - Mu receptors Psychomimetic and dysphoria effect - Kappa receptors Mu and Kappa receptors

81. Analgesic drugs Nonsteriodal anti-inflammatory drugs (NSAIDs) Less effective than opioids Less chance of tolerance and physical dependence ↓ the formation of pain mediators (prostaglandins, PGs) in PNS by inhibiting cyclooxygenase (COX) enzyme Arachidonic acid (AA) Prostanoids Prostanoids are involved Pain and Fever:- PGE, PGI Inflammatory responses in tissue:- PGE, TXA , PGD Maintenance of the gastric mucosal lining:- PGE, PGI Renal functions:- PGE, PGI, TXA

82. Analgesic drugs NSAIDs cont… Classification of NSAIDs A. Non selective COX inhibitors Salicylates – Aspirin Propionic acid derivatives- Ibuprofen Acetic acid derivatives- Diclofenac , indomethacin Oxicam – Piroxicam B. Selective cox-2 inhibitors Coxibs – Celecoxib

83. Analgesic drugs NSAIDs cont… Actions of NSAIDS Anti pyretic, Anti inflammatory, Analgesic Anti aggregatory (Reduce platelet plug and clot formation) Uses of NSAIDs Mild analgesic and anti- pyretics Anti-inflammatory Inflammation associated with arthritis in joints Anti-platelet agents

84. Analgesic drugs NSAIDs cont… Adverse effects Gastrointestinal Local irritation because of their acidic nature High absorption at the stomach Inhibit the mucosal synthesis of PGI2 and PGE2 ↓ the defense mechanisms of the GIT (mucus, bicarbonate secretion, blood flow)

85. Analgesic drugs NSAIDs cont… Adverse effects Bleeding time ↓ in TxA 2 synthesis, will prevent platelet aggregation Renal Cause renal failure only if there is an underlying condition that results in underperfusion of the kidney Pulmonary Bronchoconstriction -due to high production of leukotriene

86. Analgesic drugs NSAIDs cont… 1. Salicylates - Aspirin, Diflunisal Aspirin Analgesic, Antipyretic, Antithrombotic (drug of choice for being an antithrombotic) Anti-inflammatory Additional SE Reyes syndrome - Not recommended in children less than 14 years with chicken pox, measles and mumps as anti- pyretics Tinnitus and Uric acid retention

87. Analgesic drugs NSAIDs cont… 2. Propionic acids - Naproxen, Ibuprofen More potent than aspirin Ibuprofen Anti-inflammatory, analgesic and antipyretic GI irritation less frequently than aspirin SE - Pruritus , rash, tinnitus, dizziness, fluid retention Rarely - Agranulocytosis , aplastic anemia Kideny (renal failure, interstitial nephritis, nephrotic syndrome)

88. Analgesic drugs NSAIDs cont… Ibuprofen indications Relief of signs and symptoms of rheumatoid arthritis Osteoarthritis Degenerative disease of joint which become stiff and painful Ankylosing spondylitis Inflammation of vertebrae and joints which become stiff Acute gouty arthritis Relief of mild to moderate pain and fever reduction Treatment of dysmenorrhea

89. Analgesic drugs NSAIDs cont… 3. Acetic acids - Indomethacin , Diclofenac Indomethacin Has prominent antiinflammatory and analgesic-antipyretic properties similar to those of the salicylates More potent inhibitor of COX than aspirin Patient intolerance (Due to its ulcerogenic effect) generally limits its use to short-term dosing Used only for its anti inflammatory effect

90. Analgesic drugs NSAIDs cont… Diclofenac Potent COX inhibitor Its potency against COX-2 is substantially greater than that of indomethacin , naproxen, or several other NSAIDs Accumulates in synovial fluid Indications Acute or long-term treatment of mild to moderate pain, including dysmenorrhea Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis

91. Analgesic drugs NSAIDs cont… Acetaminophen ( Paracetamol ) Weak PG synthesis inhibitor in peripheral tissues and possesses no significant anti-inflammatory effect Effective analgesic and antipyretic agent Use - Mild to moderate pain - Head ache, postpartum pain SE - Hepatotoxic , hemolytic anemia

92. Analgesic drugs NSAIDs cont… Coxibs – Selective COX-2 inhibitors Meloxicam , celecoxib , etoricoxib , rofecoxib Reduces prostaglandins produced in pathological situations Analgesic, antipyretic and anti-inflammatory effect similar to nonselective NSAIDs Less GIT adverse effects

93. Anti-rheumatoid drugs Rheumatoid arthritis (RA) is a long lasting autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints NSAIDs Slow acting anti-rheumatoid drugs (SAARDs) or disease modifying anti-rheumatoid drugs (DMARDs) Glucocorticoids

94. Anti-rheumatoid drugs DMARDs Do not have general anti-inflammatory effects May take 6 weeks to 6 months to produce their effects They are slow-acting compared with NSAIDs Included in this category are Chloroquine Sulfasalazine Gold compounds Methotrexate Penicillamine

95. Anti-rheumatoid drugs DMARDs cont… 1. Chloroquine Is used in the treatment of malaria Anti-inflammatory only in rheumatic disease Less adverse systemic effects but tends to seriously affect the eyes Cornea of the patient undergoing this treatment needs to be monitored. Retinopathy may be irreversible, causing blindness Very slow onset (months) 2. Sulfasalazine A free radical scavenger? Free radicals cause cell injury and inflammation Has marked GI irritation - Only available with an enteric coating

96. Anti-rheumatoid drugs DMARDs cont… 3. Gold compounds Aurothiomalate (IM), Auranofin (Oral, less common) MOA ↓ lymphocyte proliferation, ↓ lysosomal enzyme release ↓ superoxide production, ↓ neutrophil chemotaxis , ↓ IL-1 synthesis May take months to see a beneficial effect. Adverse effects Allergic type reactions at the skin and mucous membranes, Renal injury Blood dyscrasias (any adverse change in blood function)

97. Anti-rheumatoid drugs DMARDs cont… 4. Methotrexate Immunosuppresant ( Folate antagonist) Also used to treat cancer Affects the functions of leucocytes and macrophages 5. Penicillamine Adverse effects similar to gold compounds Not effective, most probably be obsolete soon Once the effects of the above drugs are observed, they will slow the disease progress, not just treating the inflammation

98. Gout Gout - Due to an accumulation of uric acid (a breakdown product of adenosine) High concentrations of uric acid lead to crystallization and deposition in the synovium of joints, resulting in arthritic pain Acute treatment of gout involves NSAIDs ( NOT aspirin as it inhibits the excretion of uric acid) Colchicine Glucocorticoids Chronic treatment involves Allopurinol , Colchicine , Probenecid

99. Gout cont… Its difference from rheumatoid arthritis (RA) Gout usually occurs in the foot, most commonly at the base of the big toe. RA can affect any joint on either side of the body, but most commonly occurs in small joints of hands, wrists and feet Gout is always accompanied by redness, swelling, and intense, agonizing pain A joint affected by RA also may become painful, but won’t always be red or swollen. RA pain varies in quality and intensity – Mild to excruciating

100. Gout cont… Synthesis of uric acid

101. Drugs for Gout Colchicine Anti-mitotic agent (interferes with tubulin ) which prevents leukocyte migration Reduced leukocytes in synovial joints affected by gout would reduce the pain and discomfort Can be used as an acute treatment Also can be used as a chronic treatment as prevention ( prophylactically ) in conjunction with allopurinol

102. Drugs for Gout cont… Allopurinol Analogue of hypoxanthine which Inhibits xanthine oxidase Preventing hypoxanthine from binding Product of allopurinol with xanthine oxidase is alloxanthine Alloxanthine is an irreversible inhibitor of xanthine oxidase ↓ synthesis of uric acid and the concentrations fall Even though underexcretion rather than overproduction is the underlying defect in most gout patients, allopurinol remains effective therapy

103. Drugs for Gout cont… Probenecid Uricosuric agent (increases the excretion of uric acid) Inhibits the tubular reabsorption of uric acid in the kidneys Limited use, not as effective as allopurinol

104. Anesthetics agents Depress the nervous system, causing a loss of consciousness (except for local and regional anesthetic agents) and relieving pain during surgery Anesthetic agents are classified as General Anesthetic – Act on the CNS Used for surgery consists of one medication or a combination that causes a temporary loss of consciousness Local Anesthetic Block specific nerve pathways in a region and result in temporary analgesia and paralysis but no loss of consciousness

105. Anesthetics agents Local anesthetic Blocks pain at the site where the medication is administered Used to render a specific portion of body insensitive to pain Interfere with nerve impulse transmission to specific areas of the body Do not cause loss of consciousness Procaine, Tetracaine , Bupivacaine , Lidocaine It is used for Suturing lacerations, short-term localized surgery, spinal anesthesia, diagnostic producers

106. Anesthetics agents Local anesthetic Lidocaine Moderate-acting local anesthetic agent Systemically used for cardiac arrhythmia management Side effects CNS depression, convulsion and respiratory depression Main toxic actions are in the heart - Arrhythmias, decreased contraction, hypotension, cardiovascular collapse Caution Dosage should be reduced for elderly, debilitated, acutely ill

107. Anesthetics agents Local anesthetic Lidocaine Contraindications Do not use a vasoconstrictor on appendages such as fingers, toes, earlobes, and penis. Use with caution with cardiac patients. Hypersensitivity to amide-type local anesthetics, arrhythmias Anesthetic solutions containing epinephrine should be used with caution in peripheral or hypertensive vascular disease and during or following potent general anesthesia

108. Anesthetics agents General anesthetics Four stages of Anesthesia 1. Analgesia - Patient is conscious and able to converse, no pain 2. Excitement: Breathing ↑, BP ↑ and become irregular. Delirium sets in and the patient may become violent 3. Surgical Anesthesia: Eye movement slows then stops as breathing becomes regular. Skeletal muscles relax and surgery begins 4. Medullary Paralysis: The respiratory center (medulla oblongata) becomes paralyzed. Breathing and vital functions cease. Death occurs

109. Anesthetics agents General anesthetics cont… General anesthetics – IV or inhalational IV anesthetics To induce or maintain general anesthesia, To induce amnesia, as an adjunct to inhalation-type anesthetics Includes Short acting barbiturates - Thiopental, methohexital Benzodiazepines - Midazolam , diazepam, Lorazepam Propofol Ketamine

110. Anesthetics agents General anesthetics cont… Short acting barbiturates – Thiopental Short acting due to their redistribution phenomenon Produce rapid unconsciousness & amnesia Don’t produce analgesia & skeletal muscle relaxation MOA - They promote the action of GABA SE - CVS and respiratory depression, precipitation of drugs ↓ force of contraction & vasodilation

111. Anesthetics agents General anesthetics cont… Benzodiazepines (BDZ) Midazolam is the most popular agent due to Its high water solubility Short duration of action (enables rapid recovery) Lorazepam is the most potent agent Lorazepam & diazepam are not water soluble Dissolved in propylene glycol which is irritant to vasculature

112. Anesthetics agents General anesthetics cont… Benzodiazepines Produce unconsciousness & amnesia but not analgesia So they can be used in place of barbiturates Advantages of BDZs over barbiturates Produce lesser CVS & respiratory depression Have antagonist called flumazenil Used in the cases of BDZ overdosage

113. Anesthetics agents General anesthetics cont… Propofol IV anesthetic which is rapidly metabolized (rapid recovery from the anesthesia) P atients are able to ambulate earlier after general anesthesia It produces less postoperative nausea and vomiting It is used f or induction and maintenance of anesthesia E ffective to induce prolonged sedation for patients in critical care settings (by applying prolonged infusion )

114. Anesthetics agents General anesthetics cont… Ketamine Block glutamate activity on NMDA receptor The only IV anesthetic with analgesic effect It differs from the other IV anesthetics in two ways Produces dissociative anesthesia and cardiac stimulation Patient may seem awake & reactive but doesn’t respond to sensory stimuli By stimulating SNS and by inhibiting NE/EP reuptake

115. Anesthetics agents General anesthetics cont… Ketamine Side effects Most common side effects are post anesthesia effects Patients in the recovery period may Be agitated Hallucinate Cry Scream Vomiting, salivation, shivering

116. Anesthetics agents General anesthetics cont… Inhalational anesthetics Halothane, isoflurane , sevoflurane , desflurane Other - Nitrous oxide, Ether Use - General anesthesia & severe refractory status asthmaticus (rare indication) Mainly used for maintenance of anesthesia Contraindication: Malignant hyperthermia (MH) SE – Hypotension, respiratory depression, liver and kidney damage, carcinogenesis, hematotoxicity

117. Anesthetics agents General anesthetics cont… Halothane – Liver toxicity Nitrous oxide – Laughing gas – Bone marrow toxicity Analgesic action Enflurane – Some risk of epilepsy-like seizures Desflurane – Respiratory irritant – Cough and laryngospasm Isoflurane – Respiratory irritant and precipitate MI Sevoflurane – Lack respiratory irritation