PHARMACOLOGY TWO Drugs acting on gastrointestinal tract- 1 - PowerPoint Presentation

1. PHARMACOLOGY TWODrugs acting on gastrointestinal tract- 1 antidiarrhoeals,antiemeticsDrugs targeting endocrine system-2antidiabetics thyroid drugs 7Drugs used in surgery-3Anticonvulsants.-4Antipsychotics- 5,Antipsychotics or neurolepticsAntidepressant-6

2. MODULE UNITSDrugs acting on gastrointestinal tract- 1 antidiarrhoeals,antiemeticsDrugs targeting endocrine system-2antidiabetics thyroid drugs 7Drugs used in surgery-3Anticonvulsants.-4Antipsychotics- 5,Antipsychotics or neurolepticsAntidepressant-6

3. DRUGS ACTING ON GITCONTENT.CLASSIFICATION OF GIT DRUGSPeptic ulcer drugsProton pump inhibitors-PPI H2 -histamine receptor blockers Prostaglandin analogsCytoprotectants (sucralfate ,antacids)H. pylori eradications -(H pylori kit, metronidazole

4. Cont.Bulk forming drugsEmollientsStimulants-AntidiarrhoealsAnticholernergicsAdsorbentsOpiate related agentsProbiotics

5. ANTIEMETIC'SSerotonin( 5HT3) receptor antagonistdopamine antagonist.NK1 RECEPTOR ANTAGONIST-Neurokinin antagonisr for chemo N&VH1 RECEPTOR ANTAGONISTCANNBINOIDSANTICHOLINERGICS

6. Drugs acting on symptoms manifested in the GASTROINTESTINAL SYSTEMPEPTIC ULCERS AND GERD Physiology - participating cell-types Parietal cells – secrete HCL and intrinsic factor.2. Peptic cells (chief cells) –secretes pepsinogen3. Neuroendocrine cells- secretes histamine4. Mucous and bicarbonate secreting cells5. Prostaglandin-secreting cells 6

7. HCL secretion stimulated by  ACh  Gastrin hormone  Histamine HCL secretion inhibited by prostaglandins Histamine 7

8. PEPTIC ULCERSA breach in the mucosaLocation: Duodenum, stomach etc ♦ Basis: Imbalance between damaging factors and mucosal defense mechanisms8

9. Pathophysiology PUDA peptic ulcer is an excavation that form in the mucosal wall of the stomach, duodenum or in the esophagus.Peptic ulcer mainly occur in the gastroduodenal mucosa. The erosion is caused by the increased concentration or activity of acid-pepsin or decreased resistance of the mucosa.Damage of the mucosa decreases resistance to bacteria predisposing to infection with H.pylori

10. CAUSES & DEFENSE MXN AGAINST PEPTIC ULCERNormal stateDAMAGING FORCESAcid – gastricPeptic enzymesNormal stateDEFENSIVE FORCESSurface mucusBicarbonateBlood flowProstaglandinsEpithelial RegenerationMucus layerExogenous injurious factorsH.pyloriNSAIDSCigarettesAlcoholEndogenous injurious factorsIschemiaShockDelayed gastric emptyingGastric refluxNo. of parietal cells etc10

11. DRUGS FOR PEPTIC ULCERSPrinciple/Mxn: ♦ Reduction of gastric acid secretion 1. H2-histamine receptor blockers 2. Proton-pump inhibitors 3. Anticholinergic agents(antimuscarinic) ♦ Neutralization of secreted acid - Antacids ♦ Promoting mucosal protection (cytoprotectants) - Prostaglandins - Bismuth cpds - Sucralfate ♦ Eradication of H. pylori infection11

12. H2-HISTAMINE RECEPTOR ANTAGONISTS♦ Moa: competitively bind and block Histamine H2 receptors  reduce all phases of gastric acid secretion  No effect on gastric emptying►E.g. cimetidine, famotidine, ranitidine, nizatidine, roxatidine(CRAFARON)P’kinetics♦ Rapid oral absorption, Parenteral♦ Distribution – wide- breast milk, placenta♦ Elimination – urine 12

13. N/B-if drug receptor binding site results in activation of the receptor the drug is termed as an agonistIf inhibition results the drug is considered an antagonist

14. Uses of H2-HISTAMINE RECEPTOR BLOCKERS1. Duodenal ulcer2. Gastric ulcer 3. GERD4. Prophylaxis 5. As pre-anesthetic agent 6. Zollinger-Ellison syndrome 7. with oral enzyme supplements14

15. Adverse effects of H2-HISTAMINE RECEPTOR ANTAGONISTS  Hypergastrinemia  CNS effects headache and confusion  Muscular pains  Skin rashes  Cimetidine (only) is a weak anti-androgen –  Nizatidine – urticaria, somnolence, sweating  rapid infusion – release of histamine, bradykinin 15

16. Ranitidine (zantac) Is a histamine H2 receptor antagonist that helps lower the production of stomach acid.Indications :Short-term treatment of active duodenal ulcer  Short-term treatment of active, benign gastric ulcerContraindicated with allergy to ranitidine, lactation.Use cautiously with impaired renal or hepatic function, pregnancy.

17. Ranitidine S.E: Headache, malaise, dizziness, somnolence (drowsiness), insomnia, vertigo, Tachycardia, bradycardia, Rash, alopeciaAdult: Active duodenal ulcer: 150 mg bid PO for 4–8 wkPaediatrics: Safety and efficacy not established.Crosses placenta; enters breast milk

18. Ranitidine Decrease doses in renal and liver failure. Provide concurrent antacid therapy to relieve pain.·        Arrange for regular follow-up, including blood tests, to evaluate effects.Teaching: Take drug with meals and at bedtime. Therapy may continue for 4–6 wk or longer.

19. cimetidineCimetidine is associated with more side effectswhich include:GranulocytopeniaGynecomastiaDiarrheaFatigueDizzinessRashMental confusion

20. PROTON PUMP INHIBITORSBlock H+ /K + ATPase  acid production reduced by ~95%They act by irreversiblly inhibiting the H- ∕ K+ ATPase proton pump (hydrogen- potassium adenosine triphosphatase enzyme system) which is necessary for acid secretion from gastric parietal cells. They block the transport of acid from the cell into the lumen. Omeprazole reduces both stimulated and basal acid secretion

21. 2. PROTON PUMP INHIBITORSMOA ► Block H+ /K + ATPase  acid production reduced by ~95%DRUGSOmeprazoleEsomeprazoleIansoprazoleRabeprazole P’kinetics Abs: Rapid, enteric coated, swallow whole; can be reduced by some drugs e.g. sucralfate Metabolized (1st pass)- rapid21

22. 2. PROTON PUMP INHIBITORSUses ofZollinger-Ellison syndrome - DOC –(DRUG OF CHOICE). -GERD –2nd line-Peptic ulcers –1st lineGastritis-Dyspepsia-Prevention of stress related mucosal bleedingAdverse effects Dry mouth,  Hypergastrinemia  CNS effects  Skin Rashes Mild liver damage GIT disturbance - diarrhea can be severe Gynecomastia and impotence (the sexual adverse effects are specific for omeprazole). 22

23. 3. ANTIMUSCARINIC AGENTSMOA: block muscarinic receptorE.g. Pirenzepine, telezepine more selective for receptors in stomach mucosal cellsPotency: telezepine more potent than pirezepine♦ Other antimuscarinicis – mepenzolate, hyoscamineP’kineticsAbs: Poor CNS entryLargely biliary & renal eliminationUsesDuodenal and gastric ulcers23

24. CytoprotectantsDrugs that Protect Gastric Mucosa The cytoprotective agents are used said to enhance mucosal protection mechanisms and/or to provide a barrier over the surface of the ulcer.4. PROSTAGLANDIN ANALOGUES E.g. Misoprostol Effects of PGE2 & PGE1 - ● stimulate secretion of mucus and HCO3(BICARBONATE) ● Increase blood flow ● *Inhibit gastric acid secretion Uses 1. Prevention/ prophylactic & NSAID 2. Peptic ulcers Adverse effectsCommonest -Diarrhea, abdominal painUterus -, spotting, dysmenorrhoea, arbotifacient (to be taken after day 1 of menses)C/I in pregnancy24

25. 5. SUCRALFATE (a cytoprotectant) is a prodrugMOA : form a viscous, sticky gel in the acidic environment & coats the mucosaS/EConstipation D/I – Chelates some drugs ∟↓absorption e.g. phenytoin, digoxinUses Peptic ulcers – long term maintenance Prophylaxis – stress ulcers25

26. 6. BISMUTH COMPOUNDSThis agent just like prostaglandin analogues, are described as cytoprotective. They enhance endogenous mucosal protection mechanisms. Bismuth chelate such as tripotassium dicitratobismuthate can be used in combination with other agents to treat H.pylori infections.a. PharmacodynamicsThis chelate acts in different ways: It has direct toxic effect to bacteria stimulates mucosal prostangladins and bicarbonate secretion, adsorption of pepsin, coats ulcer base and inhibits H.pylori proteolytic enzymesUnwanted effectsBlacken feaces, nausea and vomiting, darken tongueUses: Peptic ulcers H. PyloriContra indications -Renal impairment and pregnancy26

27. 7. ANTACIDSMxn: neutralize HCL  may inactivate Pepsin (pH 5) E.g. Are AL3+, Mg2+ or Na+ hydroxides, carbonates or bicarbonates, Mg-trisilicates Comparison of properties: differ in their capacities, rates, duration and adverse effects – Often prepared as mixtures Na+ salts – most rapid, most potent, most absorbed, Mg2+ & Al3+ – slower, more sustained action  Additive with presence of food Ca2+ can cause rebound hyperacidity Cations absorbed eliminated by kidneyUses Symptomatic relief of dyspepsia(heartburn)27

28. S/E of ANTACIDS On GIT – abdominal distension, belching, flatulence  Diarrhea (Mg) Kidney stones (silica) Constipation (Al) Encephalopathy, osteoporosis, myopathy (Al) Hypophosphotemia (Al)  Systemic alkalosis (Na)  Hypercalcemia & milk-alkali syndrome (Ca) Bismuth salts - encephalopathy and arthropathy.28

29. H. PYLORI ERADICATION. Treatment of Helicobacter Pylori Dual and triple therapy in the treatment of peptic ulcers. Helicobacter pylori has been implicated in 90% of cases of peptic ulcers, hence the treatment usually involves use with antibiotics together with other ulcer healing drugs. The triple therapy comprises a proton pump inhibitor in combination with the antibacterials 1. Penicillins – Amoxycillin2. Metronidazole, tinidazole3. Clarithromycin4. Tetracycline5. Bismuth compounds 29

30. E.g. Regimens used Amoxicillin, metronidazole + omeprozole Omeprozole + either amoxycillin or clarithromycin Bismuth + two antibiotics (metronidazole or tinidazole with amoxicillin or tetracycline

31. ANTIDIARRHOELS

32. Classification.Opioid related/antimotility drugs- loperamide,diphenoxylate Adsorbent Antidiarrheal Agents-kaolin absorbs bactrial toxins and fluid resulting in decreased stool liquidity

33. Antidiarrheals MOA: prevents or relieves diarrhea; inhibits peristalsis and reduces fecal volume E.g. loperamide (slows the passage of stools through the intestines. This allows more time for water and salts in the stools to be absorbed back into the body)S.Es: drowsiness, tiredness, or constipation may occur.

34. Loperamide Tablets, capsules, and liquid:Initial: 4 mg orally after the first loose stool, thenMaintenance: 2 mg after each loose stool, not to exceed 16 mg in any 24-hour period. Clinical improvement is usually observed within 48 hours.Chewable tablets:Initial: 4 mg after the first loose stool, thenMaintenance: 2 mg after each subsequent loose stool, but not exceeding 8 mg in 24 hours.

35. Loperamide Monitor fluid and electrolyte balance.Patient & Family EducationNotify physician if diarrhea does not stop in a few days or if abdominal pain, distension, or fever develops.Record number and consistency of stools.Do not drive or engage in other potentially hazardous activities until response to drug is known.Do not take alcohol and other CNS depressants concomitantly unless otherwise advised by physician; may enhance drowsiness.

36. Bismuth subsalicylateMOA: Hydrolyzed in GI tract to salicylate, which inhibits synthesis of prostaglandins responsible for GI hypermotility and inflammation.Dosage: 262 mg tablets prn not more than 8 doses/dayChild: 131mgS.E: Temporary darkening of stool and tongue, metallic taste, bluish gum line; bleeding tendencies. With high doses: fecal impaction. Encephalopathy (disorientation, muscle twitching). Hematologic: Bleeding tendency. Special Senses: Tinnitus, hearing loss. Urogenital: Incontinence.

37. Nursing ResponsibilitiesMonitor bowel function; note that stools may darken and tongue may appear black. These are temporary effects and will disappear without treatment.

38. Laxatives

39. Introduction.Laxatives/purgatives /carthartics are drugs that promote defecation .They loosen the bowel.Should never be given to pt with undiagnosed abdominal pain

40. General Indications . impacted stool, anal fissures, haemorrhoids, short term treatment of constipation. Preventing straining in postoperative patients. Post myocardial infarction. recent rectal surgeryTo evacuate the bowel for diagnostic procedures. To remove ingested poison form the lower GI tract. As adjunct in anthelmintic therapy

41. Contraindication and Cautions appendicitisdiverticulitis ulcerative colitis. They should be used cautiously in pregnancy . they can stimulate GI tract and induce labor.

42. Laxatives This group is also subdivided as below: bulk products, -high residue foods eg plantago seeds,methycelluloselubricants, mineral oil,liquid paraffinOsmotics causes retention of water increasing bulk of intestinal content eg lactulose ,magnesium sulphatesaline laxative stimulants, and stool softeners E.g. magnesium hydroxide, mineral oil, bisacodyl

43. MOA OF LAXATIVES. Bulk laxatives - absorb water thus adding bulk to the stool,and evokes reflex contraction of the bowel.(increase volume stimulating evacuation)Lubricants- ease the passage of stool Stimulants- speed up peristalsis Saline laxatives- pull water into the intestines increasing fluid content.Osmotics- enhance peristalsis and increase distention/water content stimulating reflex actionStool softeners- reduce the surface tension of liquids within the bowel, acts by softening the hard /impacted stool.

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45. Laxatives Uses: ConstipationAdverse Reactions and Side Effects: abdominal Cramping, diarrhea, and nausea Contraindications: abdominal pain, nausea, vomiting, GI obstruction or perforation, gastric retention and colitis. Caution with large hemorrhoids and rectal bleeding

46. Laxatives Nursing considerations: Monitor blood, I & O, and urine electrolytes.Administer only with water to enhance absorption.

47. Drugs that promote GIT motility/Stimulant LaxativeDrugs-bisacodyl,metoclopramide anthraquinone group for example Senna and dantron; sodium Pico sulfate and glycerol. MOA- stimulate the mysenteric plexus in the intestinal wall causing increased intestinal motility and stimulation of defecation indication –constipation,post surgical to prevent emesis c/i- intestinal obstruction General Adverse Effects of laxatives diarrhea, abdominal cramping, nausea, dizziness, headache, weakness, fluid and elecrolyte imbalance, sweating, palpitations, flushing and fainting metoclopramideextrapyramidal effects, hyperprolactinemia,parkinsonism -metoclopramide

48. Review quizName four classification groups of laxatives indicating MOA giving at least two example in each class.20mksState mode of action of bulk forming laxatives-5mksWhat are the contraindications for bisacodyl-3mks

49. Antiemetic Drugs These are drugs which are used for controlling of nausea and reduction of vomiting. Vomiting is a complex reflex and protective mechanism that promotes the rejection of ingested toxins but may be stimulated by other factors including fear, pain, movement, pregnancy and drugs. There are four receptors that have been identified as being involved in mediating the emetic response namely: dopamine type 2; histamine type 1; serotonin type 3 and muscarinic type 1 receptors. The reflex reaction of vomiting may not be beneficial and antiemetics would become necessary. The available antiemetic drugs acts on these different receptors.

50. CLASSIFICATION OF ANTIEMETIC'S Anti emetics are classified depending on the receptors they act on. acetylcholine receptor antagonist, dopamine receptor antagonists antihistamines (H1 BLOCKER) serotonin receptor antagonist. OTHERS;NK1 receptor antagonist- Neurokinin antagonist used during chemotherapy to tx N&V.Corticosteroids.eg dexamethasoneCannabinoids e.g dronabinol (marijuana)use in ca chemotherapy tx N&VAntimuscarinics e.g scopolamine useful for motion sickness

51. Acetylcholine Receptor Antagonist/Antimuscarinics MOAThey act by blockage of muscarimic type- one receptors in the vestibular system. Examples of drugs in this class include scopolamine and hyoscine.Pharmacokinetics Metabolised in the liver & excreted in urine Indications Prophylactic motion sickness. Pre anesthetic agent for drying of saliva and respiratory secretions. Unwanted effects Blurred vision decreased sweating, constipation, dry mouth. Contraindications cardiac diseases, children, elderly and lactating mothers.

52. Anti-histaminic Antiemetic's Examples of drugs here include cyclizine, promethazine, meclizine, hydroxyzine and buclizine. They act by blocking the action of histamine on H1 receptors. Pharmacokinetics The drugs should be taken 30 minutes before travel. Excretion occurs in urine within 24 hours. Indications Motion sickness Post operatively to prevent vomiting Labyrinthine/vestibular disorders Unwanted effects: include drowsiness, dry mouth. Drug interactions anti histamine antiemetics. additive depression when used concurrently with CNS depressant

53. Dopamine Receptor Antagonist Examples of drugs in this sub- chloropromazine, domperidone, phenothiazines, metoclopromide, haloperidol, and levomepromazine. Pharmacokinetics metabolized in the liver and excreted in urine. Pharmacodynamics Dopamine receptor antagonists block the effect of dopamine 2 receptors on the chemoreceptor trigger zone (Dopamine antagonist). Indications Prevent vomiting caused by cancer chemotherapy and radiation therapy. Control of post operative vomiting. motion sickness. intractable hiccoughs

54. Serotonin (5HT3) Receptor Antagonists Examples include: Granisetron, Ondansetron, Tropisetron, dolasetron. Pharmacodynamics They block the 5HT receptors . General adverse effects drowsiness, dizziness, weakness, tremor and headaches,dry mouth, urinary retention, nasal congestion, sweating, pallor, and anorexia. Photosensitivity is a common problem with many antiemetic's. General Contraindications and Cautions Patients in coma or with severe CNS depression or those who experienced brain damage or injury. Others include severe hypertension and liver dysfunction. Caution should be taken in pregnancy, lactation, renal dysfunction and peptic ulceration. Drug interactions Benzodiazepines, alcohol and other CNS depressant drugs can worsen CNS depression when used with ant emetics, especially antihistamines.

55. DRUGS ACTING ON ENDOCRINE SYSTEMDrugs used in hypothyroidism and hyperthyroidismHormone replacement.Antidiabetics- orals and injectablesDrugs used in cushing syndrome

56. Anti diabetic drugs

57. Anti-diabetic drugs Diabetes - Disease resulting from a breakdown in the body’s ability to produce or utilize insulin (Causes liver, muscle and fat cells to absorb glucose).Types:Type I: results from autoimmune destruction of insulin-producing beta cells of the pancreas.Type II: results from insulin resistance

58. Glycogen

59. Insulin Insulin is a hormone produced by beta cells in the pancreas. It regulates the metabolism of carbohydrates and fats by promoting the absorption of glucose from the blood to skeletal muscles and fat tissue and by causing fat to be stored rather than used for energy.

60. Antidiabetic drugs Anti-diabetics are also subdivided into the following groups: Insulin oral hypoglycemic agents

61. Insulin Insulin: Lowers the blood glucose by facilitating the uptake and utilization of glucose by muscle and fat cells and by decreasing the release of glucose from the liver.

62. Insulin Sources: beef or pork pancreases or can be produced semi-syntheticallyTypes:Rapid acting insulin e.g. Humalog (insulin Lispro)Onset: 10-30min; duration of action: 3-5hrsTime: injected 10mins before a meal. Used with longer-acting insulin.Short acting insulin e.g. actrapid (soluble insulin)Onset: 30min-1hr; duration of action: 5-8hrsTime: injected 30-60 minutes before meals

63. Types of insulinIntermediate acting e.g. Isophane insulin also known as Humulin N, Novolin NOnset: 1-2½hrs; duration of action: 18-24hrsTime: injected 1hr before meals. It is often combined with rapid- or short-acting insulin.Long acting e.g. UltralenteOnset: 30mins-3hrs; duration: 20-36hrsAction: Covers insulin needs for about one full day. This type of insulin is often combined, when needed, with rapid- or short-acting insulin.

64. Cont’dPremixed: a combination of specific proportions of intermediate-acting and short-acting insulin in one bottle. E.g. Mixtard (dose -0.3 and 1.0 IU/kg/day)Time: depending on combination given 30-45mins before mealsAdministered twice in a day.

65. MIXTARD2 formulations of MixtardMixtard® 30Containing 30% short-acting insulin and 70% intermediate actingMixtard® 50Containing 50% short-acting insulin and 50% intermediate-acting insulin

66. insulinGeneral guidelines, 0.5–1 unit/kg/day. The number and size of daily doses, times of administration, and type of insulin preparation are determined after close medical scrutiny of the patient's blood and urine glucose, diet, exercise, and inter current infections and other stresses

67. Sites of insulin injection

68. Administration of insulin

69. Uses Diabetesketoacidosis

70. Side effectsHypoglycemia hepatotoxicity allergic responsesLipodystrophy-atrophy of subcutaneous fat at the sites of injection Lipo hypertrophy-enlargement of subcutaneous fat.prevention by changing injection sites frequently.

71. Contraindications Sensitivity hypoglycemia

72. Oral hypoglycemic drugs Include: Sulfonylureas e.g. glibenclamideBiguanide e.g. MetforminThiazolidinediones e.g. pioglitazone (bladder cancer)Alpha-glucosidase inhibitors e.g. acarbose (Precose)

73. sulfonylureas

74. Oral hypoglycemic drugs 1. Sulfonylurease.g. glibenclamide/ glybride (1.25 mg),chlorpropamide / diabinese (100-500mg)MOA: stimulate insulin secretionS.E: Hypoglycemia2. Biguanide: e.g. Metformin (250mg)MOA: increases insulin action i.e. by suppression of glucose output from the liver.

75. Cont’dMetformin (glucophage) is often used in patients with type 2 diabetes who are obese, because it promotes weight reduction.Given in combination with a sulfonylurea lowers blood glucose concentrations more than either drug alone. Advantages:less likely to cause hypoglycemia. It has prominent lipid-lowering activityS.E: GIT- metallic taste in the mouth, mild anorexia, nausea, abdominal discomfort, and diarrhea.

76. Cont’d 4. Thiazolidinediones – e.g. Actos (Pioglitazone) increase glucose up take of glucose in muscle. Inhibits the breakdown of fat to FFA. 5. Alpha-glucosidase inhibitors – e.g. acarbose (Precose) & Miglitol (Glycet), available in the US. They inhibit the upper GIT enzymes that converts dietary starch and other complex carbohydrates into simple sugars which can be absorbed. The result is to slow the absorption of glucose after meals.

77. sulfonylureas

78. Nursing considerations Monitor blood glucose i.e. FBS and RBSassess for hypoglycemia –lethargy, sweating rotate insulin injection sites . and use human insulin with pork or beef sensitivity.

79. Anticonvulsants.GABA synaptic transmission enhancersMembrane permeability calcium channel reducersMembrane permeability to voltage dependents sodium channel reducers.Glutamate inhibitorsManagement of side effects.

80. Anticonvulsants

81. Convulsions A seizure occurs when the brain becomes over excited or when nerves in the brain begin to fire together in an abnormal fashion. Seizure activity can arise in areas of the brain that are malformed from birth defects or genetic disorders or disrupted from infection, injuries, tumors, strokes, or inadequate oxygenation.

82. Convulsions This electrical signal then spreads to the surrounding normal brain cells, which begin to fire in concert with the abnormal cells. With prolonged or recurrent seizures over a short period, the risk of future seizures increases.

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84.

85. Classification This classification is further divided into: Barbiturates e.g. phenobarbital,mephobarbitoneHydantoins e.g. phenytoin,mephenytoinBenzodiazepines e.g. diazepam, clonazepam (Klonopin), clorazepate (Tranxene)Iminostilbene- carbamazepine (Tegretol)GABA transaminase inhibitors -valproic acid (Depakene), gabapentin (Neurontin)

86. Uses tonic-clonic seizures (formally grand mal) (generalized seizures)-associated with epilepsy Unconsciousness, convulsions, muscle rigidity.Clonic-Repetitive, jerking movements (lasts 30-60 secs)Tonic- Muscle stiffness, rigidity (lasts 30-60 secs) petit mal seizures (last less than 15 seconds) generalized seizures of sudden onset and termination. Brief loss of consciousnessstatus epilepticus (life threatening condition in which the brain is in a state of persistent seizure seen in epilepsy, brain tumor) lasts > 5mins

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88. PhenytoinMOA: Has antiepileptic activity without causing general CNS depression; stabilizes neuronal membranes and prevents hyperexcitability caused by excessive stimulation; limits the spread of seizure activity from an active focus.USES: Prevention and treatment of seizures occurring during or following neurosurgery. Contraindicated with hypersensitivity, lactation

89. Phenytoin Status epilepticus: 10–15 mg/kg by slow IV. For maintenance, 100 mg PO or IV 6–8 hr. Follow each IV injection with an injection of sterile saline through the same needle or IV catheter to avoid local venous irritation by the alkaline solution. Pediatrics: 10–15 mg/kgS.ES: headache, photophobia, Stevens-Johnson syndrome, liver damage, Nausea, vomiting, diarrhea, constipation.

90. SJS

91. Patient teaching Take this drug exactly as prescribed, with food to enhance absorption and reduce GI upset, or without food—but maintain consistency in the manner in which you take it; be especially careful not to miss a dose if you are on once-a-day therapy.This drug is not recommended for use during pregnancy. It is advisable to use some form of contraception other than hormonal contraceptives.-malformations

92. Patient teaching Wear a medical alert tag so that any emergency medical personnel will know that you have epilepsy and are taking antiepileptic medication. Report rash, severe nausea or vomiting, drowsiness, slurred speech, impaired coordination (ataxia), swollen glands, bleeding, swollen or tender gums, yellowish discoloration of the skin or eyes

93. Diazepam MOA: Depress the CNS and produces skeletal muscle relaxation.Effects: relief of anxiety, sedationIndication: anxiety, OTHERS?Contraindication: comatose ptsS.E: headache, blurred visionN.R: Monitor BP, PR,RR prior to periodically throughout therapy Assess IV site frequently during administration, diazepam may cause phlebitis and venous thrombosis.

94. Antipsychotics

95. Antipsychotic drugsMood stabilizersAntidepressantsMOA inhibitorsPsychostimulantsSedativesHypnoticsAlcoholsBarbituratesAlcoholBenzodiazepines.

96. Antidepressants

97. Pathophysiology Causes: Stressful life events, genetics, personality, and sex may also play a role.Neurotransmitters attach themselves to the end of brain receptors as a means of communication. In depressed individuals, the neurotransmitters do not stay with the receptors long enough which upsets the balance of communication.

98. Neurotransmitters involved Serotonin: inadequate levels lead to low moodDopamine: responsible for positive effects and perceptions in the mind such as pleasure and desire , regulates memory. Evidence suggests that in depression, abnormalities in dopamine may be related to impaired motivation and concentration, low levels of noradrenaline and dopamine may play a role in the fatigue and hypersomnia, and impaired noradrenaline and serotonergic regulation may contribute to physical symptoms

99. Antidepressant drugsTricyclic antidepressantsAmitryptiline, clomipramine (also an SSRI), imipramine, desipramine, nortriptyline, doxepin, maprotiline, protriptylineSelective serotonin reuptake inhibitors (SSRIs)Fluoxetine, citalopram, fluvoxamine, clomipramine, paroxitene, sertralineMAO inhibitorsPhenelzine, tranylcypromine,clorgyline isocarboxazidOther antidepressant drugsBupropion, hypericum, mirtazapine, nefazodone, trazodone, venlafaxineMood stabilizing drugsCarbamazepine, valproate, valporic acid, lithium

100. MOA (Monoamine Oxidase) inhbitors MAOs- inhibit MAO (enzyme that breaks down serotonin, noradrenaline) and thus they increase epinephrine, norepinephrine, serotonin, and dopamine. MAO is one of the enzymes that break down biogenic amines (Norepinephrine, epinephrine & serotonin).These drugs prevents this process therefore amines accumulate in the presynaptic granules , increase the concentration of neurotransmitters causing nerve stimulation antidepressant effect

101. .Tricyclics/Heterocyclics- block the reuptake of serotonin and norepinephrine in the nerve endings, thus increasing their actions of both in the nerve cells.Indications: Major depressive disorders, anxiety disorders

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103. cont’dSSRIs (Selective serotonin reuptake inhibitors) : increase the extracellular level of serotonin by inhibiting its reuptake into the pre synaptic cell, therefore increasing the level of serotonin in the synaptic cleft available to bind to the post synaptic nerve.

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105. UsesDepression. Nocturnal enuresis in children.

106. Side effectsOrthostatic hypotension, mouth dryness, dizziness, drowsiness, urinary retention, hypertension, renal failure paralytic ileus.

107. contraindicationsHypertrophy of the prostate, seizure disorders, renal, hepatic and cardiac disease.

108. Summary antidepressants.Tricyclic antidepressants- amitriptyline,, clomipramine,imipramineMOA-Blocks norepinephrine (NE) and 5-HT transportersIndications-major depression -Chronic pain -Obsessive compulsive disordersSide effects- sedation,weight gain, dry mouth, constipation, blurred vision and urinary retention, postural hypotension, seizures and impotence.D/I Antispychotics and steroids may inhibit TCAs elimination. Asprin may displace TCAs from binding sites. TCAs and alcohol pontetiate the effect of each other hence death has been reported due to severe respiratory depression

109. Selective Serotonin Reuptake Inhibitors (SSRIs) fluoxetine, paroxetine, sertraline and citalopramMOA-SSRIs inhibit reuptake of only serotoninUSES-major depression-Anxiety-OCD-Bulimia-Bipolar disordersUnwanted Effects – N&V, d, agitation, insommia, anorgasmia and priapism

110. Mono-Amine Oxidase Inhibitors (MAOIs) E.G phenelzine, isocarboxazid, tranylcypromine, selegiline, moclobemide and pargylineMOA- Inhibit MAO type A which metabolises NE and MAO type B Metabolises dopamineIndication-major depression.Unwanted effects decrease BP, tremors, excitement, insommia, weight gain due to increase in appetite-Atropine-like effects, that is, antimuscarinic effects.-Hepatotoxicity

111. noteDrug interactions -Cheese reaction- May interact with tyramine containing foods like aged cheese, beef, liver, broad bean pods, and aged chicken to cause ‘cheese-reaction’.Tyramine causes increased adrenaline production resulting to increased sympathomimetic effect which leads to increased blood pressure, headache and intracranial hemorrhage due to hypertensive crisis

112. Nursing considerationsMonitor standing and lying BP, orthostatic hypotension blood, mental status, hepatic function. Observe for urinary retention. Withdrawal symptoms occur with abrupt cessation. Teach patient on MAO inhibitors to avoid food containing tyramine (dairy products, meat, fish, liver, some fruits (such as avocado, fig, and banana), chocolate, and yeast extracts. Coz tyramine breaks down in the GI tract (in the presence of MAO inhibitors) and release vasopressors will lead to hypertensive crisis (severe elevation in blood pressure).Teach patient to avoid alcohol and other sleep inducing drugs.

113. Central Nervous System Stimulants/ Psychostimulants amphetamines - dextroamphetamine, methamphetamine and methylphenidate MOA- increase release of catecholamines during normal CNS activity.block reuptake (amine-pump) at presynaptic membranes hence postsynaptic nerves get increased stimulationAmphetamines stimulate RAS; hence increase alertness and sensitivity to stimuliNB reticular activating system (RAS) controls the level of arousal

114. IndicationNarcolepsy ,ADHD ( attention deficit hyperactivity disorder) and obesity. Unwanted effects insomnia, irritability, irregular heartbeat, growth retardation in childrenaddictive.

115. Hypnotics and Anxiolytics Hypnotics and anxiolytics promote sleep and reduce anxiety. The commonest drugs used in this group are the benzodiazepines and sometimes barbiturates.

116. Benzodiazepines most widely used hypnotics and anxiolytics .These drugs are classified according to the half life which ranges from 5-24 hours.Short-acting - midazolam, triazolam have half life of 5 hrsIntermediate acting lorazepam, oxazepam, clonazepam have a half life of 5-24 hoursLong-acting for example diazepam, chlordiazepoxide, prazepam have half life of above 24 hrs

117. The metabolism and excretion occurs in the liver and urine respectively. Indications-Generalized anxiety disorder, situational anxiety, Panic disorders agoraphobia and insomnia.Seizures –used initially for status epilepticus. Pre-anesthetic and intraoperative medication – preferred due to their anxiolytic, sedative, amnestic actions which are required in operations for example Lorazepam, diazepam and midazolam. Muscle relaxation – muscle spasms, spasticity of cerebral palsy and spasms associated with endoscopy for example diazepam.

118. Unwanted effectsDaytime drowsiness, ataxia, rebound insomnia, confusion, blurred vision, tremors, constipation , amnesia; Respiratory depression Decreased BP and heart rate.They enhance CNS depression when taken in combination with alcohol. They also cause dependence

119. noteBenzodiazepine withdrawal syndrome develops any time upto 3 weeks after stopping long acting benzodiazepines or within few hours after stopping short acting benzodiazepines. It is characterized by anxiety, insomnia, GIT disturbances, tinnitus, perceptual disturbances, lack of appetite, perspiration

120. Contraindications and Cautions pregnancy Shock acute alcohol intoxication.Drug Interactions Alcohol plus the benzodiazepines cause severe CNS depression.Cimetidine, disulfiram, and oral contraceptives increase benzodiazepine effect.Ranitidine and theophylline decrease benzodiazepine effect.

121. DiazepamIndications i. Sedation, relaxation, muscle relaxant, symptomatic anxiety. ii. Alcohol withdrawal (acute) syndrome. iii. Induction of GA.

122. alcoholEthanol a sedative-hypnotics .-indication –antseptic,appetite stimulant,neuralgia,mngt of bedsores,beveragesAntidote in ethylene glycol poisoningEffects-CNS depression,RS failure,damage liver,pancreas,git,Methanol- use as a cleaning agent.Effects-visual dysfxn,git distress,shortness of breath,loss of consciousness and coma-retinal damage and blindnessEthylene glycolEthylene glycol

123. Drugs used to treat alcohol withdrawalThiamine.sedative –hypnotics.Drugs to treat alcohol dependenceDisufiramNaltrxoneAcamprosateDrugs to treat acute methanol or ethylene glycol intoxicationEthanol-competes for alcohol dehydrogenase hence lowers metabolism of methanol and prevent toxic metabolitesFomepizole-inhibit enzyme alcohol dehydrogenase therefore prevent toxic metabolites

124. Mood stabilizersLithium, carbamazepine and valporateLithiumRef to as mood stabilizer as it reduces both manic and depressive symptoms thereby normalizing the mood in patients with bipolar disorder MOAThought to be by suppression of the formation of inositol triphosphate (IP3) thus reducing neuronal response to serotonin and N/E.Also interferes with the formation of CAMPThis produces a calming effect after several days or weeks of Rx.124

125. A/effects of lithiumHas low margin of safety May cause neurotoxicity and cardiac toxicity leading to arrhythmiasPolyurea because it interferes with the action of Antidiuretic hormone(ADH)Nausea and vomitingDrowsiness, weight gain and fine hand tremorsInteractions-interacts with NSAIDs and antipsychotic drugs. Nacl increases its excretion.Other mood stabilizing drugsCarbamazepinevalporate125

126. Antipsychotics/Neuroleptics and Bipolar Drugs

127. ANTIPSYCHOTICThe groups are: 1)Classical/typical neurolepticsa)Phenothiazines e.g. chlorpromazine,triflupromazine,thioridazine,fluphenazine,thioridazine.b)Thioxanthenes e.g. thiothixene, chlorprothixene, flupenthixolc)Butyrophenones e.g.haloperidol,droperidol,trifluperidol2)Atypical neuroleptics e.gclozapine,olanzapine,risperidone3)Miscelaneous e.g reserpine,loxapine

128. Antipsychotics cond’Actions: All of these pharmacological agents block the dopamine receptors in the brain, the area that involves psychotic behavior Uses: Schizophrenia, mania, paranoia, and anxiety. They are also sometimes used for unrelieved hiccups, nausea, vomiting, and pediatric behavioral problems as well as pre-operative relaxation. Adverse Reactions and Side Effects: dry mouth, photosensitivity, hypotension

129. Antipsychotics contd’Contraindications: severe hypertension, severe depression, parkinsonismNursing considerations: Monitor liver function, I & O, blood pressure lying and standing (orthostatic hypotension). Observe for dizziness, palpations, tachycardia, changes in affect, level of consciousness, gait and sleep patterns. E.g. :Haloperidol, chlorpromazine

130. ArtaneIndicated for control of extrapyramidal disorders caused by antipsychotic drugs S.Es: dry mouth, nausea

131. Effects of Antipsychotic agents Psychological effects> Most antipsychotic drugs cause unpleasant subjective effects in nonpsychotic individuals;> Nonpsychotic persons also experience impaired performance Psychotic individuals, however, show improvement in their performance as the psychosis is alleviated.EEG effects-produce a shift in the pattern of EEG frequencies usually slowing & increasing their synchronization. 131

132. Endocrine effects Amenorrhea-galactorrhea, false-positive pregnancy tests, and increased libido in women,Men-decreased libido and gynecomastia. Infertility, impotenceHyperglycemia may develop.Some of these effects are secondary to blockade of dopamine's tonic inhibition of prolactin secretion; others may be due to increased peripheral conversion of androgens to estrogens. 132

133. Cardiovascular effectsOrthostatic hypotension and high resting heart rates frequently result from use of the low-potency phenothiazines. Mean arterial pressure, peripheral resistance, and stroke volume are decreased, and heart rate is increased. Abnormal ECGs , especially with thioridazine.; Changes include prolongation of QT interval and abnormal configurations of the ST segment and T waves. These changes are readily reversed by withdrawing the drug.133

134. Cont..prolongation of the QT interval with increased risk of arrhythmias > sertindole was withdrawn shortly after being marketed. Ziprasidone carries a warning about the risk of significant QT prolongation.134

135. Adverse ReactionsBehavioral effects. A "pseudodepression" due to drug-induced akinesia.> responds to treatment with antiparkinsonism drugs . Decreasing the dose may relieve the symptoms.135

136. Cont…Neurologic effectsExtrapyramidal reactions : Parkinson's syndrome, akathisia (uncontrollable restlessness), and acute dystonic reactions Tardive dyskinesia, an abnormal choreoathetoid movements Seizures, a complication of chlorpromazine treatment.136

137. Cont.. Autonomic nervous system effectsConstipation, loss of accomodation urinary retention .Dry mouthimpaired ejaculation >- chlorpromazine or mesoridazine. managed by switching to drugs with less marked adrenoceptor-blocking actions.137

138. Cont… Metabolic effectsWeight gain, especially with clozapine and olanzapine Hyperglycemia may develope.Hyperlipidenemia may occur. 138

139. Cont.. Toxic and allergic reactions Agranulocytosis, cholestatic jaundice, and skin eruptions Ocular complicationsDeposits in the anterior portions of the eye (cornea and lens) are a common complication of chlorpromazine therapy. 139

140. Cont..Thioridazine causes retinal deposits, which in advanced cases may resemble retinitis pigmentosa.The maximum daily dose of thioridazine has been limited to 800 mg/d to reduce the possibility of this complication140

141. Cont… Cardiac toxicityThioridazine in doses exceeding 300 mg daily is associated with minor abnormalities of T waves. Overdoses of thioridazine are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death.141

142. Cont.. Ziprasidone carries the greatest risk of QT prolongation and should not be combined with other drugs that prolong the QT interval, including thioridazine, pimozide, and quinidineClozapine is associated with myocarditis.142

143. Indications. Psychiatric indications -Schizophrenia the primary indication . -Schizoaffective disorders, -The manic phase in bipolar affective disorder - Tourette’s syndrome- disturbed behaviors in a pt with Alzheimer's disease -Psychotic depression 143

144. Cont.. Non psychiatric indicationsMost except thioridazine, have a strong antiemetic effect. eg prochlorperazine and benzquinamide, are promoted as antiemetics.Phenothiazines have considerable H1-receptor-blocking action and have been used for relief of pruritus .Promethazine- as preoperative sedatives. Butyrophenone droperidol is used in combination with fentanyl, in neuroleptanesthesia. 144

145. Cont…Use in pregnancyAlthough the drugs appear to be relatively safe in pregnancy, a small increase in teratogenic risk could be missed.Neuroleptic malignant syndrome Life-threatening disorder occurring in patients who are extremely sensitive to the extra pyramidal effects of antipsychotic agents. 145

146. Cont…S& S muscle rigidity.Fever, often reaching dangerous levels. The stress leukocytosis and high fever may erroneously suggest an infectious process. Autonomic instability, with altered blood pressure and pulse rate, is often present. Muscle-type creatine kinase levels are usually elevated, reflecting muscle damage due to excessively rapid blockage of postsynaptic dopamine receptors.146

147. treatment vigorous treatment of the extrapyramidal syndrome with antiparkinsonism drugs is worthwhile. Muscle relaxants, particularly diazepam. Other muscle relaxants, such as dantrolene, or dopamine agonists, such as bromocriptine, have been reported to be helpful. 147

148. References1. Katzung et al, 2009. Basic and Clinical Pharmacology, 11th ed.2. Brunton L.L et al, 2006. Goodman and Gilman’s: The pharmacological Basis Of Therapeutics, 11th ed.148

149. Drugs used in surgery.Depolarizing and non depolarizing muscle relaxant agentsGeneral anesthesia-inhalation and intravenousLocal anesthetics

150. Introduction.Anesthetic agents were introduced in mid 19th century (that is diethyl ether), chloroform was introduced. These are currently obsolete. Mostly anesthetic agents were introduced in the last 40yrs. Initially; surgery was done at high speed under alcohol, opium, cannabis etc.

151. Properties of anaesthetic agents Loss of consciousness, - nitrous oxide & halothane Analgesia -Muscle relaxation-neuromuscular blocking drugs e.g. atracurium, pancuronium

152. Balanced Anesthesia Ideal anesthesia would produce: Analgesia, Unconsciousness, Muscle relaxation and Reduction of reflex activity. Characteristics of such anesthetic agents include: Acts promptly rapidly eliminated easy to reverse Produces no unwanted effects in body tissues. several drugs are used in combination to achieve these goals as seen above. For surgical anesthesia: Opioid, Nitrous oxide, skeletal muscle relaxant. Anasthesia is induced with barbiturate or diazepam or other agents, and then nitrous, oxide, then skeletal muscle relaxantChoice of opioids depends on length of surgery.

153. General anaestheticsGAsblock conduction of pain impulses to the sensory cortexGasClassificationInhalation anaestheticsNon halogenatedNitrous oxideHalogenatedHalothane, desflurane, enflurane, isoflurane, sevoflurane ParenteralKetamine, mildazolam, fentanyl, thiopental, propofol

154. GAsInhalationMOA-interact with hydrophobic regions of proteins in neuronal membranesNon-halogenated-NO↑analgesia, ↓loss of consciousnessHalogenated-HalothaneRapid induction + recovery S/E-dose dependent resp./cardiac depressionUterine relaxation → C/I in pregnancyParenteralBarbiturates/benzodiazepines/opioidsPre anaesthetic sedation, analgesia+ anaesthesia for major/minor surgery

155. KetamineBlocks receptors for excitatory amino acids e.g. glutamateA/E-may cause unpleasant effects during recovery stageMildazolamShort acting benzodiazepinePreoperative sedation/endoscopyEffects reversed by flumazenilPropofol /ThiopentalPotentiate GABARapid onset/short duration of actionInduction of anaesthesiaFentanyl

156. Type of general anaestheticsI. V. BenzodiazepinesI. V. BarbituratesI.V. OpioidsKetaminePropofolCombinations

157. Inhalational anaestheticsRationale for the use inhalational anesthetics Provide hypnosisEnhance or provide analgesiaProvide muscle relaxation Reduce visceral reflex responses Enable lower doses of inhalational agent to be used

158. Nitrous Oxide Weak anesthetic, by itself is not suitable or safe as a sole anesthetic agentEffective analgesicMinimal skeletal muscle relaxationNo significant effects on the liver, kidney, or GI tractVery rapid onset and recoveryLittle toxicityUse as an adjunct to other inhalational agents allows reduction in their dosage

159. HalothaneLoss of consciousness; but does not provide adequate analgesia; reversible reduction in glomerular filtration rates (GFR)Advantages: Relatively potent and nonflammableRelatively rapid induction & recovery from anesthesiaIndicationsMainly used in pediatric anesthesia Infrequently used in adults due to the availability of other agents which exhibit relatively more favorable pharmacological properties e.g. isoflurane, enflurane, sevoflurane and  desflurane A/EffectsHepatitis occurrencesCauses significant myocardial depressionAssociated with malignant hyperthermia

160. EnfluraneRapid induction with limited effects on pulse or respirationLess arrhythmias, nausea, post-operative shivering and vomiting compared to halothane Adequate muscle relaxation greater than halothaneReversible reduction of GRFUses: Mainly in adults. Not widely used in pediatric casesA/EffectsNot recommended for use in patients with seizure disorders. Avoided in epileptic patients because it occasionally induces CNS excitatory effectsMay cause malignant hyperthermia

161. IsofluraneRapid induction of anesthesia with limited effects on pulse or respirationNo hepatic and renal toxicityProvides adequate muscle relaxation greater than halothaneReversible reduction of GRFUsesIsoflurane is the most widely used inhalational agent A/Effects: May cause malignant hyperthermia (as with halothane & enflurane) 

162. DesfluraneRapid onset and recovery , recovery twice as rapid as for isofluraneCauses laryngospasm and coughingDoes not provide adequate muscle relaxation Circulatory effects similar to isofluraneReversible reduction of GRFSeizure-like activity is not observedA/E: Malignant hyperthermia, coughing and laryngospasmSevofluraneLow blood solubility & high potencyPharmacological properties as of desfluraneCommonly usedIncrease fluoride levels rarely associated with kidney or renal damageCompared to desflurane,  sevoflurane is more extensively metabolized, releasing more fluoride

163. Intravenous drugs used in anaesthesiaBarbiturates – thiopental, methohexital sodium, thiamylal sodium Benzodiazepines - Diazepam,mildazolam, lorazepam Opioids - Morphine, meperidine , fentanyl , sufentanil , alfentanil , remifentanil PropofolKetamine

164. Intravenous barbiturates used in AnesthesiaThiopental, methohexital sodium, thiamylal sodium Thiopental Pharmacological properties:Rapid induction and fast recoveryRapid recovery (20-30 min) due to redistribution from brain to peripheral tissuesLittle postoperative excitement or vomitingA/EffectsCough, laryngospasm, bronchospasm & histamine releaseDose-related respiratory depression; Limited cardiovascular effectsCrosses the placental barrier and depresses the fetusContraindications: Variegate porphyria or acute intermittant porphyria. Barbiturates can cause nerve demyelination and CNS lesions which may result in pain, weakness and life-threatening paralysis

165. BenzodiazepinesIntravenous benzodiazepines used in anesthesia  Diazepam (prototype), mildazolam, lorazepam Benzodiazepines are effective in promoting sedation and reducing anxietyMidazolam has the most rapid onset of action and a shorter durationBenzodiazepines are not analgesicAmnesic in most patientsUsed alone benzodiazepines have limited depressant effects on the cardiovascular/respiratory system.CNS depression can be reversed by the specific anatagonist flumazenilWhen administered in combination with opioids, significant cardiovascular and respiratory depression may occur

166. UsesUsed alone for procedures not requiring analgesia, such as endoscopy, cardiac catherization & certain radiological proceduresUsed in combination with other drugs for "balanced anesthesia"- which include opioids, muscle relaxants & thiopental for induction and an inhalational agent

167. Intravenous opioids used in anesthesiaMorphine, meperidine , fentanyl , sufentanil , alfentanil , remifentanil Opioids are used to supplement inhalational or i.v. anestheticsMorphine-nitrous oxide combination has been used in cardiovascular surgeryA/EffectsRespiratory depression, hypotension, post-operative nausea or vomiting are associated with opioid useRespiratory depression caused by opioids is reversed by using specific narcotic antagonists – Naloxone, naltrexone, nalmefene

168. Fentanyl and related agents FentanylI.V. fentanyl causes analgesia and unconsciousnessCompared to morphine, fentanyl is: More amnestic Less likely to provoke hypotensive or hypertensive responses Shortened duration of respiratory depression Fentanyl and related agents therefore preferrred to morphineUsesFentanyl is often combined with a muscle relaxant and nitrous oxide or low doses inhalational agent for anesthesia

169. Alfentanil and sufentanilAlfentanil and sufentanil are more potent than fentanyl and produce analgesia, and at higher concentrations- anesthesiaRemifentanil - a new potent agent which produces analgesia very rapidlyReadily metabolized resulting in rapid recovery timePropofol I.V.  propofol rapidly induces anesthesia, similar to thiopental; with minimal postoperative confusionDuration of anesthesia can be increased by combination with inhalational agents, nitrous oxide, or opioidsDoes not adversely affect hepatic or renal functionPostoperative GI upset occur at a similar frequency to that of thiopentalUses: In ambulatory surgery settings

170. KetamineProduces a state that is characterized by sedation, amnesia, analgesia and immobility This type of anesthesia has been termed "dissociative anesthesia" because of patient's subjective impression of being dissociated from the environmentSignificant amnesia and analgesia rapidly follow injectionRecovery is slower than with barbiturates A/EffectsAwakening may be associated with bad dreams and hallucinations These A/E uncommon in children and can be reduced by concurrent administration with benzodiazepinesUses In conjunction with diazepam, in emergency surgery, trauma, dressing changes and certain pediatric radiological procedures

171. Skeletal muscle relaxantsNMJ blocking drugsNon-depolarizingTubocurarine, pancuronium, atracurium, vecuronium, rocuroniumDepolarizingSuccinyl cholineSpasmolytic drugsDrugs for chronic spasmDiazepam, baclofen, botulinum toxin, tizanidine, dantrolene Drugs for acute muscle spasmCyclobenzaprine

172. Non-depolarizing NM blocking drugsMOAPrevents action of Ach. at skeletal muscle end plateEffects reversed by cholinesterase inhibitors- neostigmineDepolarizing NM blocking drugsSu-cholineDepolarizes NM end plateA/E resp. paralysis, Hyperkalemia, peripheral nerve dysfunctionStimulates autonomic gangliaInteractions: inhaled anesthetics, aminoglycosides

173. Spasmolytic drugsDrugs that reduce abnormally elevated muscle tone(spasm) without causing paralysis e.g. baclofen, dantroleneAction: CNS, skeletal muscle cellsChronic painDiazepam-GABA mediated inhibition at the spinal cordBaclofen - GABAB agonistTizanidine- reinforces both pre- and post synaptic inhibition in the spinal cordDantrolene-↓ release of activator Ca from sacroplasmic reticulumRx Malignant hyperthermia

174. Acute muscle spasmCyclobenzaprineThought to act in the brain stem by interfering with polysynaptic reflexes that maintain skeletal muscle toneA/E confusion and hallucination in some patients

175. LOCAL ANAESTHETIC AGENTS.175

176. Local Anesthesia Local Anesthesia – Local anesthesia is the condition that results when sensory transmission from a local area of the body to the CNS is blocked.Local anaesthetics- Drugs which block nerve conduction when applied locally to nerve tissue in appropriate concentrations. MOA They abolish the sensory perception over a local area by acting locallyPrevent generation and conduction of nerve impulses.Blockage of voltage gated sodium channels.176

177. HISTORY.Cocaine was the first agent isolated by Niemann in 1860 and was clinically used first in eye surgery by Koller in 1884Einhorn synthesized Procaine in 1905Lidocaine was synthesized in 1943 by Lofgreen and is still a popular drug.177

178. CHEMISTRY. LA agents are weak bases which are usually water soluble Available as an acidic solution which is highly water soluble and stable. 178

179. PROPERTIES OF AN IDEAL LA AGENT. Must be water soluble. Rapid onset of action. Duration of action should be sufficient to allow surgical procedure. Should be stable in solution.179

180. cont’Be non-toxic both locally and when absorbed into the circulation (no local irritation or tissue damage). Should be effective when injected into the tissue and when applied topically to the mucous membrane. Effects should be completely reversible. No after effect180

181. CLASSIFICATION.1) According to the structure of the intermediate chainEsters—Cocaine, Procaine, Tetracaine, Benzocaine, Amethocaine—metabolized in the plasma.Amides—Lidocaine (synonyms are Lignocaine, Xylocaine), Prilocaine, Efidocaine, Mepivacaine, Bupivacaine, Ropivacaine (recent)—metabolized in the liver.2) According to the duration of actionShort acting—ProcaineIntermediate acting—Cocaine, Lidocaine, Mepivacaine, PrilocaineLong acting—Tetracaine, Bupivacaine, Efidocaine, Ropivacaine181

182. classificationEstersLong action: tetracaineShort action: procaineSurface action: benzocaine, cocaineAmides Long action: bupivacaine, ropivacaineMedium action : lidocaine182

183. MOA. Peripheral nerve blockade —blockade of the voltage gated Na-channels. Primary site of action is cell membrane. LA bind to receptors near the intracellular end of the Na-channel and block the passage of Na+ through the voltage gated Na-channel thereby preventing initiation and propagation of the nerve impulse (action potential) by—↑ the threshold for excitation. ↓ impulse conduction. ↓ the rate of rise of action potential. ↓ amplitude of action potential. Abolishing the ability to generate action potential183

184. Points to noteBlockade of Na-channel is voltage and time dependent.Effect is more marked in rapidly firing axons than in resting fibre and with longer depolarization fibres.Extracellular calcium decreases the LA activity.↑ K+ level increase LA activity.The smaller and more lipophilic the molecule, the faster the rate of interaction with Na-channel. More lipophilic—more potent and longer duration of action.184

185. Cont’Smaller fibres are blocked first- conduct pain, temperature and autonomic activity.The small type-A delta fibres blocked next.Motor fibres are blocked last.They block the small fibres because the distance over which such fibres can passively propagate an electrical impulse (related to space constant) is shorter (greater surface area). Exception—effects of fibre position in nerve bundles. In large nerve trunks, motor nerve is usually located outside, exposed first to the drug and blocked before sensory nerve.185

186. HOW TO PROLONG DURATION OF ACTION.Adding the vasoconstrictor substances like epinephrine/adrenaline usually 1:200,000 or1:40,000.Adrenaline acts on the α1 receptor and produces vasoconstriction; there is ↓ blood flow to the injection site and ↓ systemic absorption of LA from the deposit site.NB:- Should not be used in tips of finger or nose because of chances of necrosis as there is no collateral supply.186

187. If given in spinal anaesthesia.Adrenaline acts directly on the spinal cord by stimulating the α2 receptor which:- Inhibits the release of substance-P. Inhibits dorsal horn neuron firing. Enhanced local anaesthetics uptake by the nerve.Reduce systemic absorption. α2 activation in the CNS.187

188. DANGERS OF PROLONGATION OF ANAESTHESIA.Delay in the healing of wounds.Tissue oedema.Necrosis of the local parts— amines ↑ O2 consumption of the tissues and vasoconstriction leads to hypoxia and causing tissue damage. This tissue damage sometimes becomes serious specially on feet and digits.NB: Adrenaline doubles the duration of action.188

189. PHARMACOKINETICS. Can be given topically or by injection Systemic absorption of the injection LA from the site of administration is modified by— 1) Dosage. 2) Site of injection. 3) Drug tissue binding. 4) Presence of vasoconstrictor substances. 5) Physiochemical properties of the drug.189

190. Can cross the placental barrier. Chlor-procaine reaches minimum to the foetus because of rapid destruction by hydrolysis. Amide compounds—hydrolyzed by CP-450 enzyme by the process of dealkylation in the liver. Widely distributed. Esters compounds—hydrolyzed very rapidly in the blood by butyryl-cholinesterase (pseudo-cholinesterase), so they have extremely short half life (less than 1 min in case of Procaine)190

191. EFFECTS.Vasodilatation causing hypotension and bradycardiaHeadache/dizzinessSepsisNausea and vomitinghypersensitivity, local irritation ComplicationsOn Brain —anxiety, restlessness, tremors, euphoria, agitation and even convulsion.On CVS —Lidocaine is a cardiac anti arrhythmic drug. If high doses are used, absorption from the infiltration site through the systemic circulation will also be high which may cause ↓ excitability and conductivity of heart resulting in cardiac depression. RS-Respiratory paralysis Cauda equina syndrome-loss of control over bladder and bowel sphincter191

192. CLINICAL USES.LA is generally used when loss of consciousness is neither necessary nor desirableAlso can be used as an adjunct to major surgery to avoid high dose of GANB.Benzodiazepines—usually given as premedication to counteract the central excitation of LA specially of cocaine192

193. PROCEDURE OF USE OF LA. Topical or surface anaesthesia.Used on the mucous membrane of the mouth and nose. Effect on the skin is less satisfactory.Tracheobronchial tree and urethra.Available as solution, ointment, jelly, cream or lozengeContinuous use can produce allergy.Popular surface anaesthetics are Lidocaine, Divucaine, Benzocaine, Tetracaine.Lignocaine is used to control pain in haemorrhoids, small burns etc.193

194. Infiltration anaesthesiaInjection of LA under the skin. Infiltration produces anaesthesia over a local area.Paralysis of the sensory nerve endings and small cutaneous nerves.Adrenaline can be given to prolong the action. (not in the terminal parts of the body)194

195. Regional block Involves the injection near a nerve or nerve-plexus proximal to the surgical site.Provides excellent anaesthesia for a variety of procedures.These includes—Nerve block, Intravenous, Extradural (epidural) and Spinal (subarachnoid, intrathecal)Examples—Lidocaine, Procaine, Prilocaine.195

196. Nerve blockAnaesthetizes a region by injecting the drug around the peripheral nerve or a plexus.Provides its own muscular relaxation as motor fibres are blocked along with sensory fibres.Special forms are brachial plexus block (commonly used for upper extremity) and sciatic/femoral/obturator plexus block (commonly used for lower extremity)Examples—Lidocaine, Procaine.196

197. Intravenous anaesthesia.A double cuff is applied to the area, inflated above the arterial pressure after elevating the limb to drain venous system and the veins filled with 0.5% Prilocaine without adrenaline.The arm is anaesthetized in 6-8 min and the effect lasts up to 40 min if the calf remains inflated.197

198. Extradural (epidural) anaesthesiaThe drug is injected into the Extradural space to act on the nerve roots.Can be used in thoracic, lumbar and sacral regions.Widely used in obstetrics.Risk of headache and hypotension is less than spinal anaesthetics198

199. Spinal anaesthesiaThe drug is introduced directly into the CSFProduces extensive and profound anaesthesiaSites of action are spinal nerve roots, spinal ganglion and perhaps the spinal cordOnset is rapid and proper drug duration may last from 1-4 hoursThere is hypotension due to block of the sympathetic nervous systemHeadache due to CSF leakageExamples—Procaine, Lidocaine.199

200. ADVERSE EFFECTS.CNS and cardio-pulmonary systems are most commonly affected. CNS.Sleepiness, light headedness, visual and auditory disturbances, restlessness, paraesthesia (face and tongue), nervousness, nausea, vomiting, abdominal pain, tremor, nystagmus, shivering, tonic and clonic convulsion followed by CNS depression and death (Cocaine is the most widely abused). Treatment is Diazepam.200

201. PNS.Chlorprocaine is more toxic than others. Recently Lidocaine is reported as more neurotoxic. CVS. Results partly from direct effects on cardiac and smooth muscle membranes and from indirect effect on ANS. LA depress abnormal cardiac pacemaker activity, excitability and conduction. Also depress strength of cardiac contraction (except cocaine which cause arteriolar dilatation). Both effects produce hypotension.201

202. Cocaine causes hypertension. Bupivacaine is more cardiotoxic. Ropivacaine is a new drug and less toxic.202

203. Blood. Prilocaine causes Meth-haemoglobinaemia. Produces accumulation of metabolic O-toludine, an oxidizing agent converting Hb to Meth-Hb. Methylene-blue is a reducing agent that converts Meth-Hb to Hb.203

204. Allergic reaction.Ester linked compounds are metabolized and converted into PABA which is allergic.Amide linked compounds are less allergic.There are rashes, asthma, and anaphylactic shock.204

205. INDIVIDUAL LAs. Lignocaine / Lidocaine / Xylocaine.Most commonly used LA.Amide type.Surface use as well as injection.Comparatively less toxicity.Useful in cardiac arrhythmia.Rapid onset and prolonged action.205

206. Prilocaine.Lesser toxicityMeth-haemoglobinaemia Bupivacaine.Long actingUsed for nerve block (obstetrics and post surgical pain relief too) due to Prolonged duration of action used as post operative analgesic.4 times more potent and toxic than Mepivacaine.206

207. Efidocaine.Prolonged actionUsed for regional block including epidural anaesthetics Mepivacaine.Prolonged action than Lidocaine.More rapid onset of action.Topical application –not effective.Used widely in obstetrics but there is risk of early transient neuro-behavioural effect. 207

208. CHOICE OF LA.NB:-Choice of LA —none is the best. Lignocaine may be the safest and best for surface anaesthetics and for infiltration Lignocaine and Prilocaine.Potency.Procaine → Tetracaine → Lidocaine → Etidocaine → Mepivacaine → Bupivacaine.208

209. Onset of action.Procaine → Tetracaine → Mepivacaine → Bupivacaine → Lidocaine →Etidocaine → Prilocaine.Duration of action.Procaine → Tetracaine → Lidocaine → Prilocaine→ Etidocaine → Mepivacaine → Bupivacaine.209

210. TOXICITY.Procaine—lacks topical activity, minimal systemic toxicity, no local irritation, metabolized by pseudo cholinesterase and the hydrolyzed product is PABA.Tetracaine—more toxic than Procaine, commonly used for spinal anaesthesia, 2% solution is used topically.Lidocaine—moderately topical activity, mainly given as IV, nerve blocking activity.210

211. Prilocaine—Meth-haemoglobinaemia.Etidocaine—epidural, infiltrative, regional.Mepivacaine—no anti-arrhythmic activity, infiltrative, regional.Bupivacaine—cardiac arrest, regional nerve blocker.211

212. DRUG INTERACTIONS. Drugs that affect anaesthesia.Adrenal steroid—Eticlomate depress hypothalamo-pituitary-adrenal axis.Aminoglycosides—additional neuro-muscular blocking effect.Anticholinesterase—potentiate Suxamethonium.NSAID—interferes with platelet function.212

213. RULES OF USE.Cocaine (topical).Procaine (nerve blocking, infiltrative, spinal).Tetracaine (spinal, topical).Lidocaine (topical, nerve blocking, infiltrative, spinal)Prilocaine (infiltrative, regional, spinal).Etidocaine (infiltrative, regional, epidural).Mepivacaine (infiltrative, regional).Bupivacaine (regional).Dibucaine (topical).213

214. METHODS OF ADMINSTRATION, USES, & ADVERSE EFFECTS OF LA.Method.Site of action.Indication.Drugs.Adverse effects.Surface anaesthesiaMucous membrane of the mouth, nose, bronchial tree, cornea, urinary tract.EpistaxisCatheterizationLignocaineCocaine (4%)Tetracaine(solution, spray, jelly, ointment, powder)System toxicity(high concentration)Infiltration anaesthesiaDirect injection to the tissue to reach the sensory nerve endings to the sub cutisMinor surgery—Excision of lipomaExcision of cystAmputationBiopsy from growthAll LAs can be used(injection with or without adrenaline)Adrenaline often added as vasoconstrictors(not with fingers or toes, for fear of causing ischaemic tissue damage)214

215. Nerve block anaesthesiaLA is injected close to the nerve trunk (brachial plexus, intercostal nerves) to produce a loss of sensation peripherallyDentistrySurgery in the extremitiesHerpes zosterPhantom painsMost LAs(solution for injection, with or without vasoconstriction)Spinal anaesthesiaLA is injected into the subarachnoid space (containing CSF) to act on the spinal roots and spinal cordSurgery in abdomen, pelvis or legObstetrical operationsUrological operationsHernia, hydrocele operationLignocaineTetracaineBupivacaineBradycardiaHypotension due to sympathetic blockRespiratory depression due to effect on phrenic nerve or respiratory centreUrinary retentionEpidural anaesthesiaLA is injected into the epidural space blocking the spinal rootsSame as spinal anaesthesia and for painless child birthLignocaineBupivacaineSame as spinal anaesthesia215

216. THROID HORMONES AND ANTI- THYROID DRUGS.Hormones secreted from the thyroid gland include:L-thyroxine (l- tetra iodo –l thyronine or T4 and triiodo-l thyronine or T3.Term thyroxine or thyroid hormone is commonly used to include both T3 and T4 T3 is 3- 5 times more potent than T4 and is the major physiologically active thyroid hormoneThyro- calcitonin is also secreted by the thyroid gland and is involved in calcium metabolism .

217. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID HORMONESThe functional unit of the thyroid gland is the thyroid follicle-consists of a cavity lined with a single epithelial cell layer.The lumen of the follicle is filled with thyroglobulin-large glycoprotein of MW 600,000Throglobulin is synthesized in the thyoid and has 115 tyrosine residues.

218. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID HORMONESCont…Synthesis of thyroid hormone occurs in steps:Step 1-Uptake of circulating iodides by follicle cells.Energy dependent active process ,stimulated by TSH and is also dependent on thyoid iodine concentrationUptake is stimulated in case of iodine deficiency and decreased when the thyroid iodine content is high.

219. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID HORMONES Cont…Step 2-Oxidation of iodide to iodine atom or free radical .Reaction occurs inside the follicle lumen and is catalyzed by the enzyme thyroperoxidase.Thyroperoxidase requires hydrogen peroxide as the oxidizing agent.Step3-Iodination of tyrosine residues of thyroglobulin.Process also under the influence of thyroperoxidase. Mono iodo tyrosine (MIT) and di iodo tyrosine (DIT) are formed.

220. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID HORMONES Cont…Step 4- Coupling of iodotyrosine molecules to form T3 andT4.MIT +DIT =T3 and DIT + DIT=T4—these reactions are all under peroxidase.The iodinated thyroglobin is secreted and stored in the follicular lumen.Step 5-Uptake of iodinated thyroglobulin TG.Under the influence of thyrotropin (TSH), the iodinated thyroglobulin is taken back by the follicle cells by aprocess of endocytosis where the cells engulf some amount of the thyroglobulin colloid.

221. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID HORMONES Cont…Step6 Release of throid hormone into circulation.Thyroglobulin is acted upon by proteolytic enzymes to release thyroid hormones into the circulation.Most of the hormone released is T4 , and 80% of T4 is de iodinated in peripheral tissues into active T3.

222. TRANSPORT OF T3 AND T4They are transported in plasma bound to plasma proteins.The main binding plasma protein is the thyroxine binding globulin(TBG ) and thyroxin binding albumin (TBA)TBG and TBA levels in plasma are raised by: oestrogens ,oralcontraceptives ,clofibrate ,neuroleptics and pregnancy..

223. TRANSPORT OF T3 AND T4 Cont…In the presence of the above factors, more thyroxine is bound and plasma concentration is low.Concentrations of TBG andTBA are lowered by corticosteroids, androgens ,anabolic steroids, furosemide.In the presence of the above factors less thyroxine is bound and concentration of thyroxine in plasma is high.

224. TRANSPORT OF T3 AND T4 Cont…Phenytoin and salicylates displace thyroid hormones from plasma protein binding sites and increases levels of the free hormone.Systemic factorse,g liver disease ,porphyria and HIV infection decrease the binding proteins.Plasma protein binding of thyroid hormones increases their half lives by protecting them from metabolism and excretion,(free unbound T4 in plasma is 0.03% and T3 0.3% )

225. METABOLISM OF THYROID HORMONES.Part of T4 is de iodinated to active T3 The thyroid hormones are enventually de-iodinated in the liver ,deaminated and partly conjugated.Free and conjugated metabolites are excreted in bile and urine.

226. REGULATION OF THYROID FUNCTIONSecretion is mainly under thyrotropin (TSH) secreted by the anterior pituitary.Secretion of thyrotropin is increased by the hypothalamic TRH and decreased by somatostatin.TSH stimulates all aspects of thyroid hormone synthesis I.e steps 1-6.

227. REGULATION OF THYROID FUNCTION Cont…TSH exerts a trophic effect on thyroid follicular cells and influences thyroid circulation .Increase TSH activity will thus lead to hypertrophy of follicular cells ,increase in blood flow and stimulation of thyroxin synthesis and release.Plasma iodide levels also influence the thyroid function i.e iodine defiency results in reduced plasma iodide levels, reduced thyroxine synthesis and increased levels of TSH and vice-versa.Iodide administration will lead to decrease in size and vascularity of the thyroid gland due to reduced TSH activity.

228. DRUG ACTION ON THE THYROID GLANDStep 1 Trapping of iodide—inhibited by thiocyanates ,perchlorates and nitrates. These anions in high concentration competitively inhibit the iodide transport into the cell. Iodide trapping is stimulated by TSH.Step 2 –oxidation of iodide—stimulated by TSH but inhibited by antithyroid agents and iodides.

229. DRUG ACTION ON THE THYROID GLAND Cont…Step3 iodination of tyrosine intoMITandDIT –stimulated by TSH and inhibited by antithyroid agents.Step 4 Coupling of MIT and DIT into T3andT4 –stimulated by TSH and inhibited by antithyroid agents.Step 5 endocytosis of thyroglobulin,TG into follicular cells –stimulated by TSH.

230. DRUG ACTION ON THE THYROID GLAND Cont…Step6 proteolytic release of T4 and T3 –stimulated by TSH and inhibited by iodides.Step 7 –de iodination of T4 into T3 – inhibited by propyl thio uracil, propanol and ipodate.

231. EFFECTS OF DRUGS ON THYROID FUNCTIONDopamine, l-dopa corticosteroids—Inhibition of TRH and TSH secretion.Iodides, lithium--- Inhibition of thyroxine synthesis and hypothyroidism.Cholestyramine ,colestipol,sucralfatealuminium salts---Inhibit throxine absorption from the gut.Phenytoin ,carbamazepine ,rifampicin,phenobarbitone--- Enzyme induces and may increase T3 and T4 metabolism.

232. EFFECTS OF DRUGS ON THYROID FUNCTION Cont…Propyl thiuracil,amiadarone, corticosteroids ,beta blockers--- Inhibition of conversion of T4 to T3.Androgens,glucocorticoids---- Decrease thyroxin- binding globulin.Estrogens, tamoxifen ,mitotane--- Increase thyroxin –binding globulin.Salicylates ,mefenamic acid furosemide---- DisplacesT3 andT4 from thyroxin binding globulin.

233. PHARMACOLOGICAL EFFECTS OF THYROID HORMONE.The physiological effects are mainly due to T3 because it is 3-5 times more potent than T4.REGULATION OF GROWTH AND DEVELOPMENT.Regulation of growth and development of the skeletal system and CNS.Above effect is partly direct and partly by GH ,parathormone and calcitonin potentiation.--- may involve protein synthesis by inducing synthesis of specific MRNA and proteins in target cellThyroid deficiency during fetal and post natal growth and development –cretinism( physical and mental retardation.)

234. METABOLIC EFFECTS.Stimulate metabolism of carbohydrates, proteins and lipids.Above effects may be exerted directly or by modulating effects of other hormones e.g. insulin,glucagon catecholamines ,corticosteroids and parathormone.Basal metabolic rate is increased by calorigenic effect i.e increased oxygen consumption by the tissues.Uptake and utilization of glucose is increased and lipolysis in tissues results in increased levels of triglycerides, cholesterol and free fatty acids.

235. CARDIAC EFFECTS.Increased HR and cardiac output due to sensitization of cardiac beta receptors to catecholaminesAUTO REGULATION OF THYROID FUNCTIONBy negative feedback inhibition of thyrotopin from the pituitary,

236. C N S. AND G.I.TC N S.Increased thyroid hormone leads to nervousness and many psycho neurotic tendencies e,g anxiety , paranoia and extreme worries.G .I.TIncrease appetite and food intake.Increased rate of secretion of digestive juices.Increased gut motility I.e hyperthyroidism can cause diarrhea and hypothyroidism can lead to constipation.

237. EFFECT ON MUSCLE FUNCTIONIncreased thyroid hormone---increase in skeletal muscle contractility.Very high levels_----muscle weakness due to excessive protein catabolism.Hyper thyroidism manifests with fine muscle tremors. This is caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that controls muscle tone

238. EFFECT ON SLEEPHyperthyroidism leads to exicitability and lack of sleep due to CNS excitation.Hypothyroidism causes extreme somnolence ,with sleep lasting 12-14 hrs a day.

239. EFFECT ON SEXUAL FUNCTIONHypothyroidism causes loss of libido in males while very high levels may lead to impotence.In women ,hypothyroidism may cause:a) Menorrhagia ( excessive menstrual bleeding )b) Poly menorrhea (frequent menstrual bleeding)c) Irregular periods and amenorrhea.d) Decreased libido.Above effects may be due to excitatory and inhibitory effects of thyroid hormones on anterior pituitary hormones tha control sexual function (FSH and LH).

240. VITAMIN REQUIREMENTIncreases vitamin requirement because of increase metabolic rate.Metabolic reactions require enzymes which need vitamins as co- factors.Hyperthyroidism may cause vitamin deficiency unless dietary intake is increased.

241. DISORDERS IN THYROID GLAND FUCTIONHYPERTHYROIDISM. (THYROTOXICOSIS).In most patients manifests with:Increase in size of thyroid gland 2-3 times its normal size.( hyperplasia)Each follicular cell increases the rate of secretion of thyroid hormone 5-15 times the normal.Two types: Graves disease and toxic nodular goiter.

242. Graves Disease./Exophthalmic goiter /Diffuse toxic goiter.Auto immune disease in which antibodies called thyroid stimulating immunoglobulins (TSIs) form against the TSH receptor in the thyroid (TD ).The antibodies bind with the same membrane receptors that bind TSH and induce continual activation of the cAMP system of the the cells with resultant development of hyperthyroidism (hperDsm)

243. Graves Disease./Exophthalmic goiter /Diffuse toxic goiter. Cont…The TSI have a stimulating effect on the TD gland (12 hr effect in contrast to 1hr for TSH).The high level of TD hormone secretion caused by TSI in turn suppresses the anterior pituitary formation of TSH ,TSH concentration is therefore less than normal.

244. Toxic Nodular Goitre.Localised benign adenoma or tumour in the TD tissue may cause hyperthyroidism by secreting large quantities of TD hormone.There is no evidence of an auto immune disease.Increased secretion of TD hormones by the adenoma depresses the TSH levels by the pituitary gland .This in turn suppresses all the secretory functions in the remainder of the TD gland.

245. Other causesAnti arrhythmic drug amiadarone is rich in iodine and can cause either hyper or hypo thyodism .

246. GENERAL SYMPTOMS OF HYPERTHYROIDISM.A state of excitability.Intolerance to heat.Increased sweatingMild to extreme weight loss (50 kg or less).Varrying degrees of diarrhea.Muscle weakness.Nervousness or other psychic disorders.Extreme fatigue but inability to sleep.Tremors of the hands.Exopthalmos or protrusion of the eye ball.

247. ExopthalmosAffects about a third of hyperDism patients especially of diffuse toxic goiter. Toxic nodular goiter does not present with exophalmos.Protrusion of the eyeball stretches the optic nerve which in turn leads to poor vision.The eyes are eventually damaged because the eyelids do not close completely when the person blinks or falla asleep.There is increased irritation,ulceration and infection of the cornea,Patients have high levels of circulating TSIs , suggesting an auto immune component.

248. DIAGNOSIS OF HYPERTHYROIDISM.Direct measurement of free T4 OR T3 in the plasma by radio immuno assay.Measurement of basal metabolic rate .-usually increased to +30 to +60 in severe hyperDsm.Concentration of TSH in the plasma is measured by radioimmuno assay. In thyrotoxicosis TSH levels are low.The concentration of TSI is measured by radio immuno assay. it is usually high in Graves disease but low in toxic nodular goiter.

249. TREATMENT OF HYPER THYROIDISM.Surgical removal of most of the thyroid. Propyl thio uracil is administered before surgery to reduce the basal metabolic rate.Iodides : given for 1-2 weeks before surgery .Iodides cause the gland to recede in size and its blood supply to diminish. Procedures 1 and 2 before surgery reduces operative mortalities .( 1 in 1000 ,before it was 1:25)

250. TREATMENT OF HYPER THYROIDISM. Cont…Radio active iodine - -Destroys most of the secretory cells of the TD because when hyperplastic the TD can absorb about 90% of iodine. 5millicuries of radioactive iodine is given for several weeks.Additional doses may be administered until normal thyroid states is achieved.Others: Perchlorates ,lithium, and propranolol.

251. HYPOTHYROIDISM.Effects are opposite to hyperthyroidism.Autoimmune component that destroys the gland and not stimulate it ( Hashimoto disease).There is decreased secretion of TD hormones due to fibrosis of the gland.Due to low production of TD hormones there is an associated enlargement of the TD gland.

252. TYPES OF HYPOTHYROIDISM.Endemic Colloidal GoitreDue to dietary iodide deficiency.Lack of iodine leads to no production of T3 andT4 by the TD gland.T4 and T3 always exert a negative feedback on TSH levels.TSH production rises and this causes the TD to to increase the conc. Of thyroglobulin colloid into the follicles causing the TD gland to grow.

253. Idiopathic non toxic colloid goiterThese people do not suffer from iodine deficiency but goitrous glands may secrete low quantities of thyroid hormones. Colloid goiter may be caused by the abnormality in the enzyme system required for the formation of the thyroid hormones e.g.Deficient iodide trapping mechanism – iodine is not pumped adequately into the thyroid cells. Deficient peroxidase system – in which iodides are not oxidized to iodine state. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule, so the final thyroid hormone cannot be formed.

254. Myxedema (Adult hypothyroidism) This develops in patents with almost total lack of thyroid hormone function. Manifests with:Baggines under the eyes .Swelling of the face.Pitting oedema due to increase in intestinal fluid.Development of atherosclerosis (lack of thyroid hormones causes increase blood cholesterol because of altered fat and cholesterol metabolism and dimished liver excretion of cholesterol in bile.Atherosclerosis can occur in other types of hypothyroidism but is more enhanced in myxedema Atherosclerosis will lead to peripheral vascular diseases, coronary artery disease and early death.

255. Cretinism This is called congenital or neonatal hypothyroidism: It is due to: Dysgenesis or poorly formed thyroid.Iodine deficiency .In born errors of iodine metabolism.

256. Other causes of HypothyroidismGoitrogenic substances – excessive intake of these substances e.g cabbages and turnips. These foods contains compounds with anti thyroid activity (similar to propyl thiouracil) and cause TSH stimulated enlargement of the thyroid gland.

257. Clinical manifestation of hypothyroidismHypothroidism may be due to: Thyroiditis or thyroid inflammation.Endemic colloid goiter.Destruction of the thyroid gland by irradiation .Surgical removal of the thyroid .Myxedema and cretinism .

258. Effects Of hypothyroidismFatigue and extreme somnolence with prolonged sleep of upto 14hrs a day .Extreme muscular sluggishness.Slowed heart rate.Decrease CO, decrease BV.Increase BW .Constipation, mental sluggishness .Depressed growth of hair and scaliness of the skin .Development of frog like husky voice.In severe cases development of odematous appearance throughout the body called myxedema.

259. Clinical manifestationMental retardation and dwarfism due to delayed skeletal maturation Thick dry skin, protruding tongue, hypothermia and lethargy.

260. Diagnosis of hypothyroidism Free thyroxin in the blood- decreases Basal metabolic rate in myxedema range from -30 and -50. Secretion of TSH by anterior pituitary when a test dose of TRH is administered is usually increased.

261. Treatment of HypothyroidismUse thyroid hormone replacements Preparations Thyroxine – Sodium salt of L-thyroxineLiothyronine Sodium (T3) – NOT for long term use because of high potency and incidence of cardiac side effects. 25 ug of T3 has similar clinical response as 100ug of thyroxine. Liotrix (25 ug T4 with 6.5 ugT3. It does not offer any special advantage over l-thyroxine.

262. Mechanism of action of thyroid hormonesThyroid hormones probably bind to receptors on cellular surfaces increasing the uptake of glucose and amino acids. These may be used for increased synthesis of RNA which leads to accelerated protein synthesis and enhanced enzymatic and cellular activities.Stimulates sodium – potassium ATPase directly thus facilitating membrane transport of sodium and potassium and increasing cellular utilization of oxygen.

263. Summary of Pharmacological actions of thyroid hormonesIncrease rate of metabolism, total heat production and oxygen consumption in most body tissues. Promote normal physical and mental development and growth. Potentiate the cardiovascular and metabolic actions of catecholamines. At cellular level, they accelerate protein synthesis, mainly by T3 approximately 1/3 of T4 is converted to T3 in the periphery,liver,kidneys and the primary effect of the thyroid hormones is apparently due to T3 activity.

264. Therapeutic uses Of Thyroid HormonesReplacement or substitution therapy of primary hypothyroidism e.g cretinism, myxedema, non toxic goiter, hypothyroid states of childhood. Also hypothyroidism resulting from surgery, radiation, drugs pregnancy or ageing. Adjuncts to thyroid – inhibiting agents. Adjunctive therapy of follicular and papillary carcinoma of the thyroid in conjuction with radioactive iodine.

265. Side effects /adverse of thyroid hormonesPalpitations, sweating, nervousnessHeat intoleranceInsomniaAllergic skin reactionCCF and shock

266. Contra indications and precautions thyroid hormonesCI – patients with thyrotoxicosis, nephrosis and myocardial infarction, obesity. Caution – CVS diseases (angina) concomittant diabetes mellitus or adrenal isufficiency. Interactions involving thyroid hormonesPotentiates cardiovascular effects of catecholamines. Potentiate effects of oral anticoagulantsThyroid hormones decrease effectiveness and toxicity of cardiac glycosides May increase blood glucose levels thus increasing requirement for insulin and oral hypoglycemics.

267. ANTITHYROID DRUGS These drugs are used in hyper thyroidism.a) ThioamidesThese reduce the synthesis of thyroid hormones and include carbimazole, methimazole and propylthiouracil. They are called antithyroid drugs. b) Iodide – In high doses c) Radioactive iodine – 131I

268. ANTITHYROID DRUGS Cont…d) Ionic inhibitors – These inhibit iodide uptake e.g. thiocyanates, perchlorates, nitrates. Their use is obsolete due to toxicity. e) Propranolol – use as an adjunct therapy in thyrotoxicosis.

269. ThioamidesMechanism of actionThey reduce the synthesis of thyroid hormones by inhibiting iodination of tyrosine and coupling of iodotyrosine to form T3 and T4. In addition propylthiouracil inhibits the peripheral conversion of T4-T3. These drugs inhibit thyroperoxidase. There is also evidence to suggest that the drugs may suppress the synthesis of auto antibodies implicated in the aetiology of Graves disease.

270. PHARMACOKINETICS OF THIOAMIDESDrugs are absorbed orally Carbimazole is a pro-drug and is converted to methimazole. T ½ (methiomazole 4 hrs, propylthioracil 2 hrs). These short t ½ are not clinically important because there is cumulation of these drugs in the thyroid where they act for 25-35hrs. A single dose of carbimazole or propylthioracil can reduce iodination of tyrosin by 70-90% within 7-12 hrs. These drugs are excreted in urine and mothers milk and cross the placental barrier. Methimazole crosses the placental barrier to a greater extent than propyl thiouracil.

271. Therapeutic uses Of Thioamides Graves disease Carbimazole orally 30-60mg/day until remission of symptoms with maintenance dose of 5 -15 mg/d.Propyl thiouracil – orally 300 – 450ml/d maintenance dose 50-150 mg/day ii) Toxic nodular goitre iii) Prior to surgery for hypethyrodismiv) Combined with radioactive iodine to decrease symptoms before radiation effects are manifested.

272. ADR of ThioamidesPruritic rash and hypothyroidism- most common Rare effects include: Vasculitis, arthralgia, Cholestatic jaundice, lympadenopathy, Hair pigmentation and SLE like syndrome.ADR are reversible on discontinuation of the drug. Adverse cross sensitivity between propyl thiourucil and methiomazole is 50% i.e one cannot be substituted for the other.

273. Iodides Iodides after food intake are selectively trapped by the thyroid gland, uptake being increased in hyperthyroidism and reduced in hypothyroidism.Large doses of iodides:Inhibit secretion of thyroid hormonesInhibit hormone release by inhibiting thyroglobulin proteolysisDecrease vascularity of the gland.

274. Therapeutic uses of IodidesPre-operative use in thyroid surgery. Potassium iodide 60mg orally tds. Antithyroid drugs are first used to control symptoms and iodides are began 10 days before surgery to reduce gland size and vascularity. Thyroid crisis – defined as sudden aggravation of hyperthyroidism (thyrotoxicity) Accidental over-dosage of radioactive iodine. It appears to protect the thyroid follicles. Propylactic use in endemic goitre. It is added to salt (1:100,000 parts ) as iodized salts. As an expectorantAs antiseptic for topical use

275. ADR of IodidesAcute hypersensitivity Rx e.g angioedema, skin haemorrhage and dry fever.Iodism on chronic administration (salivation, lacrimation, soreness) throat, conjuctivities, coryza like symptom, skin rashes.Foetal or neonatal goiter can occur after administration to pregnant or lactating mothers.

276. RADIOACTIVE IODINEMechanism Emits both beta and gamma rays. It is absorbed after oral administration and is trapped by the thyroid follicles and incorporated into thyroblogulin. The emitted beta rays have a short range and act on thyroid tissues without injuring surrounding areas including the parathyroid gland.

277. Therapeutic uses of radioactive iodineIt is used as radio active sodium iodide Radioactive sodium iodide is administered orally in the dose of 5-8 micro curie in the following conditions: Graves disease – including relapse after sub total thyroidectomy. Toxic nodular goiterThyroid carcinomaClinical response with radioactive iodine is slow and may take 6-12 weeks for suppression of hyperthyroid symptoms. Repeated doses may be necessary in some cases.

278. ADR of radioactive iodineHypothyroidism is fairly common. Should be avoided in children (mutagenic effect) and pregnancy (teratogenecity and cretinism. Lactating mothers (hypothyroidism, cretinism).

279. PROPRANOLOLIt is not strictly an anti-thyroid drug but it inhibits many symptoms of hyperthyroidism including, palpitation or tachycardia tremors, anxiety and thyrotoxic periodic paralysis due to increased muscle activity. Therapeutic uses In thyroid crisis

280. PROPRANOLOL Cont…As an adjunct in thyrotoxicosis or hyperthyroidism Prior to thyroid surgery to reduce symptoms like tachycardiaThyroiditis (or inflammation of the thyroid) – prevents palpitations.

281. Thyroid crisisthyrotoxicosis with sudden elevation of thyroid hormones. Treatment of thyrotoxicosisPropranolol I.V Sodium iodidePropylthiouracil Hydrocortisone

282. Summary of Drugs used in thyroid diseaseHypothyroidismLevothyroxineLiothyronine HyperthyroidismThiomides eg propythiouracilIodine eg lugol solutionBeta blockers eg propranolol131I-Radio active iodine