6. Drugs acting on symptoms manifested in the
GASTROINTESTINAL SYSTEM
PEPTIC ULCERS AND GERD
Physiology - participating cell-types
1. Parietal cells – secrete HCL and intrinsic factor.
2. Peptic cells (chief cells) –secretes pepsinogen
3. Neuroendocrine cells- secretes histamine
4. Mucous and bicarbonate secreting cells
5. Prostaglandin-secreting cells
6
7. HCL secretion stimulated by
ACh
Gastrin hormone
Histamine
HCL secretion inhibited by prostaglandins
Histamine
7
8. PEPTIC ULCERS
A breach in the mucosa
Location: Duodenum, stomach etc
♦ Basis:
Imbalance between damaging factors and
mucosal defense mechanisms
8
9. Pathophysiology PUD
• A 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 ULCER
Normal state
DAMAGING FORCES
1. Acid – gastric
2. Peptic enzymes
Normal state
DEFENSIVE FORCES
1. Surface mucus
2. Bicarbonate
3. Blood flow
4. Prostaglandins
5. Epithelial Regeneration
Mucus layer
10
11. DRUGS FOR PEPTIC ULCERS
Principle/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 infection
11
12. 1. 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 agonist
• If inhibition results the drug is considered an antagonist
14. Uses of H2-HISTAMINE RECEPTOR BLOCKERS
1. Duodenal ulcer
2. Gastric ulcer
3. GERD
4. Prophylaxis
5. As pre-anesthetic agent
6. Zollinger-Ellison syndrome
7. with oral enzyme supplements
14
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 ulcer
• Contraindicated 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, alopecia
• Adult: Active duodenal ulcer: 150 mg bid PO for
4–8 wk
• Paediatrics: 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. cimetidine
Cimetidine is associated with more side effects
which include:
• Granulocytopenia
• Gynecomastia
• Diarrhea
• Fatigue
• Dizziness
• Rash
• Mental confusion
20. PROTON PUMP INHIBITORS
• Block 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 INHIBITORS
MOA
► Block H+ /K + ATPase
acid production reduced by ~95%
DRUGS
• Omeprazole
• Esomeprazole
• Iansoprazole
• Rabeprazole
P’kinetics
Abs: Rapid, enteric coated, swallow whole;
can be reduced by some drugs e.g. sucralfate
Metabolized (1st pass)- rapid
21
22. 2. PROTON PUMP INHIBITORS
Uses of
Zollinger-Ellison syndrome - DOC –(DRUG OF CHOICE).
-GERD –2nd line
-Peptic ulcers –1st line
Gastritis
-Dyspepsia
-Prevention of stress related mucosal bleeding
Adverse 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 AGENTS
MOA: block muscarinic receptor
E.g. Pirenzepine, telezepine more selective for receptors in stomach
mucosal cells
Potency: telezepine more potent than pirezepine
♦ Other antimuscarinicis – mepenzolate, 8hyoscamine
P’kinetics
Abs:
Poor CNS entry
Largely biliary & renal elimination
Uses
Duodenal and gastric ulcers
23
24. Cytoprotectants
Drugs 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 effects
Commonest -Diarrhea, abdominal pain
Uterus -, spotting, dysmenorrhoea, arbotifacient (to be taken after day 1 of menses)
C/I in pregnancy
24
25. 5. SUCRALFATE (a cytoprotectant) is a prodrug
MOA : form a viscous, sticky gel in the acidic environment & coats the mucosa
S/E
Constipation
D/I –
Chelates some drugs ∟↓absorption e.g. phenytoin, digoxin
Uses
Peptic ulcers – long term maintenance
Prophylaxis – stress ulcers
25
26. 6. BISMUTH COMPOUNDS
This 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. Pharmacodynamics
This 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 enzymes
Unwanted effects
Blacken feaces, nausea and vomiting, darken tongue
Uses:
Peptic ulcers
H. Pylori
• Contra indications -Renal impairment and pregnancy
26
27. 7. ANTACIDS
Mxn: 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 kidney
Uses
Symptomatic relief of dyspepsia(heartburn)
27
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 – Amoxycillin
2. Metronidazole, tinidazole
3. Clarithromycin
4. Tetracycline
5. 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
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, then
Maintenance: 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, then
Maintenance: 2 mg after each subsequent loose stool, but not
exceeding 8 mg in 24 hours.
35. Loperamide
• Monitor fluid and electrolyte balance.
• Patient & Family Education
• Notify 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 subsalicylate
MOA: 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/day
Child: 131mg
• S.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 Responsibilities
•Monitor bowel function; note that
stools may darken and tongue
may appear black.
•These are temporary effects and
will disappear without treatment.
40. General Indications .
• impacted stool, anal fissures, haemorrhoids, short term treatment of
constipation.
• Preventing straining in postoperative patients.
• Post myocardial infarction.
• recent rectal surgery
• To evacuate the bowel for diagnostic procedures.
• To remove ingested poison form the lower GI tract.
• As adjunct in anthelmintic therapy
41. Contraindication and Cautions
• appendicitis
• diverticulitis
• 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,methycellulose
• lubricants, mineral oil,liquid paraffin
• Osmotics causes retention of water increasing
bulk of intestinal content eg lactulose
,magnesium sulphate
• saline 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 action
• Stool softeners- reduce the surface tension of liquids
within the bowel, acts by softening the hard
/impacted stool.
44.
45. Laxatives
• Uses: Constipation
• Adverse 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
47. Drugs that promote GIT motility/Stimulant Laxative
• Drugs-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
• metoclopramide
• extrapyramidal effects, hyperprolactinemia,parkinsonism -metoclopramide
48. Review quiz
1. Name four classification groups of laxatives indicating MOA giving
at least two example in each class.20mks
2. State mode of action of bulk forming laxatives-5mks
3. What 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 dexamethasone
• Cannabinoids e.g dronabinol (marijuana)use in ca chemotherapy tx N&V
• Antimuscarinics e.g scopolamine useful for motion sickness
51. Acetylcholine Receptor Antagonist/Antimuscarinics
• MOA
• They 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 SYSTEM
• Drugs used in hypothyroidism and hyperthyroidism
Hormone replacement.
• Antidiabetics- orals and injectables
• Drugs used in cushing syndrome
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
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.
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-synthetically
• Types:
• Rapid acting insulin e.g. Humalog (insulin Lispro)
Onset: 10-30min; duration of action: 3-5hrs
Time: injected 10mins before a meal. Used with longer-
acting insulin.
• Short acting insulin e.g. actrapid (soluble insulin)
Onset: 30min-1hr; duration of action: 5-8hrs
Time: injected 30-60 minutes before meals
63. Types of insulin
• Intermediate acting e.g. Isophane insulin also known as Humulin N,
Novolin N
Onset: 1-2½hrs; duration of action: 18-24hrs
Time: injected 1hr before meals. It is often combined with rapid- or
short-acting insulin.
• Long acting e.g. Ultralente
Onset: 30mins-3hrs; duration: 20-36hrs
Action: 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’d
• Premixed: 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 meals
Administered twice in a day.
65. MIXTARD
• 2 formulations of Mixtard
• Mixtard® 30
Containing 30% short-acting insulin and 70% intermediate acting
• Mixtard® 50
Containing 50% short-acting insulin and 50% intermediate-acting
insulin
66. insulin
• General 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
70. Side effects
• Hypoglycemia
• hepatotoxicity
• allergic responses
• Lipodystrophy-atrophy of subcutaneous fat at
the sites of injection
• Lipo hypertrophy-enlargement of subcutaneous
fat.
• prevention by changing injection sites frequently.
74. Oral hypoglycemic drugs
1. Sulfonylureas
• e.g. glibenclamide/ glybride (1.25 mg),chlorpropamide / diabinese
(100-500mg)
• MOA: stimulate insulin secretion
• S.E: Hypoglycemia
2. Biguanide: e.g. Metformin (250mg)
MOA: increases insulin action i.e. by suppression of glucose output
from the liver.
75. Cont’d
• Metformin (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 activity
S.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.
78. Nursing considerations
•Monitor blood glucose i.e. FBS and RBS
•assess for hypoglycemia –lethargy, sweating
•rotate insulin injection sites .
•and use human insulin with pork or beef sensitivity.
79. Anticonvulsants.
• GABA synaptic transmission enhancers
• Membrane permeability calcium channel reducers
• Membrane permeability to voltage dependents sodium channel
reducers.
• Glutamate inhibitors
• Management of side effects.
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.
83.
84.
85. Classification
•This classification is further divided into:
• Barbiturates e.g. phenobarbital,mephobarbitone
• Hydantoins e.g. phenytoin,mephenytoin
• Benzodiazepines 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 consciousness
• status epilepticus (life threatening condition in which
the brain is in a state of persistent seizure seen in
epilepsy, brain tumor) lasts > 5mins
87.
88. Phenytoin
• MOA: 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/kg
• S.ES: headache, photophobia, Stevens-Johnson syndrome, liver
damage, Nausea, vomiting, diarrhea, constipation.
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, sedation
• Indication: anxiety, OTHERS?
• Contraindication: comatose pts
• S.E: headache, blurred vision
• N.R:
• Monitor BP, PR,RR prior to periodically throughout therapy
• Assess IV site frequently during administration, diazepam may cause phlebitis
and venous thrombosis.
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 mood
• Dopamine: 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
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
102.
103. cont’d
• SSRIs (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.
108. Summary antidepressants.
• Tricyclic antidepressants- amitriptyline,, clomipramine,imipramine
MOA-Blocks norepinephrine (NE) and 5-HT transporters
Indications-major depression
-Chronic pain
-Obsessive compulsive disorders
Side 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 citalopram
MOA-SSRIs inhibit reuptake of only serotonin
USES-major depression
-Anxiety
-OCD
-Bulimia
-Bipolar disorders
• Unwanted Effects – N&V, d, agitation, insommia, anorgasmia and
priapism
110. Mono-Amine Oxidase Inhibitors (MAOIs)
E.G phenelzine, isocarboxazid, tranylcypromine, selegiline, moclobemide and
pargyline
MOA- Inhibit MAO type A which metabolises NE and MAO type B Metabolises
dopamine
Indication-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. note
Drug 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 considerations
• Monitor 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 stimulation
Amphetamines stimulate RAS; hence increase alertness and sensitivity to
stimuli
NB reticular activating system (RAS) controls the level of arousal
114. • Indication
Narcolepsy ,ADHD ( attention deficit hyperactivity disorder) and
obesity.
Unwanted effects
insomnia, irritability, irregular heartbeat, growth retardation in
children
addictive.
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 hrs
Intermediate acting lorazepam, oxazepam, clonazepam have a half life
of 5-24 hours
Long-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 effects
• Daytime 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. note
• Benzodiazepine 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. Diazepam
• Indications
• i. Sedation, relaxation, muscle relaxant, symptomatic anxiety.
• ii. Alcohol withdrawal (acute) syndrome.
• iii. Induction of GA.
122. alcohol
• Ethanol a sedative-hypnotics .
-indication –antseptic,appetite stimulant,neuralgia,mngt of
bedsores,beverages
Antidote in ethylene glycol poisoning
Effects-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 blindness
• Ethylene glycol
Ethylene glycol
123. Drugs used to treat alcohol withdrawal
• Thiamine.
• sedative –hypnotics.
• Drugs to treat alcohol dependence
• Disufiram
• Naltrxone
• Acamprosate
• Drugs to treat acute methanol or ethylene glycol intoxication
• Ethanol-competes for alcohol dehydrogenase hence lowers metabolism of
methanol and prevent toxic metabolites
• Fomepizole-inhibit enzyme alcohol dehydrogenase therefore prevent toxic
metabolites
124. 124
Mood stabilizers
Lithium, carbamazepine and valporate
Lithium
• Ref to as mood stabilizer as it reduces both manic and
depressive symptoms thereby normalizing the mood in
patients with bipolar disorder
MOA
• Thought 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 CAMP
• This produces a calming effect after several days or weeks of
Rx.
125. 125
A/effects of lithium
• Has low margin of safety
• May cause neurotoxicity and cardiac toxicity leading to
arrhythmias
• Polyurea because it interferes with the action of Antidiuretic
hormone(ADH)
• Nausea and vomiting
• Drowsiness, weight gain and fine hand tremors
• Interactions-interacts with NSAIDs and antipsychotic drugs.
Nacl increases its excretion.
Other mood stabilizing drugs
• Carbamazepine
• valporate
127. ANTIPSYCHOTIC
The groups are:
1)Classical/typical neuroleptics
a)Phenothiazines e.g.
chlorpromazine,triflupromazine,thioridazine,fluphenazine,thiori
dazine.
b)Thioxanthenes e.g. thiothixene, chlorprothixene, flupenthixol
c)Butyrophenones e.g.haloperidol,droperidol,trifluperidol
2)Atypical neuroleptics e.gclozapine,olanzapine,risperidone
3)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,
parkinsonism
• Nursing 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. Artane
• Indicated 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, impotence
Hyperglycemia 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 effects
• Orthostatic 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 Reactions
• Behavioral 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 effects
• Extrapyramidal 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 effects
• Constipation,
• loss of accomodation
urinary retention .
• Dry mouth
• impaired ejaculation >- chlorpromazine or mesoridazine.
• managed by switching to drugs with less marked adrenoceptor-
blocking actions.
137
138. Cont…
• Metabolic effects
Weight 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 complications
• Deposits 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 complication
140
141. Cont…
• Cardiac toxicity
Thioridazine 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 quinidine
• Clozapine 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 indications
• Most 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 pregnancy
Although 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. References
• 1. 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 agents
• General anesthesia-inhalation and intravenous
• Local 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 relaxant
• Choice of opioids depends on length of surgery.
153. General anaesthetics
GAs
• block conduction of pain impulses to the sensory cortex
Gas
Classification
Inhalation anaesthetics
• Non halogenated
– Nitrous oxide
• Halogenated
–Halothane, desflurane, enflurane, isoflurane, sevoflurane
Parenteral
–Ketamine, mildazolam, fentanyl, thiopental, propofol
154. GAs
Inhalation
MOA-interact with hydrophobic regions of proteins in neuronal
membranes
• Non-halogenated-NO
– ↑analgesia, ↓loss of consciousness
• Halogenated-Halothane
– Rapid induction + recovery
– S/E-dose dependent resp./cardiac depression
– Uterine relaxation → C/I in pregnancy
Parenteral
– Barbiturates/benzodiazepines/opioids
– Pre anaesthetic sedation, analgesia+ anaesthesia for major/minor surgery
155. Ketamine
• Blocks receptors for excitatory amino acids e.g. glutamate
• A/E-may cause unpleasant effects during recovery stage
Mildazolam
• Short acting benzodiazepine
– Preoperative sedation/endoscopy
• Effects reversed by flumazenil
Propofol /Thiopental
• Potentiate GABA
• Rapid onset/short duration of action
– Induction of anaesthesia
Fentanyl
156. Type of general anaesthetics
• I. V. Benzodiazepines
• I. V. Barbiturates
• I.V. Opioids
• Ketamine
• Propofol
• Combinations
157. Inhalational anaesthetics
• Rationale for the use inhalational anesthetics
• Provide hypnosis
• Enhance or provide analgesia
• Provide 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 agent
• Effective analgesic
• Minimal skeletal muscle relaxation
• No significant effects on the liver, kidney, or GI tract
• Very rapid onset and recovery
• Little toxicity
• Use as an adjunct to other inhalational agents allows reduction in their dosage
159. Halothane
• Loss of consciousness; but does not provide adequate analgesia; reversible reduction in
glomerular filtration rates (GFR)
Advantages:
• Relatively potent and nonflammable
• Relatively rapid induction & recovery from anesthesia
Indications
• Mainly 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/Effects
• Hepatitis occurrences
• Causes significant myocardial depression
• Associated with malignant hyperthermia
160. Enflurane
• Rapid induction with limited effects on pulse or respiration
• Less arrhythmias, nausea, post-operative shivering and vomiting compared to
halothane
• Adequate muscle relaxation greater than halothane
• Reversible reduction of GRF
Uses:
• Mainly in adults. Not widely used in pediatric cases
A/Effects
• Not recommended for use in patients with seizure disorders. Avoided in epileptic
patients because it occasionally induces CNS excitatory effects
• May cause malignant hyperthermia
161. Isoflurane
• Rapid induction of anesthesia with limited effects on pulse or respiration
• No hepatic and renal toxicity
• Provides adequate muscle relaxation greater than halothane
• Reversible reduction of GRF
Uses
• Isoflurane is the most widely used inhalational agent
A/Effects:
• May cause malignant hyperthermia (as with halothane & enflurane)
162. Desflurane
• Rapid onset and recovery , recovery twice as rapid as for isoflurane
• Causes laryngospasm and coughing
• Does not provide adequate muscle relaxation
• Circulatory effects similar to isoflurane
• Reversible reduction of GRF
• Seizure-like activity is not observed
• A/E: Malignant hyperthermia, coughing and laryngospasm
Sevoflurane
• Low blood solubility & high potency
• Pharmacological properties as of desflurane
• Commonly used
• Increase fluoride levels rarely associated with kidney or renal damage
• Compared to desflurane, sevoflurane is more extensively metabolized, releasing more
fluoride
164. Intravenous barbiturates used in Anesthesia
• Thiopental, methohexital sodium, thiamylal sodium
Thiopental
Pharmacological properties:
• Rapid induction and fast recovery
• Rapid recovery (20-30 min) due to redistribution from brain to peripheral tissues
• Little postoperative excitement or vomiting
• A/Effects
• Cough, laryngospasm, bronchospasm & histamine release
• Dose-related respiratory depression; Limited cardiovascular effects
• Crosses the placental barrier and depresses the fetus
Contraindications:
• 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. Benzodiazepines
Intravenous benzodiazepines used in anesthesia
• Diazepam (prototype), mildazolam, lorazepam
• Benzodiazepines are effective in promoting sedation and reducing anxiety
• Midazolam has the most rapid onset of action and a shorter duration
• Benzodiazepines are not analgesic
• Amnesic in most patients
• Used alone benzodiazepines have limited depressant effects on the
cardiovascular/respiratory system.
• CNS depression can be reversed by the specific anatagonist flumazenil
• When administered in combination with opioids, significant cardiovascular and
respiratory depression may occur
166. Uses
• Used alone for procedures not requiring analgesia, such as endoscopy, cardiac
catherization & certain radiological procedures
• Used 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 anesthesia
Morphine, meperidine , fentanyl , sufentanil , alfentanil , remifentanil
• Opioids are used to supplement inhalational or i.v. anesthetics
• Morphine-nitrous oxide combination has been used in cardiovascular surgery
A/Effects
• Respiratory depression, hypotension, post-operative nausea or vomiting are
associated with opioid use
• Respiratory depression caused by opioids is reversed by using specific narcotic
antagonists – Naloxone, naltrexone, nalmefene
168. Fentanyl and related agents
Fentanyl
• I.V. fentanyl causes analgesia and unconsciousness
• Compared 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 morphine
Uses
• Fentanyl is often combined with a muscle relaxant and nitrous oxide or low doses
inhalational agent for anesthesia
169. Alfentanil and sufentanil
• Alfentanil and sufentanil are more potent than fentanyl and produce analgesia, and
at higher concentrations- anesthesia
• Remifentanil - a new potent agent which produces analgesia very rapidly
• Readily metabolized resulting in rapid recovery time
Propofol
• I.V. propofol rapidly induces anesthesia, similar to thiopental; with minimal
postoperative confusion
• Duration of anesthesia can be increased by combination with inhalational agents,
nitrous oxide, or opioids
• Does not adversely affect hepatic or renal function
• Postoperative GI upset occur at a similar frequency to that of thiopental
Uses: In ambulatory surgery settings
170. Ketamine
• Produces 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 environment
• Significant amnesia and analgesia rapidly follow injection
• Recovery is slower than with barbiturates
A/Effects
• Awakening may be associated with bad dreams and hallucinations
• These A/E uncommon in children and can be reduced by concurrent administration with
benzodiazepines
Uses
• In conjunction with diazepam, in emergency surgery, trauma, dressing changes and
certain pediatric radiological procedures
172. Non-depolarizing NM blocking drugs
MOA
• Prevents action of Ach. at skeletal muscle end plate
• Effects reversed by cholinesterase inhibitors- neostigmine
Depolarizing NM blocking drugs
• Su-choline
• Depolarizes NM end plate
A/E
• resp. paralysis, Hyperkalemia, peripheral nerve dysfunction
• Stimulates autonomic ganglia
Interactions: inhaled anesthetics, aminoglycosides
173. Spasmolytic drugs
• Drugs that reduce abnormally elevated muscle tone(spasm) without causing paralysis
e.g. baclofen, dantrolene
• Action: CNS, skeletal muscle cells
Chronic pain
• Diazepam-GABA mediated inhibition at the spinal cord
• Baclofen - GABAB agonist
• Tizanidine- reinforces both pre- and post synaptic inhibition in the spinal cord
• Dantrolene-↓ release of activator Ca from sacroplasmic reticulum
• Rx Malignant hyperthermia
174. Acute muscle spasm
Cyclobenzaprine
• Thought to act in the brain stem by interfering with polysynaptic reflexes
that maintain skeletal muscle tone
• A/E confusion and hallucination in some patients
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 locally
• Prevent 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 1884
• Einhorn synthesized Procaine in 1905
• Lidocaine 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 effect
180
181. CLASSIFICATION.
1) According to the structure of the intermediate chain
• Esters—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 action
• Short acting—Procaine
• Intermediate acting—Cocaine, Lidocaine, Mepivacaine, Prilocaine
• Long acting—Tetracaine, Bupivacaine, Efidocaine, Ropivacaine
181
182. classification
• Esters
• Long action: tetracaine
• Short action: procaine
• Surface action: benzocaine, cocaine
• Amides
• Long action: bupivacaine, ropivacaine
• Medium action : lidocaine
182
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 potential
183
184. Points to note
• Blockade 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 bradycardia
• Headache/dizziness
• Sepsis
• Nausea and vomiting
• hypersensitivity, local irritation
Complications
• On 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 sphincter
191
192. CLINICAL USES.
• LA is generally used when loss of consciousness is neither necessary
nor desirable
• Also can be used as an adjunct to major surgery to avoid high dose of
GA
NB.Benzodiazepines—usually given as premedication to counteract the
central excitation of LA specially of cocaine
192
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 lozenge
• Continuous 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 anaesthesia
• Injection 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 block
• Anaesthetizes 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) anaesthesia
• The 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 anaesthetics
198
199. Spinal anaesthesia
• The drug is introduced directly into the CSF
• Produces extensive and profound anaesthesia
• Sites of action are spinal nerve roots, spinal ganglion and perhaps the
spinal cord
• Onset is rapid and proper drug duration may last from 1-4 hours
• There is hypotension due to block of the sympathetic nervous system
• Headache due to CSF leakage
• Examples—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 toxicity
• Meth-haemoglobinaemia
Bupivacaine.
• Long acting
• Used 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 action
• Used 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
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
214. METHODS OF ADMINSTRATION, USES, &
ADVERSE EFFECTS OF LA.
Method. Site of action. Indication. Drugs. Adverse effects.
Surface
anaesthesia
Mucous membrane of the
mouth, nose, bronchial tree,
cornea, urinary tract.
Epistaxis
Catheterization
Lignocaine
Cocaine (4%)
Tetracaine
(solution, spray, jelly,
ointment, powder)
System toxicity
(high concentration)
Infiltration
anaesthesia
Direct injection to the
tissue to reach the sensory
nerve endings to the sub
cutis
Minor surgery—
Excision of lipoma
Excision of cyst
Amputation
Biopsy from growth
All 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
anaesthesia
LA is injected close to
the nerve trunk
(brachial plexus,
intercostal nerves) to
produce a loss of
sensation peripherally
Dentistry
Surgery in the
extremities
Herpes zoster
Phantom pains
Most LAs
(solution for injection,
with or without
vasoconstriction)
Spinal anaesthesia LA is injected into the
subarachnoid space
(containing CSF) to act
on the spinal roots and
spinal cord
Surgery in abdomen,
pelvis or leg
Obstetrical operations
Urological operations
Hernia, hydrocele
operation
Lignocaine
Tetracaine
Bupivacaine
Bradycardia
Hypotension due to
sympathetic block
Respiratory depression
due to effect on phrenic
nerve or respiratory
centre
Urinary retention
Epidural anaesthesia LA is injected into the
epidural space blocking
the spinal roots
Same as spinal
anaesthesia and for
painless child birth
Lignocaine
Bupivacaine
Same as spinal
anaesthesia
215
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 hormone
Thyro- calcitonin is also secreted by the thyroid gland and is involved in
calcium metabolism .
217. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID
HORMONES
• The 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 600,000
• Throglobulin is synthesized in the thyoid and has 115 tyrosine residues.
218. SYNTHESIS ,RELEASE AND METABOLISM OF THYROID
HORMONES
Cont…
• 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 concentration
• Uptake 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 T4
• They 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 FUNCTION
• Secretion 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 GLAND
• Step 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 FUNCTION
• Dopamine, 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
cell
• Thyroid 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 catecholamines
AUTO REGULATION OF THYROID FUNCTION
• By negative feedback inhibition of thyrotopin from the pituitary,
236. C N S. AND G.I.T
C N S.
• Increased thyroid hormone leads to nervousness and many psycho
neurotic tendencies e,g anxiety , paranoia and extreme worries.
• G .I.T
• Increase 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 FUNCTION
• Increased 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 SLEEP
• Hyperthyroidism 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 FUNCTION
• Hypothyroidism 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 REQUIREMENT
• Increases 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 FUCTION
HYPERTHYROIDISM. (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 causes
• Anti 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 sweating
• Mild 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. Exopthalmos
• Affects 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 Goitre
• Due 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 goiter
• These 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 Hypothyroidism
• Goitrogenic 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 hypothyroidism
• Hypothroidism 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 hypothyroidism
• Fatigue 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 manifestation
• Mental 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 Hypothyroidism
• Use thyroid hormone replacements
• Preparations
• Thyroxine – Sodium salt of L-thyroxine
• Liothyronine 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 hormones
• Thyroid 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 hormones
• Increase 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 Hormones
• Replacement 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 hormones
• Palpitations, sweating, nervousness
• Heat intolerance
• Insomnia
• Allergic skin reaction
• CCF and shock
266. Contra indications and precautions thyroid hormones
• CI – patients with thyrotoxicosis, nephrosis and myocardial infarction, obesity.
• Caution – CVS diseases (angina)
• concomittant diabetes mellitus or adrenal isufficiency.
• Interactions involving thyroid hormones
• Potentiates cardiovascular effects of catecholamines.
• Potentiate effects of oral anticoagulants
• Thyroid 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) Thioamides
• These 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. Thioamides
• Mechanism of action
• They 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 THIOAMIDES
• Drugs 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 hypethyrodism
iv) Combined with radioactive iodine to decrease symptoms before
radiation effects are manifested.
272. ADR of Thioamides
• Pruritic 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 hormones
• Inhibit hormone release by inhibiting thyroglobulin proteolysis
• Decrease vascularity of the gland.
274. Therapeutic uses of Iodides
• Pre-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 expectorant
• As antiseptic for topical use
275. ADR of Iodides
• Acute 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 IODINE
Mechanism
• 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 iodine
• It 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 goiter
• Thyroid carcinoma
• Clinical 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 iodine
• Hypothyroidism is fairly common.
• Should be avoided in children (mutagenic effect) and pregnancy
(teratogenecity and cretinism.
• Lactating mothers (hypothyroidism, cretinism).
279. PROPRANOLOL
• It 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