The document provides information on human anatomy and physiology, with a focus on the digestive system. It describes the structure and functions of the cells, tissues, organs and body systems. It then discusses the layers, organs and functions of the digestive system in detail. This includes the mouth, salivary glands, esophagus, stomach, small intestine, large intestine, liver and pancreas. It also covers the mechanisms of acid secretion in the stomach and factors that regulate gastric juice production. Finally, it provides an overview of acid peptic disorders like gastritis, GERD, peptic ulcers, and their causes and treatments.
3. Human body develops from union of
SPERM + OVUM=FIRST CELL OF HUMAN BODY
Group of cells
Tissues
Organs
Systems
4. Structure of Cell
• Cell is a structural & Functional unit of human body, capable of
carrying out functions of life independently.
– Nucleus
– Cytoplasm
– Cell Membrane
Functions of Cell
- Production of Bio-Energy
- Storage
- Multiplication
- Specific function according to location
5.
6. Systems
• Muscular System
• Skeletal System
• Digestive System
• Respiratory System
• Circulatory System
• Excretory System
• Reproductive System (Male & Female)
• Nervous System
• Endocrine System
8. Digestion is chemical and mechanical
process on the ingested food to prepare it
for assimilation by the body.
• Function of Digestive System
– Ingestion
– Chewing
– Swallowing
– Digestion
– Absorption
– Excretion of undigested food
9. • Organs of Digestive System
– Mouth
– Pharynx (Throat)
– Oesophagus (Food tube)
– Stomach
– Small intestine
– Large intestine
– Rectum
10.
11. Layers of Digestive System
• Inner Epithelial layer
– Secretion of enzyme and mucus
– Soft and pink in colour
• Middle Muscular layer
– Outer layer (Longitudinal muscles)
– Inner layer (Circular muscle)
– Peristalsis (Segmental contraction)
• Outer Serous layer
– Protective function
– Diagram
12.
13. • Mouth
– Beginning of Digestive system
– Lips, teeth, gums, tongue.
– Palate (soft and hard), tonsils
– Opening of Salivary glands
• Teeth
– Total 32 in adults
• Tongue
– Functions
• Helps in mastication
• Mixing all saliva with food
• Swallowing
• Sensation of taste
• Speech
14. • Salivary glands
– 3 pairs
• Parotid in front of ear
• Submandibular below lower jaw
• Sublingual below tongue
• Saliva
– Secretion of salivary glands
– Secreted with ingestion, memory, smell of food
– Ptylin converts starch into sugar
• Pharynx (Throat)
– Posterior of nose, mouth & larynx
– Musculo membranous tube
15. • Swallowing
– Voluntary and Involuntary stages
• Voluntary
– Bolus formation
– By movement of tongue and cheeks
– Bolus pushed into pharynx
• Involuntary
– Soft palate raised up & closes nasal passage
– Glottis contracts and closes
– Larynx lifted upwards and forwards
– Food passes to Oesophagus
– Breathing ceases during this step
16. • Stomach
– Dilated part of Digestive system
– Lies in upper abdomen below diaphragm
– Slightly left to midline
– Upper opening connected to Oesophagus
– Lower opening connected to Duodenum
– Both remain closed during gastric digestion
– J shaped in standing position
– Elastic muscular bag with capacity of 2 liters
– 3 muscular layer- vertical, circular, oblique
17. • Functions of the Stomach
– Storage of food for 3 hours
– Partial digestion of proteins and fats
– Semi digested food from stomach enters the
Duodenum
• Oesophagus
– 25cm long muscular tube
– From pharynx to stomach
– Behind trachea and in front of vertebral column
– Major part passes to Thorax
– Food passes to stomach by active muscular action
– Solid food reaches stomach in 7 to 8 seconds
– Liquids reaches stomach in 2 to 3 seconds
18. • Small intestine
– 6 to 7 meter long, 2.5cm diameter
– Lies in center of abdomen
– Divided into 3 parts
• First part – Duodenum
• Second part – Jejunum
• Third part – ileum
• Alkaline Secretions
– Protects from acid contents of stomach
• Small intestine
– Mucosa
• Deeply folded to increase the surface area
• Helps in absorption of food.
19. • Large intestine
– 1.5meter long, 5 to 6cm diameter
– Divided into 3 parts
• Right ascending colon
• Transverse colon
• Left descending colon
• Sigmoid Colon & Rectum
– Temporary storage of faeces
– Anus is guarded by external & internal
sphincters
20. Liver
• Functions
– Synthesis of bile
– Formation of urea
– Detoxification of drugs
– Destruction of RBC
– Storage of excess glucose in form of glycogen
– Storage of Vitamin A & D
– Storage of Hemoglobin
– Manufacturing of blood proteins, albumin & globulin
– Manufacturing of prothrombin & fibrinogen
21. • Gall bladder
– Stores the liver bile (60ml)
• Pancreas
– Located in upper abdomen behind the stomach
– Right part in the C of Duodenum
– Extends to the left up to the spleen
– Manufactures digestive enzymes
– Manufactures insulin
22. • most complex organ system comprising alimentary
canal, extending from mouth to anus & associated
glandular organ,
• 15-18 ft,
• wall composed of four layers.
Anatomy and physiology of GI tract
23. • Mucosa composed of simple gland - pit, neck & base.
• Stomach - several region on the basis of structure & function:
1. Cardia - doesnot secrete acid.
2. Corpus or body, containing parietal cells.
3. Pyloric antrum - secretes hormone gastrin from G cells.
Anatomy and Histology of Stomach
25. There are three phases in the secretion of gastric acid:
• The basal phase: A small amount of acid is always being secreted into the stomach. The
three following phases increase the secretion rate in order to digest a meal.
• The cephalic phase: Thirty percent of the total gastric acid secretions to be produced is
stimulated by anticipation of eating and the smell or taste of food. This signalling occurs
from higher centres in the brain through the Vagus Nerve. It activates parietal cells to
release acid and ECL cells to release histamine. The Vagus nerve also releases Gastrin
Releasing Peptide onto G cells.. Enterochromaffin-like cell
• The gastric phase: About fifty percent of the total acid for a meal is secreted in this
phase. Acid secretion is stimulated by distension of the stomach and by amino
acids present in the food.
• The intestinal phase: The remaining 10% of acid is secreted when chyme enters the
small intestine, and is stimulated by small intestine distension and by amino acids.
26. Gastric Juice
• About 2 to 3 liters of gastric juice are secreted
daily by special secretory glands in the mucosa.
• It consists of:
Water, mineral salts: secreted by gastric glands
Mucus: secreted by goblet cells in the glands and
in the stomach surface
HCl and Intrinsic factor: secreted by parietal cells
in the gastric glands
Inactive enzyme precursors: pepsinogens secreted
by chief cell in the gland.
27. Mechanism of Acid Secretion in Stomach
Hydrochloric acid-one of the constituents of gastric
juice
Synthesized by the parietal cells of gastric mucosa
and secreted into large cannaliculi which are the deep
invaginations of the plasma membrane of the parietal
cell.
The key player in acid secretion is H+/K+ ATPase or
“PROTON PUMP" located in the cannalicular
membrane.
28. • GI secretion is regulated by nerves (acetylcholine),
hormones (Gastrin) & pancrin substances (Histamine)
• These three factors results
1. Activation of ATPase at H+K+ pump in the parietal
Cell.
Gastric acid secretion
29. In parietal cells CO2 + H20 H2CO3 which further
dissociate into H+ and HCO3
-.
HCO3
- is transported to blood in exchange of Cl-. CL-
ions are transported into the lumen of the canaliculus.
H+ is pumped out of the cells into the lumen in
exchange of K+ through the action of proton pump
31. Receptor is a molecule most often found on the surface of a cell, which receives
chemical signals originating externally from the cell. Through binding to a receptor,
these signals direct a cell to do something—for example to divide or die, or to allow
certain molecules to enter or exit.
32. Inside the parietal calls
Water molecules dissociates and combine with CO2
Hydrogen ions and bicarbonate ions are formed
Carbonic anhydrase
Hydrogen ions thus formed comes out into the lumen by
the help of H+K+ATPase enzyme with exchange with Potassium
Releasing HCl in the gastric lumen upon stimulation
of acetylcholine, gastrin, and histamine
33.
34. After taking food
Stimulation of Parasympathetic (vagal) take place
Release of acetylcholine
Direct Effect
Binds with Muscarinic
Receptor on the partial cell
Stimulates
Histaminocytes
to release
Histamine
Stimulates gastric
antrum to secrete
Gastrin
Release of HCl from H+K+ATPase
Parietal cells bear receptors for 3 stimulators of acid secretion:
Acetylcholine (muscarinic type receptor)
Gastrin
Histamine (H2 type receptor)
35. ACID PEPTIC DISORDERS
• Acid peptic disorders include a number of
conditions whose pathophysiology is believed
to be the result of damage from acid and peptic
activity in gastric secretions
37. GASTRITIS
Gastritis means inflammation of the gastric
mucosa
The inflammation of gastritis may be only
superficial and therefore not very harmful, or it
can penetrate deeply into the gastric mucosa
and in many long standing cases almost
complete atrophy of the gastric mucosa.
38. GERD
Gastroesophageal Reflux Disease is defined as chronic
symptoms or mucosal damage produced by the abnormal
reflux of gastric contents into the esophagus.
GERD occurs when the normal antireflux barrier between
the stomach and the esophagus is impaired either transiently
or permanently.
Classic symptoms are heartburn, discomfort, acid
regurgitation. Symptoms often occur after meals and may
increase when a patient is recumbent.
39. PEPTIC ULCER
A peptic ulcer is an excoriated(damaged) area of the mucosa
caused principally by the digestive action of gastric juice.
Basic Cause of Peptic Ulceration
The usual cause of peptic ulceration is an imbalance
between the rate of secretion of gastric juice and the degree
of protection afforded by
1. the gastro duodenal mucosal barrier
2. the neutralization of gastric acid by duodenal juices.
40. DYSPEPSIA
Dyspepsia is the classic symptom of peptic ulcer
disease .
It is defined as pain centered in the upper abdomen or
discomfort characterized by fullness, bloating,
distention or nausea.
41. SPECIFIC CAUSES OF PEPTIC ULCER IN THE
HUMAN BEING
Bacterial Infection by Helicobacter Pylori breaks down the
Gastro duodenal Mucosal Barrier.
H. Pylori is a gram negative, spiral, flagellated bacterium..
The organism is uniquely adapted for survival in the
hostile environment of the stomach.
For example, H. pylori produce large amounts of urease,
an enzyme that catalyzes the breakdown of urea to alkaline
ammonia and carbon dioxide. Through this reaction the
bacterium may protect itself from acid injury by
surrounding itself with alkaline material. The spiral
structure and the flagella enable the organism to burrow
through the gastric mucus layer.
42. Bacterial Infection by Helicobacter Pylori breaks down
the Gastro duodenal Mucosal Barrier.
H. Pylori is a gram negative, spiral, flagellated bacterium..
The organism is uniquely adapted for survival in the
hostile environment of the stomach.
For example, H. pylori produce large amounts of urease,
an enzyme that catalyzes the breakdown of urea to alkaline
ammonia and carbon dioxide. Through this reaction the
bacterium may protect itself from acid injury by
surrounding itself with alkaline material. The spiral
structure and the flagella enable the organism to burrow
through the gastric mucus layer.
H.Pylori & Ulcer
44. Increased secretion of Acid Peptic Juices can
contribute to Ulceration
In addition to bacterial infection and neurogenic stimulation
of excess secretion of gastric juices, other factors that
predispose to ulcers include
1. Smoking, presumably because of increased nervous
stimulation of the stomach secretory glands;
2. Alcohol, because it tends to breakdown the mucosal barrier
and,
3. Aspirin, which also has strong propensity for breaking
down this barrier.
45. ZOLLINGER ELLISON
SYNDROME
Zollinger-Ellison syndrome (ZES) is a rare disorder
that causes tumors in the pancreas and duodenum and
ulcers in the stomach and duodenum.
The tumors secrete a hormone called gastrin that
causes the stomach to produce too much acid, which
in turn causes stomach and duodenal ulcers (peptic
ulcers).
The ulcers caused by ZES are less responsive to
treatment than ordinary peptic ulcers.
46. DRUGS FOR PEPTIC ULCER
Peptic ulcer occurs in that part of the gastrointestinal
tract (g.i.t) which is exposed to gastric acid and
pepsin i.e. the stomach and the duodenum.
The etiology of peptic ulcer is not clearly known. It
results probably due to an imbalance between the
aggressive (acid, pepsin and H. pylori) and the
defensive (gastric mucosa and bicarbonate secretion,
prostaglandins, innate resistance of the mucosal cells)
factors
47. Approaches for the treatment of peptic
ulcer are
1.Reduction of gastric acid secretion
a. H2 antihistaminics :Cimetidine,Ranitidine,Famotidine, Roxatidine
b. Proton pump inhibitor : Omeprazole, Lansoprazole,Pantoprazole
c. Anticholinergics :Pirenzipine, Propanatheline,Oxyphenonium,Doxepin,
d. Prostaglandin analogues : Misoprostal, Enprostil,Rioprostil
49. ANTACID
Antacids are basic substances which neutralize gastric
acid and raise the pH of gastric contents. Antacids
may be systemic or nonsystemic.
e.g. of systemic antacids include Sodium
bicarbonate, Sodium citrate.
e.g. of nonsystemic antacids include Magnesium
hydroxide, Magnesium carbonate, Magnesium
trisilicate, Aluminium hydroxide gel, Magaldrate ,
Calcium carbonate
50. ANZEL
Available as ANZEL 170 ml
Composition:
Each 10 ml contains: Magaldrate USP 1g and Simethicone
USP 100 mg
Dosage: One or two teaspoonfuls between meals and at bedtime.
Presentation: 170 ml bottle
Therapeutic Category: Antacids
FDA Pregnancy Category: C
51. INDICATIONS
For the relief of heartburn, sour stomach, reflux
esophagitis and acid indigestion accompanied by the
symptoms of gas.
For symptomatic relief of hyperacidity associated
with the diagnosis of peptic ulcer, gastritis, peptic
oesophagitis, gastric hyperacidity, hiatal hernia , and
post-operative gas pain
52. ANZEL
Mechanism of Action
Anzel is a antacid plus anti-gas combination product containing the
unique chemical entity Magaldrate.
Magaldrate is a complex hydroxymagnesium aluminate with the
approximate formula [Mg (OH) +] 4 [Al2(OH)10 4 -].2H2O .It reacts
with acid in stages. The hydromagnesium is relatively rapidly
converted to magnesium ion and the aluminate to hydrated aluminium
hydroxide; the aluminium hydroxide then reacts more slowly to give a
sustained antacid effect.
Simethicone reduces the surface tension of gas bubbles so that the gas
is more easily eliminated.It is a surface active agent and dispenses
foam to diminish gastroesophageal reflux and the dyspeptic
symptoms.
53. Contraindications, Adverse reactions and
Precautions
Patients should not take more than 12 teaspoonfuls, in
a 24-hour period or use the maximum dosage for
more than two weeks, except under the advice and
supervision of a physician. If there is kidney disease,
do not prescribe this product.
Do not use in patients presently taking an antibiotic
drug containing any form of tetracycline.
54. H2 receptor antagonist-ULFAM
Available as ULFAM 20 mg & ULFAM 40 mg
Composition:
ULFAM 20
Each film coated tablet contains
Famotidine USP 20 mg
ULFAM 40
Each film coated tablet contains
Famotidine USP 40 mg
55. MOA
• H2 blockers, also called H2 -receptor antagonists
(H2RAs) are medicine that reduce the amount of
gastric acid by blocking the histamine.Ulfam inhibits
acid production by reversibly competing with
histamine for binding to H2 receptors at the
basolatetral membrane of parietal cells.
• Ulfam especially effective at inhibiting nocturnal acid
secretions (which depends largely on histamine) but
have a modest impact on meal-stimulated acid
secretion ( Which is stimulated by gastrin & Ach
along with histamine).
56. Indications
Short term treatment of active duodenal ulcer. Most
patients heal within 4 weeks.
Maintenance therapy for duodenal patients at reduced
dose after healing of active ulcer.
57. Pharmacokinetics
Ulflam is rapidly and well absorbed after oral administration.
Peak concentration in plasma is attained within 1 to 2 hours.
The half life for elimination of Ulflam is 2 to 3 hours. It is
metabolized in liver, excreted by the kidneys and large portion
is excreted in urine without being metabolized. Elimination
half life is increased in severe renal failure to about 13 hours
by extra glomerular secretion.
Adverse reactions
Famotidine has been found to be well tolerated; incidence of
adverse effect is low only headache, dizziness, bowel upset,
rarely disorientation and rash have been reported.
58. Contraindications
Hypersensitivity to any component.
Precautions
The dose should be reduced in patients with severe renal
insufficiency with creatinine clearance 10 ml/min.
Use in pregnant/nursing mother only if potential benefit
outweighs the potential risk.
Use in elderly with severe renal insuffiency, adjustment in
dose is required.
Pediatric safety and effectiveness in children have not been
established.
59. Mechanism of acid secretion
Binding of any or all three receptors on parietal cells
i.e histamine, acetylcholine and gastrin on their
respective receptors receptors stimulates parietal cell
to secrete HCl .
Morphological changes takes place within the
parietal cell.
The vesicles containing H+K+ATPase migrate and
insert into the secretory membrane of parietal cells.
60. Mechanism of acid secretion
Simultaneously cAMP activates KCl pathway due to
which K+and CL- move out of the lumen of the
parietal cells.
The enzyme H+K+ATPase at the secretory membrane
facilitates exchange of K+ which is present in the
lumen of
parietal cells with H+ which is present in the
cytosol of the cell.
61. Mechanism of acid secretion
H+ and Cl- which are now present in the secretory
canaliculi together form HCl.
This HCl formed in the secretory canaliculi then
enters the lumen of the oxyntic gland and from there
enters the stomach.
62. Mechanism of acid secretion
H+ and Cl- which are now present in the secretory
canaliculi together form HCl.
This HCl formed in the secretory canaliculi then
enters the lumen of the oxyntic gland and from there
enters the stomach.
64. PPI
Proton Pump Inhibitors like Omeprazole , Pantoprazole
inhibits the final common step in gastric acid secretion.
These accumulates in the acidic environment of the parietal
cells after absorption . There it is converted to a cyclic
sulphenamide which react covalently with the SH groups of
the H+K+ATPase enzyme and inactivate it irreversibly.
Acid secretion resumes only when new H+K+ATPase
molecules are synthesized.
65. ZES
Available as ZES 20 mg
Composition: Each capsule contains 20mg of
Omeprazole IP as enteric coated granules.
Dosage: 20mg once a day or b.i.d depending
upon the severity.
Presentation: Each box contains 10X20
tablets,
Price: Rs 6.00 per tablet.
68. Dose
• Duodenal Ulcer: 20 mg once daily
• Gastric Ulcer: 40 mg once a day for 4-8 weeks
• Gastroesophageal Reflux Disease (GERD):
20 mg daily for up to 4 weeks
• Erosive esophagitis and accompanying symptoms
due to GERD : 20 mg daily for 4 to 8 weeks
• Maintenance Healing of Erosive Esophagitis: 20
mg daily
69. • Pathological Hypersecretory Conditions:
• 60 mg once a day
• Dose may increase upto 120 mg t.i.d.
• Zollinger-Ellison syndrome have been
treated continuously with omeprazole for
more than 5 years
70. Pharmacokinetics
• ZES is rapidly absorbed to a variable extent following
oral administration. Following absorption, it is almost
completely metabolized in the liver and rapidly
eliminated in the urine. Elimination half-life varies
from 0.5 to 3 hours. ZES is highly bound to plasma
proteins. (About 95%).
71. • Oral absoprtion: 50%
• Highly plasma bound
• Rapidly metabolized in liver
• Onset of effect-within one hour,
• Maximum effect -within two hours.
• Inhibition of secretion - 50%
• Max effect: at 24 hours
• Duration of inhibition - 72 hrs.
72. • The anti-secretory effect thus lasts far
longer than that expected from a drug
having a very short plasma half-life (less
than one hour)
• This is apparently due to Omeprazole’s
prolonged binding to the parietal H+/K+
ATPase enzyme
73. • When the drug is discontinued, secretory
activity returns gradually, over 3 to 5
days.
• The inhibitory effect of omeprazole on
acid secretion increases with repeated
once-daily dosing, reaching a max after
four days.
74. Pharmacodynamics
ZES suppresses gastric acid secretion by specific
inhibition of the enzyme H+/K+ ATPase present on
the secretory surface of the gastric parietal cell. This
blocks the final and common step in gastric acid
secretion.
75. Contraindications
• Hypersensitivity, lactation, children,
neonates.
Cautions
• Proton pump inhibitors should be used
with caution in-patients with liver disease,
in pregnancy and breast-feeding women.
76. Side effects
• Headache, diarrhoea, rashes, pruritis and dizziness
urticaria, nausea, vomiting constipation, flatulence,
abdominal pain, malaise, muscle and joint pain,
blurred vision, peripheral oedema & liver enzyme
level disturbances.
Interaction
• ZES inhibits oxidation of certain drugs like
diazepam; phenytoin and warfarin levels may be
increased.
77. PANTOP
• Generic Name: Pantoprazole
• Therapeutic Category: Proton pump inhibitors
• FDA Pregnancy category: B
Indications
• Pantoprazole (PANTOP) is indicated for the short-term
treatment of
• Duodenal ulcer
• Gastric ulcer
• Reflux oesophagitis, GERD
• Zollinger Ellision Syndrome (ZES).
• Duodenal ulcer associated with Helicobacter pylori infection
as a part of combination therapy.
78. Dosage and Direction for use
The recommended 40mg once daily dose should be taken in the
morning. Pantoprazole (PANTOP) should be swallowed whole with
a little water either before or during breakfast.
• Duodenal ulcer
• The recommended oral dose is 40 mg pantoprazole (PANTOP)
once daily in the morning for 2 to 4 weeks.
•
• Gastric ulcer
• The recommended oral dose is 40 mg pantoprazole (PANTOP)
once daily in the morning for 4 to 8 weeks.
• In the case of a suspected gastric ulcer, malignancy of gastric
carcinoma should be excluded, as treatment could conceal the
symptoms and may delay diagnosis.
•
79. Reflux oesophagitis
• The recommended oral dosage is 40 mg pantoprazole
(PANTOP) once daily in the morning for 4 to 8 weeks.
Long -term treatment
• Long -term treatment with pantoprazole (PANTOP) is
currently not indicated since sufficient clinical data is
not available.
Elderly patients: No dose adjustment is necessary in
the elderly.
Impaired renal and liver function
• No dose adjustment is required in the presence of
impaired renal and liver function.
80. Pharmacological Action
Site and mechanism of action
• Pantoprazole is a proton pump inhibitor (PPI) that
suppresses the final step in gastric acid production.
• Pantoprazole (PANTOP) is a proton pump inhibitor,
i.e. , it inhibits specifically and dose - proportionally H+
K+ - AT Pase, the enzyme which is responsible for
gastric acid secretion in the parietal cells of the
stomach. Pantoprazole (PANTOP) exerts its full effect
in a strongly acidic environment (pH< 3) and remains
mostly inactive at higher pH values, which explains its
selectivity for the acid secreting parietal cells of the
stomach.
81. Pharmacokinetics
Absorption and distribution
• Pantoprazole (PANTOP) is unstable in acid and is administered orally in the form of an
enteric-coated tablet. Absorption takes place in the small intestine. On average, the
maximum serum /plasma concentrations are approximately 2 to 3 g/ml about 2 1/2 hours
after administration of 40mg Pantoprazole as single or multiple daily doses in healthy
volunteers.
Metabolism
• Pantoprazole (PANTOP) is almost exclusively metabolized in the liver. The main
metabolite is desmethyl- pantoprazole which is conjugated with sulphate.
Elimination
• Renal elimination represents the most important route of excretion (approximately 80%) for
the metabolites of pantoprazole, the rest are excreted via the faeces.
Pharmacokinetic profile in patients
• In patients with renal impairment the half- life of the main metabolite is moderately
increased but there is no accumulation at therapeutic doses.
82. Interactions
Concomitant intake of food has no influence on the
bioavailability. Studies with pantoprazole in humans reveal no
interaction with the cytochrome P450 - system of the liver. No
interactions are observed after concomitant administration of
pantoprazole with antipyrine, diazepam, theophylline, digoxin,
oral contraceptives, phenytoin, nifedipine, carbamazepine,
diclofenac, metoprolol, glibenclamide, ethanol and caffeine.
Antacids do not interact with Pantoprazole (PANTOP).
Contraindications
• Hypersensitivity to pantoprazole. Safety in pregnancy and
during lactation has not been established .
• Safety and efficacy in children have not been established.
83. Side Effects
• Headache and diarrhoea have been
reported. In most cases the complaints
improve despite continued treatment.
• There have been reports of skin rashes,
pruritus and dizziness.