TEST 2

PHARMACOLOGY
 DMD2003
LECTURE #6
GASTROINTESTINAL (GIT)
PHARMACOLOGY

DRUGS USED TO TREAT PEPTIC ULCER DISEASE (PUD)

Anishka Lewis
 objectives

■ Upon the completion od this lecture, students should have an

understanding of:
– The pathophysiology of peptic ulcer disease
– Agents used to treat peptic ulcer disease
Structure and function of the
GIT system
 Gastrointestinal activities

■ The GI system has four major activities:

– Secretion of enzymes, acid, bicarbonate and mucus.

– Absorption of water and almost all of the essential nutrients

needed by the day.

– Digestion of food into usable and absorbable components

– Motility (movement of food and secretions through the system

(what is not used is excreted in the form of feces)
 Secretions of the GIT
GASTRIC GLAND
❖ Mucus cells- secretes a bicarbonate
rich in mucus

❖ Parietal cells- secretes

Hydrochloric acid

❖ Chief /Peptic cells- secretes

pepsinogen(pepsin)

❖ G cells- secretes gastrin

 Gastric acid secretion
PARIETAL CELLS
■ Hydrochloric acid is
secreted into the stomach
by parietal cells.
■ Parietal cell actively
transports H+ across its
apical canalicular
membranes via H+/K+
ATPases (proton pumps)
that exchange intracellular
H+ for extracellular K+
ENDOGENOUS
G CELLS
SECRETAGOGUES
▪ Gastrin is secreted into ▪ Histamine and
the bloodstream by G Acetylcholine also
cells in the mucosa of regulates acid
the gastric antrum. secretion.
▪ ACh binds to M3
▪ Stimulates contraction receeptors on the
of the stomach muscles stomach.
→ parietal cells release
HCL and the chief cells ▪ Histamine is binds to
release pepsin the H2 receptors.
Gastric acid secretion
Mucus secretion
 Peptic ulcer disease (pud)
■ An “Ulcer” is an open sore.

■ “Peptic” means that the cause of the problem is due to acid.

■ Peptic Ulcer disease can involve the stomach or duodenum and is

therefore a breakdown in the mucosa of the stomach (gastric ulcer) or
duodenum (duodenal ulcer).

– Characterized by a gnawing or burning sensation and that

occurs after meals - classically, shortly after meals with
gastric ulcers and 2-3 hours afterward with duodenal ulcers.
 Peptic ulcer disease
■ Imbalance between aggressive and defensive factors.
DEFENSIVE FACTORS
▪ Prevents the stomach and duodenum
from self-digestion;
✔ Mucus: continually secreted
protective effects
✔ Bicarbonate: secreted from
endothelial cells
✔ Blood flow: good blood flow
maintains mucosal integrity.
✔ Prostaglandins: stimulates secretion
of bicarbonate and mucus, promotes
blood flow and suppresses secretion
of gastric acid
▪ AGGRESSIVE FACTORS
✔ Helicobacter pylori: gram negative
bacteria can live in the stomach and
duodenum, may breakdown mucus
layer.
✔ Gastric acid: needs to be present for
ulcer to form → activates pepsin and
injures mucosa.
✔ Decreased blood flow: causes
decrease mucus production and
bicarbonate synthesis, promote gastric
acid secretion.
✔ NSAIDS: inhibits the production of
prostaglandins.
Peptic ulcer disease
 Pharmacological
management of PUD
Mechanisms
a. Neutralize the acid (HCL)
b. Inhibition of proton pump (H+/K+ ATPase)
i. Inhibition of histamine activity
ii. Direct inhibition
iii. Inhibition of cholinergic activity
iv. Prostaglandin analogs
c. Increasing mucus secretion (mucosal protective agents)
 Neutralizing acids - antacids
■ Antacids are basic compounds that neutralise acid in gastric lumen.

An ideal Antacid should be: Role of Antacids:

• Potent in neutralizing acid.
• Inexpensive. • Is primarily in pain relief.
• Not absorbed from GIT. • Higher dose given
• Should be sufficiently palatable to continuously can promote
be readily tolerated with repeated ulcer healing.
dosage. • Are superior to H2 blockers
• Not absorbed from GIT and in bleeding peptic ulcer.
contain negligible sodium.
• Free from side effects.
 antacids
SYSTEMIC NON_SYSTEMIC

■ Sodium bicarbonate ▪ Aluminium hydroxide

▪ Magnesium trisilicate
▪ Magnesium hydroxide
▪ Calcium carbonate
 antacids
Magnesium Salts Aluminium Hydroxide ▪ Calcium Carbonate

▪ Magnesium – It is a weak and ▪ Potent with rapid

Hydroxide: slow reacting acid neutralizing
▪ Magnesium antacid. capacity.
Trisilicate:
▪ Action is quick and – Delays gastric ▪ Causes
prolonged emptying and hypercalcemia,
▪ Rebound acidity is causes hypercalciuriaand
mild constipation formation of calcium
▪ Osmotic purgatives stones in the kidney
with long term use.
 antacids
Magaldrate Drug Interactions of Antacids.
– Combination of Al3+ and
Mg2+ ion salts ▪ Antacids form complexes with iron,
tetracyclines, digoxin, ranitidine,
– More commonly used.
fluoroquinolones, sulfonamides and
– This combination gives a
rapid and sustained antimuscarinics drugs.
relief.
▪ To avoid these, antacids should be
– No effect on motility taken 2 hours before or 2 hours after
– No effect on motility. the other drugs.
 H2 receptor antagonists
■ Competitively and reversibly inhibit the
interaction of histamine with H2 receptors.

■ Cause 90% reduction in gastric secretion by

a single dose (both volume and H+ ion
conc.).

■ Indirectly decreases gastrin and

acetylcholine-induced gastric acid
secretion.

■ Indicated for duodenal & gastric ulcers,

GERD, NSAID’s induced ulcer,
Zolliner-Ellison Syndrome (ZES)
H2 receptor antagonists - MOA
 H2 receptor antagonists
Pharmacokinetics Adverse effects Drug interaction
■ Rapidly and well ▪ Well tolerated with ▪ Cimetidine
absorbed
minor side effects inhibits/slows
■ Partly metabolised in the metabolism of of
liver and excreted by the ✔ Diarrhoea other drugs using
kidneys.
✔ dizziness, CYP450
■ Cimetidine’s long term ✔ muscle pain ✔ Lidocaine
use and high doses will ✔ Headache ✔ Phenytoin
increase prolactin release
(gynaecomastia). It also ✔ Dry mouth ✔ Theophyline
binds to androgen ✔ Propranolol
receptors (impotence) ✔ Warfarin
 Proton pump inhibitors
■ The most efficacious inhibitors of
gastric acid secretion

■ Prodrugs which are converted to

their active form (sulfonamide) at
acidic pH

■ Indicated for duodenal ulcer,

gastric ulcer, reflux oesophagitis,
Zollinger-Ellison syndrome

■ 95% inhibition of acid secretion

Proton pump inhibitors - MOA
 Proton pump inhibitors
Pharmacokinetics
■ Given as enteric coated
granules.
■ Highly protein bound
■ Metabolised in the liver by
CYP450 enzymes.
■ Accumulates in parietal
cells canaliculi for 2-3
days.
Adverse Effects Drug Interaction
▪ Increased serum levels
✔ Dizziness and increased toxicity
of benzodiazepines,
✔ Headache phenytoin, warfarin
and lidocaine.
✔ Insomnia
▪ Decreased levels of
✔ Abdominal pain ketoconazole and
theophylline leading to
✔ Nausea loss of effectiveness.
Gi mucosal protective agents

■ Known as GI protectants

■ Provides symptomatic relief of PUD

■ Includes;
– Sucralfate
– Bismuth Subsalicylate
– Prostaglandins (Misoprostol)
 sucralfate

■ An ulcer protective agent

■ It is a basic aluminium salt of sucrose octasulfate.

■ Promotes healing of both gastric and duodenal ulcers and also

prevents ulcer recurrence.
 sucralfate

■ MOA
■ In pH < 4, sucralfate is
polymerised to form a sticky,
viscid yellow white gel which
adheres to ulcer base,
protecting the site against
acid, pepsin and bile salts.

■ also inhibits pepsin activity in

gastric juices, preventing
further breakdown of proteins
in the stomach.
 sucralfate
Pharmacokinetics Adverse effects Drug Interaction
■ Rapidly absorbed
after oral ✔ Dry mouth ▪ Risk of high aluminium
administration ✔ Constipation levels and aluminium
✔ Nausea toxixity when combined
■ Metabolized in the ✔ Vomiting with aluminium salts.
liver and excreted in
feaces ✔ Rash
✔ Pruritis ▪ Interferes with the
■ Crosses placenta and ✔ dizziness absorption of
may enter breast tetracyclines, digoxin,
milk phenytoin and
cimetidine
 Bismuth subsalicylate
■ Pepto-Bismol

▪ Bismuth salts combines with mucus glycoproteins to form a barrier

that protects an ulcer from further damage by acid and pepsin

▪ Antibacterial effect against H. Pylori

✔ It impedes its growth and is frequently use as a part of a multidrug

regimen for the eradication of H. Pylori-associated peptic ulcer.
✔ May cause constipation and black stools
 prostaglandins
■ Used to protect the stomach lining.

■ PGE1 and PGI2 are synthesized by the gastric mucosa to inhibit

gastric secretion, enhance mucus production as well as mucosal
blood flow.

■ Misoprostol is a synthetic PGE1 analog given orally.

■ It is of special value in preventing NSAIDs induced gastric

ulceration.
 Prostaglandins
MOA:
– They act by binding to the PG receptor (EP3) present on the
parietal cells and inhibit cAMP production.

■ Pharmacokinetics:
– Given orally, rapidly absorbed from the GIT, metabolized in the liver
and excreted in the urine.

■ Adverse Effects:
– Diarrhoea, Muscle cramps, nausea, vomiting, constipation
 Anticholinergic agents
■ Includes Dicyclomine and Atropine

■ MOA: they antagonize the muscarinic Ach receptors on the

parietal cells to decrease the secretion of gastric acid.

■ Adverse Effects: dry mouth, blurred vision, cardiac

arrhythmia and urinary retention.

■ NOTE: Seldom used for PUD due to them being less effective
when compared to H2 antagonist and PPI
 Antibiotic ulcer therapy
■ Combination must be used.

■ Bismuth Subsalicylates – disrupts cell wall of H. Pylori

■ Carithromycin – Inhibits protein synthesis

■ Amoxicillin – disrupts cell wall

■ Tetracycline – inhibits protein synthesis

■ Metronidazole – used often due to bacterial resistance to amoxicillin

and tetracycline, due to intolerance by the patient or penicillin allergy
to amoxicillin.
 Dental implications of PUD
■ The dental provider must identify intestinal symptoms through a careful
history that is taken before dental treatment is initiated because many
GI diseases, although they are chronic and recurrent, remain undetected
for long periods.
■ This history includes a careful review of medications (e.g., aspirin and
other NSAIDs, oral anticoagulants) and level of alcohol consumption
that may result in GI bleeding. If GI symptoms are suggestive of active
disease, a medical referral is needed.
■ When the patient returns from the physician and the condition is under
control, the dentist should update current medications in the dental
record, including the type and dosage, and should follow physician
guidelines.
 Dental implications of PUD –
Drug consideration
■ Of primary importance are the impact and interactions of certain drugs
prescribed to patients with PUD

■ In general, the dentist should avoid prescribing aspirin,

aspirin-containing compounds, and other NSAIDs to patients with a
history of PUD because of the irritative effects of these drugs on the GI
epithelium.
 Dental implications of PUD –
Drug consideration
■ Acetaminophen and compounded acetaminophen products are
recommended instead. If NSAIDs are used, a COX-2–selective inhibitor
(e.g., celecoxib (Celebrex]) given in combination with a PPI or misoprostol
(Cytotec), 200 µg four times per day—a prostaglandin E 1 analogue—is
advised for short-term use to reduce the risk of GI bleeding.

■ Analgesic selection should be based on patient risk factors (previous GI

bleeding; advanced age, use of alcohol, anticoagulants, or steroids) and the
lowest dose for the shortest period to achieve the desired effect. Histamine
H 2 receptor antagonists and sucralfate are not beneficial selections because
they do not appear to protect patients from NSAID-induced complications.
 Dental implications of PUD –
Drug consideration
■ Selection of antibiotics for oral infections may be influenced by recent
use of antibiotics for PUD; certain drugs can increase the risk of
intestinal flare-up in patients with IBD. Avoid long-term use of
antibiotics, especially in older and debilitated persons, to minimize the
risk of pseudomembranous colitis. Monitor for signs or symptoms
(diarrhea, GI distress) suggestive of pseudomembranous colitis or
disease worsening. Contact patient’s physician if GI symptoms worsen
while patient is on antibiotics so that alternative therapies can be
initiated.
 Dental implications of PUD –
Drug consideration
■ Lower doses of diazepam, lidocaine, or TCAs may be required if the
patient is taking acid-blocking drugs, such as cimetidine, which
decreases the metabolism of some dentally prescribed drugs and
enhances the duration of action of these medications. PPIs may reduce
absorption of select antibiotics and antifungals. Monitor effects of
immunosuppressant medications. If patient has recently taken
corticosteroids, dosage modification generally is not needed; however,
the clinician should evaluate the need for supplemental steroids as
indicated by health status, level of anxiety or fear, presence of infection,
and invasiveness of the dental procedure
 oral complication and
manifestation
■ H. pylori is found in dental plaque and may serve as a reservoir of
infection and reinfection along the alimentary tract. Good oral hygiene
measures and periodic scaling and prophylaxis may be useful in
reducing the spread of this organism. The need for rigorous hygiene
measures should be explained to the patient and consideration given to
laboratory detection of oral organisms in patients who have a history of
PUD and are symptomatic or are experiencing recurrences.
■ The use of systemic antibiotics for PUD may result in fungal
overgrowth (candidiasis) in the oral cavity. The dentist should be
alert to identifying oral fungal infections, including median
rhomboid glossitis.
 oral complication and
manifestation
■ Vascular malformations of the lip and erosion of the enamel are two
less common oral manifestations of PUD. The former have been
reported to range in size from a small macule (microcherry) to a large
venous pool, and they typically occur in older men with PUD.

■ Enamel erosion is the result of persistent regurgitation of gastric juices

into the mouth when pyloric stenosis occurs
 DMD2003
LECTURE # 7

GASTROINTESTINAL
PHARMACOLOGY 2
EMETICS, LAXATIVES AND
ANTIDIARRHEAL AGENTS
Anishka Lewis
 objectives
■ Upon completion of this Lecture, Students should have an
understanding of:

– Drugs used as Emetics, Laxatives and Antidiarrheal agents

emetics
 Emesis/vomiting
■ Emesis (vomiting) is a complex reflex reaction of the emetic/vomiting
center (found in the medulla oblongata) to various stimuli.

■ The chemoreceptor trigger zone (CTZ) relays sensory impulses from

areas such as the GIT, throat, etc. to the vomiting center.

■ There are different drugs which stimulates the CTZ

– Morphine
– Digitalis glycosides,
– Apomorphine, etc.
 Mechanism of Vomiting

■ CTZ contains receptors for

– Dopamine,
– Serotonin,
– Opioids,
– Acetylcholine
– The neurotransmitter Substance P.

■ Stimulation of these receptors gives rise to pathways leading to vomiting

and nausea.

■ The CTZ lies outside the blood-brain barrier (BBB).

 Mechanism of Vomiting – inputs to
the vomiting center
1. Inputs from the vestibular system of the inner ear are involved in
motion sickness. There is an abundance of H1 receptor in this system.
2. The vagus nerve carries signal from the CTZ when the back of the
throat or pharynx is irritated or stimulated.
3. The enteric nervous system (gut) also transmits signals to the brain via
the vagus nerve. It is via this system that radiation therapy,
chemotherapy and gastroenteritis activate the 5-HT3 receptors leading
to vomiting.
4. Dopamine receptors are activated by stress and several psychiatric
conditions, leading to vomiting.
 Mechanism of Vomiting – The
process of vomiting
■ Stimulation of the CTZ leads to activation of the motor, parasympathetic
and sympathetic nervous system.

■ Stimulation of the parasympathetic nervous system leads to increased

salivation.

■ Deep breathing proceeds the actual vomiting to protect the lungs from
aspiration.

■ Heaving or retching occur before the actual vomiting

 Mechanism of Vomiting – The
process of vomiting
■ Relaxation of the pyloric sphincter that guards the lower end of the
stomach to bring up content from the gut.

■ The pressure within the abdomen rises and the pressure within the chest
or thorax is lowered. The abdominal muscles contract to expel the
contents of the stomach.

■ Activation of the sympathetic nervous system leads to sweating,

palpitation and rapid heart rate.
 emetics
■ Drugs which produce or evoke vomiting.

■ Most common compounds used are:

– Apomorphine
– Ipecacuanha (Ipeca)
 apomorphine
■ A semisynthetic opioid which acts a dopaminergic agonist on the CTZ.

■ Given by subcutaneous or IM route in a dose of 6 mg.

■ Produces vomiting within 15 minutes.

■ Apomorphine induced vomiting can be antagonized by Chlorpromazine.

■ Side Effects: tremors and restlessness

– In toxic doses may cause convulsions and respiratory depression
 ipecacuanha
■ Syrup containing alkaloid emetine obtained from the plant
Cephaelis ipeca-cuanha.

■ Acts on both gastric mucosa and the CTZ.

■ Given as a syrup (15-20 ml)

■ Produces vomiting in 15 minutes.

 Vomiting and oral health

■ The bile and acids from your stomach coming through your mouth to be
expelled can cause damage to your teeth, gums, and throat. It’s important
to take proper care of your mouth, even when you’re not feeling very
well. After you vomit, rinse your mouth with water, and then use a
mouthwash with fluoride.
■ Be aware that brushing your teeth immediately after vomiting can cause
additional problems. Stomach acid weakens the enamel on your teeth, so
brushing them right away can cause the enamel to erode. After you have
stopped throwing up, make sure to brush your teeth with toothpaste that
contains fluoride.
Vomiting and oral health

■ Frequent vomiting can have a negative effect on your oral

health. Issues include dryness, sores, redness of the mouth and
tongue, chronic sore throats, and erosion of the enamel that
protects your teeth. Erosion increases the risk of decay, causing
more cavities and sensitivity of the teeth. Over time, more
severe cases of erosion can also change the way your lower
and upper teeth come together, and you could end up losing
some of your teeth.
Vomiting and oral health

■ The chronic vomiting patient’s first contact with the dentist

may be for treatment of an emergency situation.

■ The dentist must determine if the erosion that is causing severe

thermal sensitivity will necessitate endodontic therapy.
 Vomiting and oral health

■ If the sensitive tooth, or teeth, is not affected endodontically, the exposed

dental surfaces must be protected.

– This is best accomplished by placing a calcium hydroxide preparation

on the dentin and retaining it with a layer of composite resin using the
acid-etch technique.

■ Sensitive teeth that are affected endodontically should be treated as soon

as possible to prevent acute pain or swelling (or both).
laxatives
 constipation
■ Difficulty or infrequent passage of stool, hardness of stool, or a
feeling of incomplete evacuation.

■ Types of constipation:

– Acute: bowel obstruction, drug related

– Chronic: colonic tumors, metabolic disorders, CNS

disorders.
 Laxative (purgatives)
■ Drugs which promote
defecation and the evacuation
of bowels.
■ Enhance/speed up the passage of
food through the small intestine
bowel movement.
■ Classification of Laxatives:
– Bulk laxatives
– Faecal softeners
– Osmotic laxatives
– Stimulant laxatives
 Bulk Laxatives
■ Examples: Bran, Psyllium, Methylcellulose (citrucel), Calcium Polycarbophil.
■ MOA: increases the volume of stool by absorbing water and swelling. Upon swelling
the distend the colon and increases peristaltic motility. Softening of feaces also
occur.
■ Adequate hydration of the patient is to be maintained.
■ Onset of action: 12-24hrs
 Surfactant laxatives (Faecal
softener)
■ Examples: Docusate (dioctyl sodium sulfosuccinate), Glyerin,
Mineral oil.

■ MOA: soften feaces by lowering their surface tension of the

intestinal contents which allows more water to be retain in the
faeces.

■ Side Effects: oil leakage into anal sphincter, long term use interfere
with absorption of fat –soluble vitamin.
 Osmotic laxatives
■ Solutes that are not absorbed in the intestine.

■ Examples: Magnesium Sulphate (Epsom salts), Magnesium

Hydroxide (milk of magnesia), Lactulose (miralx)

■ MOA: osmotically retain water in bowel lumen and distend the

bowel therefore increasing peristalsis indirectly.

■ Onset: 1-3 hrs

■ Used to prepare the bowel before surgery and in food poisoning.
■ Lactulose is reserved for chronic constipation.
 Stimulant laxatives
■ Examples: Castor Oil (ricinoleic acid), Bisacodyl (ducolax)
– Anthraquinone Derivatives: Cascars (buckhorn tree) and Senna
(plantains).

■ MOA: Direct stimulation of nerves in the enteric nervous system to

result in increased water and electrolyte secretion from mucosa,
also increase peristaltic activity.

– They mainly alter absorptive and secretory activity by inhibiting

Na+ K+ ATPase in mucosal cells, leading to water and electrolyte
accumulation in lumen.
antidiarrheal
 diarrhoea
■ Diarrhoea is the frequent passage of liquid stools with or without blood
and mucos.

■ Due to a variety of causes like infection, toxins, anxiety and drugs.

■ Approaches in treatment:
– Replacement fluid and electrolytes
– Treatment of cause
– Antidiarrhoeal agents
 Fluid and electrolyte
replacement
■ ORAL REHYDRATION SALTS (eg. Pedialyte®), Usually the only
therapy needed for acute diarrhea (body defense mechanism).

■ Eg: WHO formulation

– NaCl 3.5 g/L
– KCl 1.5 g/L
– Na Citrate 2.9 g/L
– Glucose 20 g/L
 Drugs to decrease motility

■ ANTIMUSCARINIC DRUGS:
– Atropine
– Hyoscine
– Dicyclomine

■ MOA: Block muscarinic receptors (m3), thus inhibiting

parasympathetic activity.
 Drugs to decrease motility

■ OPIATE-LIKE DRUGS

– Diphenoxylate (Lomotil)
– Loperamide

■ MOA: Stimulate µ opiate receptors in the myenteric plexus to

reduce Ach release and therefore decrease peristaltic activity.
Also reduces pain
 Drugs to decrease motility

■ OPIATE-LIKE DRUGS
■ Greater potency than morphine: Diphenoxylate (2 x)
Loperamide (40-50 x)
■ Limited entry into CNS, therefore activity only on peripheral opiate
receptors

■ Side effects: nausea, drowsiness, dizziness, paralytic ileum

 Drugs to decrease motility

■ MEBEVERINE
– Activity only on GIT (no activity on other smooth muscles).
– Direct relaxant action on smooth muscles.

■ MOA: very weak Atropine-like effect

– Local anaesthetic effects
 Drugs that reduce GIT
secretions
■ Bismuth Subsilicylate (Pepto-bismol)

■ MOA: converted by HCl to salicylic acid and bismuth oxynitrate.

Bismuth absorbs bacterial toxins.

■ Used for travellers’ (infection) diarrhea.

■ Salicylate content = anti-inflammatory action

 Anti-infective drugs
■ Usually used if diarrhoea is viral

■ Bacterial infections:

– E.g. Salmonella – Tetracycline

– Shegella – Ampicillin
– Campylobacter -Erythromycin
 DMD2003
LECTURE #9

AUTOCOIDS, INFLAMMATION,
ALLERGY &
IMMUNOMODULATORS
Anishka Lewis
 Objectives

■ Upon completion of this Lecture, students should be able

to:
– Describe the mechanism involved in allergic reaction.

– Discuss the actions of histamine, serotonin and

angiotensins.

– Discuss eicosanoids as they relate to inflammation.

Allergies
 allergies
■ “Allergy is an ‘over reaction’ of the immune system response to
a foreign substance that’s not typically harmful to the body.

■ Also known as hypersensitivity reactions

■ Requires a presensitized (immune) state of the host

■ Hypersensitivity reactions can be divided into 4 types based on

the mechanisms involved and time taken for the reaction
 Allergies - sensitization

■ Reaction in which specific antibodies develop in response to

an antigen.

■ So Allergic reactions result from excess sensitization to a

foreign protein.

■ Sensitization can be induced by immunization, in which a

pathogen that has been made noninfectious is introduced into
the body.
 Types of hypersensitivities
■ Hypersensitivity reactions – originally divided into 2 categories:
immediate and delayed. In 1968 Coombs & Gell defined the 4 types
used today
– Type I: immediate hypersensitivity (anaphylactic)

– Type II: cytotoxic hypersensitivity

– Type III: immune-complex mediated hypersensitivity

– Type IV: cell mediated or delayed hypersensitivity contact,

tuberculin & granulomatous
 Factors determining
hypersensitivity type
■ Chemical nature of allergen

■ Route involved in sensitization i.e. inhalation, ingestion,

injection

■ Physiological state of individual / genetic potential

allergies
 What is inflammation?
■ Complex biological response of
vascular tissues to harmful
stimuli such as:
– Pathogens
– Damaged cells
– Irritants

■ It is a protective attempt by the

organism to remove the injurious
stimuli as well as initiate the
healing process for the tissue
 Phases of inflammation

■ Two distinct phases of inflammatory response:

– Acute (transient or short-term)

– Chronic (proliferative or prolonged)

 Phases of inflammation
1. Acute (transient or short-term)
– Local vasodilation → ↑ blood flow → redness (rubor) and heat
(calor)

– Increased permeability of the blood vessels → ↑ fluid exudation

(leakage) into tissue → swelling (edema or tumor)

– → Pain (dolor) and loss of function (functio laesa) –

sensitization of pain receptors (nociceptors) → hyperalgesia →
local release of enzymes → ↑ tissue pressure
 Phases of inflammation

2. Chronic (proliferative or prolonged)

– Delayed Phase – Infiltration of leukocytes and phagocytes

to the injured area

– Tissue degeneration and fibrosis

 Mediators of inflammation

1. Complement system and complement-derived peptides: a

biochemical cascade which helps clear pathogens from an
organism

– Forms part of the innate immune system – not adaptable

and does not change over the course of an individual's
lifetime
 Mediators of inflammation

2. Local hormones

■ Autocoids – Histamine, Serotonin (5-HT), Eicosanoids,

Bradykinin, Angiotensin, Nitric Oxide, Substance P, and
Cytokines.

■ Can be categorized as:

– Autocrine secretions eg. cytokines
– Paracrine secretions eg. histamine
– Neurocrine secretions eg. Ach and NE
 Autocoids includes

■ Histamine

■ 5-hydroxytryptamine (Serotonin/5-HT)

■ Angiotensin

■ Prostaglandins

■ Leukotrienes
histamine
Histamine synthesis & metabolism
• A biogenic amine formed in
many tissues.

• One of the major mediators that

initiate acute inflammatory
responses.

• Stored and found in the highest

amounts in mast cells and
basophil.

• Released in response to injury or

to any antigen-antibody reaction.
 Histamine release (immunologic)
1. During inflammatory or allergic reactions, humans produce IgE
antibodies when exposed to allergen
2. Mast cells bind to the IgE antibodies
3. Initial exposure to an allergen: large numbers of IgE antibodies are
formed which attach to mast cells surfaces
4. Second exposure to an allergen: IgE antibodies bound to the mast cell
surface can bind to allergen
5. The allergen causes crosslinking of the IgE molecules on the cell surface
6. This allergen-antibody complex stimulates a signal transduction that
causes the mast cell to ‘degranulate’, and release their granules (with
histamine) into the tissues
 Histamine receptors
■ Histamine produces its pharmacological effects via three groups of
receptors – (main = H1, H2) and H3

■ Histamine receptors are G-protein-coupled receptors

 effects of histamine
CVS : Histamine dilates small blood vessels resulting in hypotension
accompanied by reflex tachycardia. Cerebral blood vessels dilate which
causes severe throbbing headache.

■ Triple response Intradermal injection of histamine elicits triple response

comprising of:
(i) red spot at the site (flush).
(ii) flare - redness surrounding the ‘flush’ .
(iii) wheal - local oedema due to the escape of fluid from the
capillaries.
 effects of histamine
Activation of H1 receptors Histamine Substitutes
1) Erythema (redness of the skin)
• Betazole is a H2 agonist and
2) Congestion
can be used in
3) Edema gastric function tests.
4) Inflammation
• Betahistine is a H1 agonist
5) Pruritus (itching)
used to control vertigo in
6) Initiate the cough reflex Meniere’s disease
7) Bronchoconstriction
8) Contraction of most GIT smooth
muscle
 effects of histamine
Adverse effects Clinical use
■ Flushing
■ Hypotension ■ Histamine has no therapeutic
■ Tachycardia applications.
■ Headache
■ Bronchoconstriction ■ Drugs that block histamine’s
effects are very important in
■ GI upset clinical medicine.
Histamine antagonists
 antihistamine

■ Refers to the classic H1-receptor blockers.

■ Do not influence the formation or release of histamine.

■ Divided into 1st and 2nd generation drugs.

 antihistamine
1st Generation
■ Examples: Diphenhydramine (DPH;
Benadryl), Chlorpheniramine
(Histal®), Brompheniramine,
Doxylamine, Cyclizine,
Dexchlorpheniramine, Pheniramine,
Promethazine, Triprolidine
■ Highly lipid soluble → alters
wakefulness → drowsiness and
sedation
■ Most have a short duration of action
2nd Generation
■ Examples: Loratadine (Claritin),
Cetirizine (Zyrtec), Fexofenadine
(Allegra), desloratadine(Aerius®),
Azelastine, Levocarbastine,
Levocetirizine
■ Less lipophilic than first generation
agents → cross the blood–brain barrier in
only relatively small amounts → less
sedation
■ Most have a more prolonged action
(12–24 hours)
 Antihistamine

■ Therapeutic uses ■ Pharmacokinetics • Adverse Effects

1. Allergic and ■ Well absorbed after
inflammatory oral administration. • Sedation
conditions ■ Metabolized by CYP • Dizziness
450 system.
2. Motion Sickness ■ Excreted in feces • Dry mouth

■ Most effective when • Constipation

used prophylactically
rather than as needed • Urinary retension
Serotonin
 Serotonin (5-ht)
■ 5-HT is formed from the amino acid tryptophan in
enterochromaffin cells in the wall of intestine (90%) and in
nerves (neurotransmitter)

■ 5-HT is not made in platelets – 5HT actively accumulated from

the plasma into platelets as they pass through intestinal
circulation

■ 5HT is also found in foods such as pineapples, bananas, & also

found in nettle stings
Biosynthesis of 5-ht
 Serotonin receptors
■ There are 7 main types of serotonin receptors:
– 5-HT1 - 5-HT7

■ 5HT1 & 5HT2 receptors are further subdivided:

– 5-HT1 : A, B, D, E*
– 5-HT2: A, B, C
 Effects of serotonin
■ Platelets in circulating blood
adhere to the endothelium
Endothelium is intact →
vasodilation
■ 5-HT is released from platelets →
5-HT1 receptors → vasodilation
to sustain blood flow by:
■ On the endothelial cells →
NO release → relaxation
■ On the sympathetic nerve
terminal → Inhibit NE
release
Endothelium damaged e.g. in
Atherosclerosis
■ 5-HT is released from platelets
→ 5-HT2A receptors →
impairs blood flow
– Platelet aggregation
– Direct vasoconstrictor
action on arteries and
veins
 Effects of serotonin

Effects in Inflammation
■ Vasodilation and increased vascular permeability : 5HT
released from platelets and causes vasodilation by acting on
5HT1 receptors on the endothelial cells → NO release→
relaxation
 Clinical uses of 5-ht
AGONIST
■ 5-HT1D – sumatriptan – Used in
migraine therapy
– A high specificity for these receptors
on the cranial blood vessels
– Decrease activity of trigeminal nerve
(useful in treating cluster headaches).
■ 5-HT3 – ondansetron,
■ 5-HT4 – metoclopramide, cisapride
– Used to treat GIT disorders e.g.
gastric reflux
ANTAGONIST
■ 5-HT2 - dihydroergotamine,
ketotifen, pizotifen, methysergide,
cyproheptadine, ketanserin
– Used to treat migraine
headache
granisetron, tropisetron
– Used to suppress nausea and
vomiting (anti-emetic effect
angiotensins
 angiotensins

■ Peptides synthesized from

angiotensinogen.

■ Apart of the renin – angiotensin

– aldosterone system.

■ Receptors: AT1 and AT2

 Actions of Angiotensin II
■ Blood vessels – it increases blood pressure by causing constriction (narrowing) of
the blood vessels

■ Nerves: it increases the sensation of thirst, the desire for salt, encourages the release
of other hormones that are involved in fluid retention.

■ Adrenal glands: it stimulates production of the hormone aldosterone, resulting in

the body retaining sodium and losing potassium from the kidneys.

■ The kidneys: it increases sodium retention and alters the way the kidneys filter
blood. This increases water reabsorption in the kidney to increase blood volume and
blood pressure. 
 Angiotensin
■ Inhibitors of ACE and blockers of angiotensin II receptors
are now used in the treatment of hypertension, congestive heart
failure and other conditions that are due to excess of
angiotensin II activity
Eicosanoids
 eicosanoids
■ Can be classified as:

■ Prostaglandins (PGs)
■ Thromboxanes (TXs)
■ Leukotrienes (LTs)

■ Lipids formed from the phospholipid component of the cell

membrane in all mammalian cells except erythrocytes (RBCs
 Actions of eicosanoids
■ VASCULAR SMOOTH MUSCLE
– PGE2 and PGI2 are potent
vasodilators in most vascular beds.
– Thromboxane is a potent
vasoconstrictor
■ Inflammation
– PGE2 and PGI2 cause an increase
in blood flow and promote, but do
not cause edema.
– leukotrienes cause chemotaxis of
neutrophils and eosinophils.
■ BRONCHIAL SMOOTH
MUSCLE
– PGFs cause smooth muscle
contraction
– PGEs cause smooth muscle
relaxation
– Leukotrienes and Thromboxanes
are potent bronchoconstrictors
and are the most likely candidates
for mediating allergic
bronchospasm.
 Actions of eicosanoids
■ UTERINE SMOOTH
MUSCLE
– PGE2 and PGF2α cause
contraction of uterine
smooth muscle in pregnant
women.
– The non-pregnant uterus
has a more variable
response to prostaglandins
■ PGF2α causes
contraction
■ PGE2 causes relaxation
■ GASTROINTESTINAL TRACT
– PGE2 and PGF2α : increases the rate
of longitudinal contraction in the gut
and decrease transit time.
– The Leukotrienes: are potent
stimulators of gastrointestinal smooth
muscle.
– PGE2 and PGI2: inhibit acid and
pepsinogen secretion in the stomach.
– Prostaglandins: increase mucus,
water, and electrolyte secretion in the
stomach and the intestine.
 Actions of eicosanoids
■ BLOOD ■ INDUCTION OF LABOUR
– TXA2: a potent inducer of AT TERM
platelet aggregation

– PGI2 and PGE2: Inhibit – Induction of PGF2α

platelet aggregation (carboprost tromethamine)
[Hemabate] or
– PGEs: induce erythropoiesis
by stimulating the renal
release of erythropoietin – PGE2 (dinoprostone)
[Prostin E]
– PGI2 and PGD: inhibit
histamine release
 Therapeutic uses of eicosanoids
■ THERAPEUTIC ABORTION
– A. Inducing abortion in the
second trimester:
■ Infusion of carboprost
tromethamine or
■ Administration of vaginal
suppositories containing
dinoprostone
– B. Inducing first-trimester:
■ These prostaglandins are
combined with mifepristone
(RU486)
■ MAINTAINANCE OF
DUCTUS ARTIOSUS
– Produced by PGE1
[Prostin VR] infusion
– PGE1 will maintain
patency of the ductus
arteriosus, which may
be desirable before
surgery.
 Therapeutic uses of eicosanoids
■ TREATMENT OF PEPTIC ■ ERECTILE DYSFUNCTION
ULCER
– Alprostadil (PGE1) can be
– Misoprostol [Cytotec] injected directly into the
corpus cavernosum or
■ A methylated derivative of administered as a
PGE1
transurethral suppository to
■ Approved for use in patients cause vasodilation and
taking high doses of enhance tumescence.
non-steroidal
anti-inflammatory drugs
(NSAIDs) to reduce gastric
ulceration.
Transurethral Injected directly into
suppository the corpus cavernosum
 Adverse effects

■ Local pain and irritation

■ Bronchospasm

■ Gastrointestinal disturbances: nausea, vomiting, cramping, and

diarrhea.
 DMD2003
LECTURE # 11

RESPIRATORY
PHARMACOLOGY

ANISHKA LEWIS
 objectives
■ Upon completion of this Lecture, students should be able to:

– Discuss the action and use of adrenergic agents

– Discuss the action and use of beta-selective agents

– Discuss the action and use of methylxanthine agents

– Discuss the action and use of cromolyn sodium

– Discuss the action and use of corticosteroids

Structure & function of the
respiratory system
Structure & function of the
respiratory system
Structure and function of the
respiratory system
 Gaseous exchange

■ Occurs in the alveoli.

■ Carbon dioxide is lost from the

blood and oxygen is transferred
to the blood.

■ The exchange of gases at the

alveolar level is called
respiration
 respiration
■ The inspiratory muscles—diaphragm, external intercostals, and
abdominal muscles—are stimulated to contract by the respiratory center
in the medulla.
■ The medulla receives input from to increase the rate and/or depth of
respiration to maintain homeostasis in the body.
■ Vagal stimulation also leads to a bronchoconstriction or tightening.
■ Stimulation of the sympathetic system leads to increased rate and depth of
respiration and dilation of the bronchi to allow freer flow of air through
the system
 Respiratory pathophysiology
UPPER RESPIRATORY LOWER RESPIRATORY
TRACT CONDITIONS TRACT CONDITIONS

■ The common cold ■ Atelectasis

■ Pneumonia
■ Bronchitis
■ Seasonal Rhinitis ■ Bronchiectasis
■ Obstructive Pulmonary Disease
■ Sinusitis – Asthma
– COPD
■ Pharyngitis and Laryngitis – Respiratory distress
syndrome
 asthma
■ Characterized by reversible bronchospasm, inflammation, and
hyperactive airways, causing wheezing coughing, chest tightness and
shortness of breath.
■ The hyperactivity is triggered by allergens or non-allergic inhaled
irritants or by factors such as exercise and emotions.
■ Appropriate treatment depends on understanding the early and late
responses.
Pathophysiology of asthma
Pathophysiology of asthma
Chronic obstructive pulmonary
disease (copd)
■ A lung disease characterized by chronic obstruction of lung airflow
that interferes with normal breathing and is not fully reversible.

■ Results in airway obstruction, dyspnea, decrease blood oxygen

concentration and increases blood carbon dioxide concentration.

■ Includes chronic bronchitis and emphysema.

Classification of agents used to
manage respiratory conditions
■ Sympathomimetics
– Beta-selective agents
■ Albuterol, Terbutaline, Metaproterenol
■ Methylxanthine
– Theophyline
■ Cromolyn Sodium

■ Corticosteroids
– Prednisone, Prednisolone, Beclomethasone diphosphate
 Sympathomimetic drugs
■ Selective beta-2 agonists are primary bronchodilators.

■ Relieves bronchospasm

■ Includes:
– Short acting β2 agonists
■ Salbutamol (Albuterol) and Terbutaline
– Longer acting β2 agonists
■ Salmeterol, Formoterol, Fenoterol, Bambuterol &
Pirbuterol
 Sympathomimetic drugs
MOA:

■ Adrenergic agonists stimulate β2 receptors in the bronchial smooth

muscles which in turn cause activation of adenylyl cyclase resulting
in increased cAMP levels. This increased cAMP leads to
bronchodilatation. The increased cAMP in mast cells inhibits the
release of inflammatory mediators

■ They also reduce bronchial secretions and congestion.

 Sympathomimetic drugs
SHORT ACTING β2 AGONISTS LONG ACTING β2 AGONISTS

■ Given by inhalation ■ Slow onset of action

■ Fast acting, peak effect in 10
■ Effects last for 12 hours
minutes, lasting for 6 hours.

■ Adverse Effects: Muscle ■ Used for long-term maintenance

tremors, Palpitation & and for prevention of nocturnal
nervousness asthmatic attacks.
 Sympathomimetic Drugs
■ Long Term use – development
of tolerance

■ Others include: Adrenaline,

Ephedrine and Isoprenaline
– Risk of adverse effects.

■ Clinical Uses: Symptomatic

relief or prevention of
bronchial asthma, and for
bronchospasm associated
with COPD
 methylxanthines
■ Theophylline and its
derivatives like
aminophylline are good
bronchodilators.
■ Have a direct effect on the
smooth muscles of the
respiratory tract, both in the
bronchi and blood vessels.
■ Uses: Acute and Chronic
asthma, bronchospasm
associated wit COPD
Table 1. Proposed mechanisms of action of theophylline.
MOA.
•Phosphodiesterase inhibition (non-selective)
■
•Adenosine receptor antagonism (A1-, A2A-,
A2B-receptors)
•Inhibition of nuclear factor-κB (↓ nuclear
translocation)
•Inhibition of phosphoinositide 3 kinase-δ
•↑ Interleukin-10 secretion
•↑ Apoptosis of inflammatory cells
•↓ poly(ADP-ribose)polymerase-1 (inhibits cell death)
•↑ Histone deacetylase activity (↑ efficacy of
corticosteroids)
 methylxanthines
MOA
1. Phosphodiesterase (PDE) is the enzyme that degrades cyclic
AMP. Methylxanthines inhibit PDE and thereby enhance
cAMP levels which brings about bronchodilation. cAMP also
inhibits the release of mediators of inflammation.

2. Theophylline is a potent inhibitor of adenosine receptors at

therapeutic concentrations. Both A1- and A2-receptors are
inhibited, but theophylline is less effective against
A3-receptors, suggesting that this could be the basis for its
bronchodilator effects.
 methylxanthines
PHARMACOKINETICS
■ Rapidly absorbed from the GIT
when given orally, reaching peak
levels within 2 hours.
■ Also given IV, reaching peak
effects within minutes.
■ Widely distributed and
metabolized in the liver and
excreted in urine.
ADVERSE EFFECTS
■ Gastric irritation, vomiting,
insomnia, tremors
■ Hypotension are quite common.
Higher doses
■ Restlessness, delirium, convulsions
and arrhythmias.
■ Children may develop behavioural
abnormalities on prolonged
use—should be avoided
 glucocorticoids

■ Anti-inflammatory drugs.

■ Inhaled steroids

■ Includes: Beclomethasone (Beclovent), Budesonide

(Pulmicort), Ciclesonide (Alvesco), Fluticasone (Flovent).

■ USES: Prevention and treatment of asthma

 glucocorticoids
MOA:
■ They bind to steroid
receptors in the cytoplasm,
drug receptor complex
moves to the nucleus, binds
to DNA and induces the
synthesis of specific mRNA.
This in turn results in the
synthesis of specific proteins
to bring about the following
effects;
MOA:
■ They decrease the formation of cytokines.
■ ↓ PG synthesis.
■ Inhibit the production of leukotrienes and
platelet activating factor.
■ Reduce the influx of eosinophils into the
lungs and thus reduce the release of
mediators from them.
■ ↓ synthesis of interleukins.
■ Restore response to β2 agonist -(if tolerance
has developed)-by upregulating β2 receptors.
 glucocorticoids
PHARMACOKINETICS ADVERSE EFFECTS

■ May be given systemically in acute ■ Hoarseness of voice

episodes. Oral prednisolone is
commonly used (dose 30-60 ■ Sore throat and
mg/day).The onset of response
requires about 12 hours. oropharyngeal candidiasis.

■ They prevent episodes of acute

asthma, reduce bronchial
hyperreactivity and effectively
control symptoms.
 Mast cell stabilizers
■ Cromolyn Sodium (NasalCrom,
disodium cromoglycate)
■ Prevents bronchospasm and
inflammation following exposure
to allergen and decreases
bronchial hyper-reactivity.
■ USES: Prophylaxis of
bronchial asthma, Allergic
rhinitis,
MOA
■ Cromolyn inhibits the
degranulation of mast cells and
thereby inhibits the release
of mediators of inflammation,
particularly histamine.
■ It also inhibits the release of
cytokine
 Mast cell stabilizers

■ PHARMACOKINETICS
– It is given orally. Beneficial effects are seen after 6-12 weeks of
use.
– It is used for the prophylaxis of bronchial asthma and other
allergic disorders like allergic rhinitis

■ ADVERSE EFFECTS
– Drowsiness, dry mouth, dizziness and weight gain
 Bronchial asthma and dentistry
1. A small amount of water or dental materials used in dental procedures
may aspirate into the respiratory passage and trigger an acute attack of
bronchial asthma. Salbutamol inhalation should be given immediately.
The dental procedure may be continued after the patient recovers.

2. Analgesics (NSAIDs) prescribed for relief of pain may trigger acute

episodes of asthma. This should be kept in mind. Depending on the
severity of asthma and the dose of the NSAID required, appropriate
drug should be prescribed. If the patient has severe asthma and requires
an anti-inflammatory drug for his dental problem prednisolone should
be considered.
Bronchial asthma and dentistry

3. If the patient has been receiving steroid inhalation for

prophylaxis of bronchial asthma for a long period, the oral
microflora could be altered. This predisposes the oral mucosa to
infection with microorganisms like candida and certain bacteria.
Appropriate care should be taken
 DMD2003
LECTURE #12

CARDIOVASCULAR
PHARMACOLOGY

ANISHKA LEWIS
 objective

■ Upon completion of this lecture, students should be able to:

– Discuss the action and use of antihypertensive and

antianginal agents.

– Discuss the action and use of drugs in heart failure and

arrhythmias.
Structure and function of the
heart
■ The CVS is responsible for;
– delivering oxygen and nutrients to all cells of the body
– removing waste products by excretion.

■ Consists of the heart (a pump) and a series of interconnecting

of vessels that continually move blood throughout the body.
Structure and function of the
heart
 Chambers and circulation

CHAMBERS CIRCULATION

■ The human heart consists of ■ There are 2 distinct however

four chambers linked circuits in the human
circulation.
– Atria (atrium singular) –
upper chambers – Pulmonary Circuit

– Ventricle – lower chambers – Systemic Circuit

Electrophysiology of normal
cardiac rhythm
 Cardiovascular diseases

■ Hypertension

■ Angina

■ Heart failure

■ Arrhythmia
antihypertensive
 Control of blood pressure
■ The pressure in the CVS is determined by 3 elements.
– Heart Rate

– Stroke volume: the amount of blood that is pumped out of

the ventricle with each heartbeat (primarily determined by
the volume of blood in the system).

– Total peripheral resistance: the resistance of the muscular

arteries to the blood being pumped through.
 hypertension

■ The most common Cardiovascular Disease.

■ Often there are no symptoms associated with Hypertension

(Silent Killer).

WHAT IS HYPERTENSION?
 hypertension

■ Sustained increase in systemic blood pressure

(systolic or diastolic) greater than 140/90
mmHg respectively.
 antihypertensives
1. Diuretics

2. Angiotensin converting enzyme inhibitors

3. Angiotensin II receptor anatgonists

4. Sympatholytics

5. Calcium channel blockers

6. Vasodilators
 Diuretics
■ Mild antihypertensive effects

■ BP falls by 15-20 mm of Hg over 2-4 weeks.

■ Classes:
– Loop diuretics

– Thiazide diuretics

– Potassium Sparing Diuretics

Diuretics
 Diuretics
MECHANISM OF ACTION:
■ Diuretics enhance the excretion of sodium and water
resulting in:
1. ↓ Plasma volume → ↓ cardiac output → ↓ BP

2. ↓ Body sodium → relaxation of vascular

smooth muscles (due to Na+ depletion in the
vascular smooth muscle) - ↓ PVR → ↓ BP
 Diuretics
THIAZIDE LOOP DIURETICS POTASSIUM
DIURETICS ■ Furosemide, SPARING DIURETICS
■ Hydrochlorothiazide, Bumetanide, ■ Spironolactone,
Bendroflumethiazide, Piretanide, Amiloride,
Chlorothiazide Torasemide Triamterene

■ Most commonly used ■ Most powerful of all ■ Most commonly used

antihypertensive diuretics antihypertensive
diuretics ■ Acts on distal thick diuretics
■ Acts on distal ascending loop of ■ Acts on distal
convoluted tubule henle convoluted tubule
 Diuretics
THIAZIDE LOOP DIURETICS POTASSIUM SPARING
DIURETICS
DIURETICS ■ Reversible competitive
■ Block the Na+K+Cl- antagonist of aldosterone
cotransporter in the at aldosterone
■ Inhibition of Na+/Cl- apical membrane of receptor→ blocks Na+
cotransporter. the thick ascending reabsorption, H+ & K+
limb of the loop of excretion.
■ Decrease
reabsorption of Na henle. ■ both inhibit the Na+
and Cl →↓ BP channel in the collecting
■ ↑↑ excretion of H2O duct to reduce its
Na+ K+ Ca2+ Mg2+ reabsorption.
 Diuretics
THIAZIDE LOOP DIURETICS POTASSIUM SPARING
DIURETICS DIURETICS
■ IV & Orally
■ Orally ■ Adverse Effects:
– Hypokalemia ■ Orally
■ Adverse Effects: – Metabolic alkalosis
– Hypokalemia, – Nausea
– Metabolic ■ Adverse Effect
– Urinary frequency
alkalosis, – Hypotension – Hyperkalemia
– Increased plasma – Hypocalcemia – Gynecomastia
uric acid – Hypomagnesemia – Metabolic acidosis
– Decrease calcium – Hypovolemia
excretion
 Angiotensin converting enzyme
inhibitors
■ Captopril, Enalopril, Lisinopril, Trandolapril, Ramipril
MOA:
1. Molecular: inhibition of ACE activity

2. Cellular: a. reduced angiotensin II formation

b. reduced metabolism of kinins eg.
Bradykinin=↓BP

■ USES: Hypertension, Myocardial Infarction, Coronary artery

disease
 Angiotensin converting enzyme
inhibitors
PHARMACOKINETICS ADVERSE EFFECTS

– Generally well absorbed ■ Hypotension

– Except for captopril & ■ Persistent dry cough

lisinopril, all others are
prodrugs. ■ Hyperkalemia

– Excreted through the

kidneys
 Angiotensin II receptor
antagonists
Losartan (active metabolite), Candesartan, Irbesartan

▪MOA: Selective antagonism of the angiotensin II receptor (AT1)→

Inhibition of angiotensin II activity =↓BP

▪Losartan does not affect bradykinin metabolism, no dry cough

▪USES: Hypertension & Cardiac Failure

 Angiotensin II receptor
antagonists
PHARMACOKINETICS ADVERSE EFFECTS

■ All given orally ■ Hypotension

■ Extensively protein bound ■ Hyperkalemia

■ Excreted by the kidneys

 sympatholytics
1. Centrally acting drugs
✔ Clonidine, Methyldopa, Guanabenz, Guanfacine

2. Ganglion blockers
✔ Trimethaphan

3. Adrenergic neuron blockers

✔ Guanithidine , reserpine

4. Adrenergic receptor blockers

✔ α-blockers, β-blockers
 sympatholytics
■ DRUGS ACTING GANGLION BLOCKERS
CENTRALLY
■ Trimethaphan – only one in
■ Clonidine – α2 agonist use.
■ Blocks both sympathetic and
■ Blocks the release of parasympathetic ganglia.
Noradrenaline
■ Produce controlled
■ USES: Mild to moderate hypertension during certain
hypertension, Opioid surgeries.
withdrawal
 sympatholytics
ADRENERGIC NEURON
BLOCKERS
■ Guanethidine: depletes the
stores of noradrenaline in the
adrenergic neurons and also
blocks its release
■ Reserpine: Binds to the vesicles
that stores monoamines and
destroy these vesicles
ADRENERGIC RECEPTOR
BLOCKERS
■ β-blockers are mild
antihypertensives
■ α-blockers: Peripheral vascular
resistance is decreased leading to a
fall in BP with only mild
tachycardia
 Calcium channel blockers

■ Verapamil, nifedipine, nicardipine, nimodipine, amlodipine,

felodipine

■ MOA: CCBs inhibit the movement of calcium ions across the

membranes of myocardial and arterial muscle cells, altering the
action potential and blocking muscle cells, altering the action
potential and blocking muscle cell contraction.
 Calcium channel blockers

ADVERSE EFFECTS: ORAL MANIFESTATION:

■ Excessive hypotension, ■ Xerostomia

dizziness, lightheadedness,
■ Dysgeusia
■ Nausea, vomiting,
constipation, bradycardia, ■ Gingival enlargement
edema
 vasodilators
■ Reserved for use in severe hypertension or hypertensive emergencies.

■ Hydralazine, Minoxidil, Nitroprusside

■ MOA: Act directly on vascular smooth muscle to cause muscle

relaxation, leading to vasodilation and fall in blood pressure.

■ ADVERSE EFFECTS: headache, dizziness, flushing, hypotension, salt

and water retention.
 Hypertension and dentistry
■ During a procedure, BP is to be maintained below 150/100 mm of Hg.

■ To control post operative bleeding ethamsylate is given.

■ When local anaesthetic is required, for minor procedures plain

lignocaine is used and adrenaline avoided.

■ Procedures are done in multiple sittings

Antianginal drugs
 What is angina pectoris

■ Chest Pain resulting from insufficient OXYGEN supply to

the heart.
■ * Pain can radiate to the lower jaw – Can be confused as
Toothache.

■ Three Types
1. Stable Angina
2. Unstable Angina
3. Variant Angina
 angina

■ Drugs are used to improve the balance between oxygen

supply and demand.
– By increasing oxygen supply to the
myocardium (coronary dilation) or

– By reducing preload/afterload/heart rate or

all of these.
 Antianginal drugs

■ NITROGLYCERIN LIKE COMPOUND (nitrates)

■ CALCIUM CHANNEL BLOCKERS

■ BETA BLOCKERS

■ POTASSIUM CHANNEL OPENERS

 Nitroglycerine like compounds
■ Nitroglycerine, Isosorbide dinitrate, Isosorbide mononitrate, penta
erythritol tetranitrate
■ NITROGLYCERIN (NTG) is the most often used nitrate used for
angina induced by stress or exercise.

■ MOA: Nitrates are vasodilators. It releases free NO which is a very

potent vasodilator. NO activates guanylyl cyclase and increases cyclic
guanosine monophosphate (cGMP), producing relaxation in vascular
smooth muscle throughout the body.
 Nitroglycerine like compounds
■ NTG decreases the oxygen demand ADVERSE EFFECTS:
with relief or reduction of angina.
■ Flushing
■ **Tolerance to these effects will occur, ■ Lightheadedness
unless there is a nitrogen free period is
observed daily. ■ Hypotension
■ Severe headache
■ Phosphodiesterase 5 (PDE5)
inhibitors
A class of drug used to treat erectile ■ Nitrates are available for oral,
dysfunction. With nitrates they can cause sublingual, parenteral use and
dangerously low blood pressure.
as ointment and transdermal
patches.
 Calcium channel Blockers
■ Useful as prophylaxis of exertional angina.

■ Relax the arterioles leading to a decrease in the peripheral vascular

resistance and a reduction in the afterload.

■ Useful in Variant angina since they dilate the coronaries and relieve
vasospasm.

■ Tend to be preferred over nitrates in variant angina

 Beta blockers

■ Reduces the frequency and severity of attacks of exertional

angina and are useful in the prevention of angina.

■ Beta blockers prevents angina by blocking all the sympathetic

activity on the cardiovascular system.

■ They are not useful in variant angina.

 Potassium channel blockers
■ Nicorandil and Pinacidil
■ Opening of the ATP-sensitive K+ channels results in efflux of K+
leading to hyperpolarization and therefore relaxation of vascular
smooth muscles.

■ They can also act through NO, similar to nitrates.

■ Used in angina when other drugs do not give significant benefit.

■ ADVERSE EFFECTS: headache, flushing, dizziness, hypotension.

 Dental implications
■ Utmost importance is given to keep patients stress free.

■ Steps taken to prevent patients from being stressed:

■ Adequate antianxiety agents, analgesics and
anaesthetics are used to avoid pain.
■ Patient is taken for the procedure as the first case in
the morning because waiting in anxiety could be
harmful to such patients.
■ Adrenaline is avoided in such patients
 Dental implication

■ For an acute episode of angina, Nitroglycerine 0.5mg

is given sublingually immediately.

■ If myocardial infarction is suspected, injection

pethidine 50mg should be given immediately even
before shifting the patient to the physician.
 Heart failure
■ The Heart acts like a pump, ensuring that adequate circulation of the
blood to meet the oxygen need of all the body tissue

■ When there is an increased need for oxygen, such as during exercise,

the heart makes adjustments to increase its output to meet the
increased demand in oxygen.

■ If the heart is unable to keep up with the body’s need, it becomes a

“failing” heart.
 Heart failure

■ This occurs when the heart muscle has suffered an injury and
cannot keep up its work.

■ Heart attack, Arrhythmias and valvular abnormalities from

rheumatic heart disease can contribute to the heart failing.
 Heart failure
■ With heart failure, there is:
■ Decreased oxygen supply to the body
■ The ventricles are not completely emptied
■ Pulmonary Oedema
■ Dyspnoea
■ Liver enlargement and peripheral oedema
 Heart failure

■ HOW DOES THE BODY CORRECT THIS?

■ There is a stimulation of the sympathetic system,
renin angiotensin system and the release of the
atrial natriuretic peptides

■ Due to the overload the ventricles, atria and

vascular endothelium releases natriuretic
peptides and release them in volume overload.
 Heart failure
■ DRUGS USED:
– Diuretics: E.g. Frusemide. They increase salt and water
excretion and reduce blood volume.

– Vasodilators: Decreases vascular resistance thus

decreasing the workload on the heart. Also, reduce venous
return to the heart thus reducing the stretching of the
ventricular walls and myocardial oxygen requirements.

– Cardiac Glycosides
 Cardiac glycosides (CGS)

Digoxin, Digitoxin, Quabain

■ The major effect of these compounds on a failing heart is to
increase the force and strength of contraction of the
myocardium.

■ They allow the heart to do more without increasing the use of

oxygen (increases cardiac output).
 Cardiac glycosides (CGs)

■ MOA:
Potent inhibitors of cellular Na+/K+ ATPase. Usually this
system moves sodium ions out of the cell and potassium into
the cell. CGs results in increased intracellular Na+. The
Na+/Ca++ exchanger compensates by removing Na+ from the
cells and increasing the entry of Ca++ into the cells. An
increase in Ca++ results in an increase in the contractility of
the heart.
 Cardiac glycosides
ADVERSE EFFECTS DENTAL DRUG
INTERACTION
■ Anorexia, nausea, vomiting ■ Sympathomimetics
(epinephrine) added to local
■ Headache, drowsiness, visual anaesthetics should be used
disturbances, with caution.
■ Sympathomimetics can
■ Arrhythmias– if a sufficient over dose increase the chance of
is given. arrhythmias occurring with
CGs.
■ Increased salivation, increase in
gagging reflex
ARRHYTHMIAS (DYSRHYTHMIAS)
■ A cardiac arrhythmia is any abnormal heart rate or rhythm.
■ Factors affecting heart rhythms:
– Coronary artery disease.
– Electrolyte imbalances in your blood (such as sodium or
potassium).
– Changes in your heart muscle.
– Injury from a heart attack.
– Irregular heart rhythms can also occur in "normal, healthy"
hearts.
Vaughan-Williams classification
of antiarrhythmic drugs
 SODIUM CHANNEL BLOCKERS
■ MOA: Binds to and block the fast sodium channels that are
responsible for the rapid depolarization (phase 0) of fast-response
cardiac action potentials.

■ ADVERSE EFFECTS: Diarrhea, Nausea, Vomiting, Dry mouth,

Urinary retention, Constipation, Precipitation of glaucoma

■ DENTAL IMPLICATION:
– Xerostomia