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
four chambers
■ There are 2 distinct however
linked circuits in the human
circulation.
– Atria (atrium singular) –
upper chambers
– Ventricle – lower chambers
– Pulmonary Circuit
– 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
DIURETICS
■ Furosemide,
■ Hydrochlorothiazide,
Bumetanide,
Bendroflumethiazide,
Piretanide,
Chlorothiazide
Torasemide
POTASSIUM
SPARING DIURETICS
■ Spironolactone,
Amiloride,
Triamterene
■ Most commonly used
antihypertensive
diuretics
■ Acts on distal
convoluted tubule
■ Most commonly used
antihypertensive
diuretics
■ Acts on distal
convoluted tubule
■ Most powerful of all
diuretics
■ Acts on distal thick
ascending loop of
henle
Diuretics
THIAZIDE
DIURETICS
LOOP DIURETICS
■ Block the Na+K+Clcotransporter in the
■ Inhibition of Na+/Clapical membrane of
cotransporter.
the thick ascending
■ Decrease
limb
of
the
loop
of
reabsorption of Na
henle.
and Cl →↓ BP
■ ↑↑ excretion of H2O
Na+ K+ Ca2+ Mg2+
POTASSIUM SPARING
DIURETICS
■ Reversible competitive
antagonist of aldosterone
at aldosterone
receptor→ blocks Na+
reabsorption, H+ & K+
excretion.
■ both inhibit the Na+
channel in the collecting
duct to reduce its
reabsorption.
Diuretics
THIAZIDE
DIURETICS
■ Orally
■ Adverse Effects:
– Hypokalemia,
– Metabolic
alkalosis,
– Increased plasma
uric acid
– Decrease calcium
excretion
LOOP DIURETICS
POTASSIUM SPARING
DIURETICS
■ IV & Orally
■ Adverse Effects:
■ Orally
– Hypokalemia
– Metabolic alkalosis ■ Adverse Effect
– Nausea
– Hyperkalemia
– Urinary frequency
– Gynecomastia
– Hypotension
– Metabolic acidosis
– Hypocalcemia
– Hypomagnesemia
– Hypovolemia
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 &
lisinopril, all others are
prodrugs.
■ Persistent dry cough
– Excreted through the
kidneys
■ Hyperkalemia
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
CENTRALLY
GANGLION BLOCKERS
■ Clonidine – α2 agonist
■ Trimethaphan – only one in
use.
■ Blocks the release of
Noradrenaline
■ Blocks both sympathetic and
parasympathetic ganglia.
■ USES: Mild to moderate
hypertension, Opioid
withdrawal
■ Produce controlled
hypertension during certain
surgeries.
sympatholytics
ADRENERGIC NEURON
BLOCKERS
ADRENERGIC RECEPTOR
BLOCKERS
■ Guanethidine: depletes the
stores of noradrenaline in the
adrenergic neurons and also
blocks its release
■ β-blockers are mild
antihypertensives
■ Reserpine: Binds to the vesicles
that stores monoamines and
destroy these vesicles
■ 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,
dizziness, lightheadedness,
■ Xerostomia
■ Dysgeusia
■ Nausea, vomiting,
constipation, bradycardia,
edema
■ Gingival enlargement
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.
■
1.
2.
3.
Three Types
Stable Angina
Unstable Angina
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
with relief or reduction of angina.
ADVERSE EFFECTS:
■ Flushing
■ **Tolerance to these effects will occur, ■ Lightheadedness
unless there is a nitrogen free period is ■ Hypotension
observed daily.
■ Severe headache
■ Phosphodiesterase 5 (PDE5)
inhibitors
■ Nitrates are available for oral,
A class of drug used to treat erectile
sublingual, parenteral use and
dysfunction. With nitrates they can cause
as ointment and transdermal
dangerously low blood pressure.
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
anaesthetics should be used
with caution.
■ Headache, drowsiness, visual
disturbances,
■ Arrhythmias– if a sufficient over dose
is given.
■ Increased salivation, increase in
gagging reflex
■ Sympathomimetics can
increase the chance of
arrhythmias occurring with
CGs.
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
L.SMITH
2019
Course Objectives
▪ Understand the pathophysiology of Peptic Ulcer
Disease, Emesis, Constipation, and Diarrhea
▪ Knowledge of the pharmacology of the appropriate
drugs to be used in the treatment of each condition
Peptic Ulcer Disease(PUD)
▪ Is a breakdown in the mucosa of the stomach(gastric
ulcer) or duodenum (duodenal ulcer)
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 by
Parietal Cells
Pharmacological classes and agents
used in the management of acid
secretion
Mechanisms
▪ (A) Neutralize the acid(HCL)
▪ (B) Inhibition of the proton pump(H+/K+ ATPase):
I. Inhibition of histamine activity
II. direct inhibition
III. inhibition of cholinergic activity
▪ (C) Increasing mucus secretion(mucosal protective
agents)
A. Antacids-Agents used to
neutralize acid
➢
Antacids are used on as needed basis for the
symptomatic relief of dyspepsia (indigestion)
1.
Sodium salts(sodium bicarbonate)
NaHCO3(aq) + HCl(aq) → NaCl(aq) + CO2(g) + H2O(l)
Na+ absorbed well from the GIT
Can produce hypernatremia (long term)
Patients with cardiovascular complications should avoid
Na+ antacids
CO2 causes belching/flatulence
▪
▪
▪
▪
▪
A. Antacids-Agents used to
neutralize acid
2.
Calcium salts(Calcium Carbonate)
▪
▪
▪
▪
▪
▪
▪
▪
▪
▪
CaCO3 + 2HCl ---> CaCl2 + CO2 + H2O
Ca2+ salts = direct increase in gastrin secretion
Ca2+ is therefore not recommended for PUD
Less absorption of Ca2+ from the GIT than Na+
Ca2+ salts may cause hypercalcemia and hypercalsuria
CO2= belching/flatulence
Contraindicated in cardiovascular complications
May cause constipation
However is indicated in oesteoporosis
POOR COICE
A. Antacids-Agents used to
neutralize acid
3.
Magnesium and Aluminium salts
▪
ALUMINIUM HYDROXIDE
3HCl(aq) + Al(OH)3(s) <-------> AlCl3(aq) + 3H2O
▪
MAGNESIUM HYDROXIDE
Mg(OH)2 + 2HCl → MgCl2 + 2H2O
A. Antacids-Agents used to
neutralize acid
▪ Al3+ and Mg2+ ion salts
✓ more commonly used
✓ Al3+ and Mg2+ are not well absorbed from the GIT
✓ Generally given in combination(magaldrate)
✓ Mg(OH)2 acts rapidly, Al(OH)3 acts slowly:
combination gives rapid and sustained relief
✓ Al3+ relaxes GIT, Mg2+ contract GIT; together = no
effect on motility
✓ Combination produces good antacid activity
Antacids
Examples of ANTACIDS-(trade name)
Content
mg/tablet or
mg/5ml
Al(OH)3
Mg(OH)2
CaCO3
Simethicone
Maalox
600
300
-
-
Mylanta
400
400
-
40
Tums
-
-
750
-
Dica
200
200
25
B. Inhibition of Proton Pump
▪ H2 receptor antagonist
▪ Proton pump inhibitors
▪ Prostaglandin analogs
▪ Anticholinergics
H2 Receptor Antagonists
▪ Cimetidine(imidazole ring like histamine)
▪ Ranitidine(furan ring)
▪ Famotidine, Nizatidine(thiazole ring)
MOA
✓ reversibly and competitively inhibit the binding of
histamine to H2 receptors. Suppressing the gastric acid
secretion(both volume and H+ ion conc.)
✓ also indirectly decrease gastrin and acetylcholine-
induced gastric acid secretion
H2 Receptor Antagonists
Cimetidine(Tagamet)
ROA=O, Onset= 1h, t ½ = 2hrs, DOA=4- R(main)/
5hrs. IV, IM
H by
• Bioavailability(50-70%)
CYP450
• with long term use and high doses
will increase prolactin
release(gynaecomastia)
• binds to androgen receptors
(impotence)
• Headache, dizziness, nausea
• inhibits the metabolism of other
drugs using CYP450
system(lidocaine,phenytoin,
theophylline, propranolol and
warfarin)
• crosses the placenta and is secreted
in breast milk
H2 Receptor Antagonists
Ranitidine(Zantac)
ROA= O, Onset= 1h, t ½ = 1-2h…. IM,
IV
• low bioavailability(50%)
• S/E: constipation, diarrhea,
headache, fatigue, insomnia
R(main)/H
(CYP450)
H2 Receptor Antagonists
Famotidine(Axid)
ROA= O, Onset= 1h, DOA= 10-12h, t ½ =
1-2h
R/H
• its high first pass metabolism results
in low bioavailability(50%)
Nizatidine(Pepcid)
ROA= O, Onset= 1h, DOA= 10h, t ½ = 1h
• high bioavailability(90%)
• may produce gynaecomastia
R
H2 Receptor Antagonists
▪ Incidence of side effects of Cimetidine is much lower
with Ranitidine, Famotidine and Nizatidine
▪ Effects on androgens not seen with Ranitidine and
Famotidine
▪ Ranitidine causes minimal inhibition of CYP450
▪ Famotidine and Nizatidine do not inhibit CYP450
Proton Pump Inhibitors
▪ Omeprazole
▪ Lansoprazole
▪ Pantoprazole
Esomeprazole
Rabeprazole
MOA
✓ are prodrugs, which are converted to their active
form(sulfenamide) at acidic pH
✓ Sulfenamide binds covalently with SH groups on H+/K+
ATPase
✓ blocks the parietal cells H+/K+ ATPase (proton pump)
✓ are superior to H2 antagonists when suppressing acid
secretion and promoting peptic ulcer healing
Proton Pump Inhibitors
Omeprazole(Priloseo)
ROA= O, Bioav. 70%, t ½ = 30-90mins,
DOA= long(days), 95% PPB
• S/E: nausea, headache, abdominal
pain, diarrhea, flatulence
• reduces the metabolism of
phenytoin, warfarin, diazepam
H CYP450
Lansoprazole
(Prevacid)
ROA= O, Bioav. 80%, t ½ = 90 mins
H CYP450
Esomeprazole(Nexium) ROA= O, Bioav. 90%, t ½ = 30-90mins,
DOA= long(days), 97% PPB
• S/E: nausea, headache, diarrhea,
abdominal pain, flatulence
• reduces metabolism of phenytoin,
warfarin, diazepam
• Inhibits acid secretion more
effectively than Omepraz and
Lansopraz
H CYP450
Anticholinergic Agents
▪ Anticholinergic agents such as dicyclomine and
atropine antagonize muscarinic Ach receptors on
parietal cells and thereby decrease gastric acid
secretion. However, anticholinergic agents are seldom
used in the treatment of peptic ulcer disease because
they are not as effective as H₂ receptor antagonist or
proton pump inhibitors.
▪ These agents also have many adverse effects,
including dry mouth, blurred vision, cardiac
arrhythmia and urinary retention.
C. Mucosal Protective agents
▪ agents that promote mucosal defense are used in the
symptomatic relief of peptic ulcer disease. These drugs
includes coating agents and prostaglandins.
▪ Cryoprotective : enhance secretion of mucus and
bicarbonate.
▪ Coating agents are:
✓ Sucralfate
✓ Bismuth Subsalicylate
▪ Prostaglandins: Misoprostol
Sucralfate
MOA:
• is a complex of aluminum hydroxide and sulfated
sucrose
• activated in an acidic medium
• binds to proteins (eg in mucus) giving a sticky viscous,
yellow-white gel
• this prevents pepsin-mediated protein hydrolysis and
decreases diffusion of H+ ions
• Avidly binds to epithelia cells in ulcerative areas, thus
promoting healing
Sucralfate
Sucralfate(Carafate)
ROA= O, poor absorption
• Al3+ content may cause
constipation
• Effective in healing gastric and
duodenal ulcers
• Antacids destroys activity
Hepatic
metabolism
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. Pyloriassociated peptic ulcer.
Prostaglandins
▪ can be used in the treatment of peptic ulcer disease,
specifically NSAIDS-induced ulcers.
MISOPROSTOL
• is a prostaglandin analog (PGE1)
• inhibit gastric acid secretion by binding to the
prostaglandin receptor ; acts on epithelial cells to
increase mucus and bicarbonate secretion
• Also decrease histamine effects and ultimately
decrease acid secretion.
• Its most frequent adverse effects abdominal
discomfort, diarrhea, uterine contraction
• Contraindicated in pregnancy
Antimicrobials to eradicate H.
Pylori
▪ METRONIDAZOLE
▪ CLARITHROMYCIN
▪ AMOXYCILLIN
▪ TETRACYCLINE
Triple therapy: amoxycillin, metronidazole and proton
pump inhibitor
Quadruple therapy: tetracycline, metronidazole,
proton pump inhibitor and bismuth
Pathophysiology of Emesis
Neurotransmitters involved in
Emesis
▪ H1histamine
▪ M1 acetylcholine
▪ 5-HT3 serotonin
▪ DA2 dopamine
▪ NK1 (neurokinin) substance P
▪ mu/kappa opioids
Anti-emetics
1.
Anticholinergics
Eg. Hyoscine or Scopolamine
▪ drug of choice for motion sickness
▪ MOA: compete with Ach at muscarinic receptors in
the gut and CNS. Antispasmodic action on the gut
wall
▪ Useful in combination with D2 antagonists(to
reduce extrapyramidal effects)
▪ S/E: dry mouth, blurred vision, difficulty in
micturition
Anti-emetics
2. H1 antihistamines
Eg. Dimenhydrinate, Diphenhydramine,
Promethazine
▪ Competitive antagonist of histamine receptors(H1)
▪ acts mainly at the vomiting centre rather than the
CTZ-chemoreceptor trigger zone
▪ use for N/V due to pregnancy, motion sickness and
vestibular disorders
▪ Ineffective against N/V due to drugs, toxins,
minimal activity against stomach irritants
Anti-emetics
H1 antihistamines
▪ S/E: drowsiness, insomnia, euphoria(potentiated by
alcohol)
▪ Antiemetic effects occurs within 4h and can last up to
24h
Anti-emetics
3. D 2 Dopamine receptor antagonists
Eg. Phenothiazine
derivatives(Chlorpromazine,Prochlorperazine)
Butyrophenones (Haloperidol, Droperidol)
Others: Metoclopramide, Domperidone(most
commonly used)
▪ MOA: blocks D2 dopamine receptors mainly at the
CTZ
▪ Effective after the start of emesis
Anti-emetics
D 2 Dopamine receptor antagonists
▪ S/E: Extrapyramidal activity-particularly in children
and adult on metoclopramide
▪ Used for N/V of cancer chemotherapy, radiation
sickness, viral gastroenteritis, narcotic analgesics
Anti-emetics
▪ Other anti-emetics includes:
✓ 5-HT3 receptor antagonist(Ondansertron)
MOA: blocks 5-HT3 receptors in the stomach(vagal nerve
endings), CTZ
✓ Steroids (Dexamethasone)
MOA: unknown
• Generally used in combination with 5-HT3 antagonist or
phenothiazine
• Useful for vomiting in cancer chemotherapy
Anti-emetics
▪ Other anti-emetics includes:
✓ Cannabinoid receptor antagonist(CB1)
(Dronabinol)
MOA: blocks CB1 receptors at the VC
▪ Used for N/V due to cancer chemotherapy
▪ SE: Extrapyramidal symptoms
Other Anti-emetics- Reading
▪ Ipecac
▪ Apomorphine
NEXT SESSION
▪ Laxatives- to treat constipation
▪ Anti-diarrhoeal agents-treatment of diarrhea
Gastrointesinal(GIT)
Pharmacology
L.SMITH
2019
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,
LAXATIVES(purgatives)
LAXATIVES
 Purgatives – drugs which increase movement and
speed up the passage of food through the small
intestines (intestinal transit time-ITT)
LAXATIVES
 intestinal transit time is ↑ by :
➢ ↑ vol. of non-absorbable solid residue
➢ ↑ water content
➢ altering faecal consistency
➢ ↑ motility and secretions
LAXATIVES
 4 types:
- Bulk
- Osmotic
- Stimulant
- Surfactant
LAXATIVES
1. BULK LAXATIVES:
BRAN,
PSYLLIUM,
METHYLCELLULOSE(citrucel),
CALCIUM POLYCARBOPHIL
BULK LAXATIVES
 MOA: unprocessed fibres/polysaccharides polymers
that remained in the GIT as they are not broken down
by the normal process of digestion in the upper GIT
Absorbing water and promoting bacterial growth; on
swelling they distend to the colon and increase
peristaltic motility. Softening of feces occurs
ONSET: 12-72h
BULK LAXATIVES
 Bulk laxatives require water intake
➢ oesophageal and intestinal obstruction if not taken
with enough water.
➢ Long term use=dehydration and electrolyte
disturbances
➢ S/E: allergic reactions (low incidence), flatulence
LAXATIVES
2. OSMOTIC LAXATIVES:
MAGNESIUM SULPHATE(Epsom salts)
MAGNESIUM HYDROXIDE(milk of magnesia)
LACTULOSE(miralax)
MOA:
• Poorly absorbed drugs which increases the bowel
volume of the small and large intestine by osmosis.
This results in increased motility that causes
distention which leads to purgation.
• Watery feces produced
ONSET: 2-3 days for lactulose and 6-8h for Mg(OH)
LAXATIVES
OSMOTIC LAXATIVES cont’d
Lactulose
• Semi-synthetic derivative of fructose and galactose
• Acted on by bacteria to produce fructose and galactose
which ferment to form lactic and acetic acids →
osmotic laxatives
• Onset: 2-3 days
LAXATIVES
OSMOTIC LAXATIVES cont’d
• For emptying the GIT prior surgery, radiology,
colonoscopy
• should be taken with adequate water to avoid
dehydration
• Lactulose is reserved for chronic constipation
S/E:
Minimal: flatulence, abdominal cramps
Long term use may result in dehydration and electrolyte
disturbances
LAXATIVES
3. STIMULANT LAXATIVES
 CASTOR OIL (recinoleic acid)
 BISACODYL(dulcolax)
ANTHRAQUINONE DERIVATIVES:
 CASCARA (buckhorn tree)
 SENNA (plantains)
LAXATIVES
STIMULANT LAXATIVES
MOA:
 Direct stimulation of nerves in the enteric nervous system
to result in increased water and electrolyte secretion from
mucosa, also increase peristaltic activity.
CASTOR OIL
 In small intestines- hydrolysed by pancreatic lipase to
active compound, recinoleic acid.
 Soft to semi-fluid faeces produced
 Onset: 2-6h for Castor oil and 15 mins for Bisacodyl
LAXATIVES
ANTHRAQUINONE DERIVATIVES
(Eg. Senna and Cascara)
* Removed from US market
• Acted on by bacteria to produce their active
forms(emodin)
• Soft/Semi fluid stool
LAXATIVES
SIDE EFFECTS OF ANTHRAQUINONES
• Minimal systemic S/E -due to limited absorption from
GIT (absorbed amount excreted via urine)
• Abdominal cramping.
• Atonic colon
• Long term use may result in melanosis of the colon=
increase risk of cancer
• Urine discoloration, electrolyte imbalance
LAXATIVES
4. SURFACTANT LAXATIVES- FECAL SOFTENERS
 DOCUSATE (Dioctyl sodium sulfosuccinate)
 GYLCERIN
 MINERAL OIL
MOA: emulsify stool, making it softer, making passage
easier.
ONSET: 1-3 days
S/E: Oil leakage at anal sphincter . Long-term use
interfere with absorption of fat- soluble vitamins
ANTIDIARRHEAL AGENTS
• In diarrhea:
- ↑motility of the GIT
- ↑ secretion
- ↓in the absorption of fluid
→ loss of electrolytes (Na+) and H2O
• Can be associated with various complications- from
discomfort to medical emergency (due to electrolyte
imbalance and hypovolemia)
CAUSES OF DIARRHEA
Acute Diarrhea
Chronic Diarrhea
 Bacteria
Tumors
Diabetes
Addison’s disease
Inflammatory bowel disease
Irritable bowel syndrome
 Viral
 Drug-induced
hyperthyroidism
 Nutritional
 Protozoal
ANTIDIARRHEAL AGENTS
1. Drugs to replace fluid
and electrolyte balance
ORAL REHYDRATION SALTS (eg. Pedialyte®)
Usually the only therapy needed for acute
diarrhoea (body defense mechanism)
Eg: WHO formulation
NaCl 3.5 g/L
KCl 1.5 g/L
NaCitrate 2.9 g/L
Glucose 20 g/L
ANTIDIARRHEAL AGENTS
2. Drugs to decrease motility
a. ANTIMUSCARINIC DRUGS:
ATROPINE, HYOSCINE
DICYCLOMINE
MOA: Block muscarinic receptors (m3), thus inhibiting
parasympathetic activity
ANTIDIARRHOEAL DRUGS
Dicyclomine (most pop)
❖ a specific anticholinergic(antimuscarinic) effect
❖ Direct smooth muscle relaxant effect
❖ Decrease gastric acid secretion
❖ Oral Route
ANTIDIARRHEAL AGENTS
2. Drugs to decrease motility
b. OPIATE-LIKE DRUGS:
DIPHENOXYLATE (Lomotil),
LOPERAMIDE(Imodium)
 MOA: Stimulate µ opiate receptors in the myenteric
plexus to reduce Ach release and therefore decrease
peristaltic activity. Also reduces pain
ANTIDIARRHEAL AGENTS
Opiates
• 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
dizziness
drowsiness
paralytic ileum
w
ANTIDIARRHEAL AGENTS
3. Drug that reduce GIT secretions
BISMUTH SUBSILICYLATE (Pepto-bismol®) ,
MOA: converted by HCl to salicylic acid and bismuth
oxynitrate. Bismuth absorbs bacterial toxins.
• For travellers’ (infection) diarrhea.
• Salicylate content = anti-inflammatory action
ANTIDIARRHEAL AGENTS
4. Drugs to increase stool bulk
KAOLIN, PECTIN, CHARCOAL
 Kaolin is a natural hydrated aluminium silicate.
 Pectin consists of purified carbohydrate extracted
from citrus fruit or apple .
 MOA: produce bulking of the stool.
ANTIDIARRHEAL AGENTS
5. Anti-infective drugs
 Usually if diarrhoea is viral- no antiviral required due
to self-limiting nature
 Bacterial infections, eg. Salmonella –Tetracycline
Shegella – Ampicillin
Campylobacter- Erythromycin
Q&A
1.
In the gastric acid secretion cascade, which cell is
responsible for histamine secretion?
a.
Chief cells
Parietal cells
G cells
ECL cells
b.
c.
d.
Q&A
2. Which H₂ receptor antagonist when given for PUD
a.
b.
c.
d.
may result in impotence?
ranitidine
cimetidine
famotidine
nizatidine
Q&A
3. Which agent used in the symptomatic relief of peptic
ulcer disease is contraindicated in pregnancy
sucralfate
b. Bismuth Subsalicylate
c. misoprostol
d. dicyclomine
a.
Q&A
4. Which salt containing antacid is a poor choice in the
management of acid secretion?
a.
b.
c.
d.
Ca2+
Mg2+
Na+
Al3+
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
1) Erythema (redness of the skin)
2) Congestion
3) Edema
4) Inflammation
5) Pruritus (itching)
6) Initiate the cough reflex
7) Bronchoconstriction
8) Contraction of most GIT smooth
muscle
Histamine Substitutes
• Betazole is a H2 agonist and
can be used in
gastric function tests.
• Betahistine is a H1 agonist
used to control vertigo in
Meniere’s disease
effects of histamine
Adverse effects
Clinical use
■ Flushing
■ Hypotension
■ Tachycardia
■ Headache
■ Bronchoconstriction
■ GI upset
■ Histamine has no therapeutic
applications.
■ Drugs that block histamine’s
effects are very important in
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
inflammatory
conditions
■ Well absorbed after
oral administration.
• Sedation
■ Metabolized by CYP
450 system.
• Dizziness
2. Motion Sickness
■ Excreted in feces
• Dry mouth
■ Most effective when
used prophylactically
rather than as needed
• Constipation
• 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 damaged e.g. in
Atherosclerosis
Endothelium is intact →
vasodilation
■ 5-HT is released from platelets
→ 5-HT2A receptors →
impairs blood flow
– Platelet aggregation
– Direct vasoconstrictor
action on arteries and
veins
■ 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
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-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
■ 5-HT3 – ondansetron,
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
– TXA2: a potent inducer of
platelet aggregation
– PGI2 and PGE2: Inhibit platelet
aggregation
– PGEs: induce erythropoiesis by
stimulating the renal release of
erythropoietin
– PGI2 and PGD: inhibit
histamine release
■ INDUCTION OF LABOUR
AT TERM
– Induction of PGF2α
(carboprost tromethamine)
[Hemabate] or
– PGE2 (dinoprostone)
[Prostin E]
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
ULCER
– Misoprostol [Cytotec]
■ A methylated derivative of
PGE1
■ Approved for use in patients
taking high doses of nonsteroidal anti-inflammatory
drugs (NSAIDs) to reduce
gastric ulceration.
■ ERECTILE DYSFUNCTION
– Alprostadil (PGE1) can be
injected directly into the
corpus cavernosum or
administered as a
transurethral suppository to
cause vasodilation and
enhance tumescence.
Transurethral
suppository
Injected directly into
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
TRACT CONDITIONS
LOWER RESPIRATORY
TRACT CONDITIONS
■ The common cold
■
■
■
■
■
■ Seasonal Rhinitis
■ Sinusitis
■ Pharyngitis and Laryngitis
Atelectasis
Pneumonia
Bronchitis
Bronchiectasis
Obstructive Pulmonary Disease
– Asthma
– COPD
– 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
minutes, lasting for 6 hours.
■ Effects last for 12 hours
■ Adverse Effects: Muscle
tremors, Palpitation &
nervousness
■ Used for long-term maintenance
and for prevention of nocturnal
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 A3receptors, suggesting that this could be the basis for its
bronchodilator effects.
methylxanthines
PHARMACOKINETICS
ADVERSE EFFECTS
■ Rapidly absorbed from the GIT
when given orally, reaching peak
levels within 2 hours.
■ Also given IV, reaching peak
effects within minutes.
■ 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
■ Widely distributed and
metabolized in the liver and
excreted in urine.
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
■ May be given systemically in acute
episodes. Oral prednisolone is
commonly used (dose 30-60
mg/day).The onset of response
requires about 12 hours.
■ They prevent episodes of acute
asthma, reduce bronchial
hyperreactivity and effectively
control symptoms.
ADVERSE EFFECTS
■ Hoarseness of voice
■ Sore throat and
oropharyngeal candidiasis.
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