Outline

• Different types of autacoids

• Histamine agonist and antagonist
• Serotonin agonist and antagonist
• Clinical use of eicosanoids

1
 Autacoids and their antagonists
Autacoids
 (Greek “self-remedy”) is a collective term for various
endogenous peptides, prostaglandins, leukotrienes and
cytokines. These are sometimes also called local hormones.

Classification

o Biogenic amines: Histamine, 5-hydroxytryptamine

o Biogenic Peptides: Angiotensin and kinins

o Small Proteins: cytokines

o Membrane derived lipids: LTs, PGs, TxA2 & PAF

o Endothelium-derived agents: NO (gas)

2
 A. Histamine
 Hetrocyclic molecule composed of imidazole ring attached
with alkyl amino group.
 It is located in many tissues.
Histos=tissue, amine

4-(B-aminoethyl)imidazole

3
 Con’t
 It is potent tissue amine (Histamine).
 Formed by decarboxylation of histidine & major portion
is stored in mast cells and basophils.
MOA:
– Stimulation of H1 receptors results in smooth muscle
contraction, increased vascular permeability, & mucus
production.
These effects are blocked by H1 antagonists
– Action of H2 receptors increases gastric acid
production, & this effect is blocked by H2 blockers
such as cimetidine.

4
 Biosynthesis
Synthesized chiefly in
• Mast cells : stomach, liver, L/S intestine, heart and lung
• Basophilic granulocytes : blood
• Other sites include: CNS Neurons and Epidermis (skin)

Role: Immediate allergic responses (antigen-IgE interaction on mast

cell surface)
– Hypersensitivity, allergic responses (Bronchial SMs & blood
vessels).
• Regulator of gastric acid secretion
• Modulator of neuro-transmitter release (CNS & Peripheral)

5
 Histamine Receptors
• 4 types identified (H1-H4)
 H1 & H2 well studied and clinically targeted
 Belong to the GPCRs super family
 Classified
• Post receptor signaling mechanism
• Tissue distribution
• Sensitivity to Ligand (agonist & antagonists)

6
 H1 receptors
• Found in periphery smooth muscle (bronchi, L/S intestine,
B.V), skin and CNS
• Mediates the increase in vascular permeability induced
by Histamine
• Mediates Inflammation and allergic response
 V.D  BP Shock
• Increased blood flow, redness, itchy eyes, hives
 Smooth Muscle Contraction
 Implicated in neurotransmission, arousal and sexual
behavior

7
 H2 Receptor
 Receptor is smaller

 Coupled to Gs and activates AC-cAMP-protein kinase A

(PKA) Path way.

  cAMP production

 Found in the stomach and heart

 Mediates the release of gastric acid

 Stomach ulcers

8
 H3 and H4 Receptors
H3 Receptor…
GPCR (coupled to Gi/o to inhibit AC)
• May play role in CNS (auto receptors)
 Possible regulation of synthesis and release of Hist
• Signaling pathway not well known

H4 Receptor…
• GPCR (coupled to Gi/o to inhibit AC)
• Found in intestines, spleen, T-cells and neutrophils
• Suggests role in Immunity.

9
 Physiological Effects
 CVS
 Blood vessels
Dilation of all vessels (H1- and H2-mediated, H1 mainly
through NO production while H2 is through  cAMP) BP
& HR
Inhibits release of NE (H3 on sympathetic neurons)
es permeability of capillaries & post-capillary vessels (H1)
 histamine-induce oedema
 Heart
+Ve inotropic and chronotropic (H2- receptors)

10
 Con’t
 Extravascular Smooth Muscle
 Bronchoconstriction (H1-mediated)- in asthmatics…
 Uterine smooth muscle contraction:
 Insignificant effect (but abortion may occur during anaphylactic
reactions)
Anaphylactic reactions: a sudden severe and potentially fatal allergic
reaction in somebody sensitive to a substance, marked by a drop
in blood pressure, difficulty in breathing, itching, and swelling.

 Stimulate GI smooth muscle contraction (H1-mediated)

11
 Con’t
 Secretory Tissue
 Stimulates secretion of gastric acid and pepsin (H2-Rs
on parietal cells of the gastric mucosa)
 Stimulates secretion by the salivary glands and glands
in the small & large intestines.
 High concentrations of histamine promote the release
of catecholamines from the adrenal gland.

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 Con’t

Nervous System
 H1- & H2-Rs participate in regulation of blood pressure,
body temperature, fluid homeostasis, and pain sensation

 H1-Rs on sensory neurons in the epidermis and dermis

mediate itch and pain, respectively.

 Presynaptic H3-R serve as feedback inhibitors of the

release of histamine, NE, & other neurotransmitters

13
 Con’t

Anaphylaxis
 Rapid release of mast cell contents, producing a
decrease in blood pressure, impaired respiratory
function, abdominal cramps, and urticaria.

 Extreme and severe anaphylaxis is life threatening

and requires prompt medical intervention.

14
 The triple response
 Intradermal injection causes triple effect
 Reddening at the site of injection (dilation of small
vessels)
 Edematous wheal at the injection site
 Red irregular flare surrounding the wheal. The
sensation of itch may also accompany the appearance
of these flares

15
Clinical pharmacology of histamine
• Clincial use
– Bronchial hyper-reactivity test (aerosol)
– Positive control injection during allergy skin testing
– No other clinical application
• Toxicity: flushing, hypotension, tachycardia,
bronchoconstiriction
• C/I: Asthma, active ulcer disease, GI bleeding
E.g : Histaprodifen
Amthamine

16
 Histamine Antagonists
(Antihistamines)
 Effects of histamine can be diminished in four ways:
 Inhibition of synthesis
 Inhibition of release from storage granules
 Cromolyn , nedocromil, 2-AR agonists

 Blockade of H-receptors
 Physiological antagonism of histamine’s effects
 Epinephrine

17
 H1-Receptor Antagonists

Divided into: 1st and 2nd generation agents

Differ in their degree of distribution in to CNS
and hence production of sedation (Second
generation agents are less sedating)
The first-generation agents are also more
likely to block autonomic receptors.

18
 Drug classification
• 1st generation
– Ethanolamines – Alkylamines
• Carbinoxamine • Chlorpheniramine

• Dimenhydrinate • Brompheniramine

• Diphenehydramine – Phenothiazines
– Piperazines • Promethazine

• Hydroxyzine, Cyclizine – Miscellaneous

• Meclizine • Cyproheptadine

• 2nd generaitons
– Piperidine
• Fexofenadine
– Miscellaneous
• Loratadine
• Cetrizine

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 MOA

Competitive inhibitors of H1-Rs

Blocks histamine mediated vasodilation,
microvascular permeability, & sensory nerve
terminal stimulation.
H1-antagonists generally produce sedation
through an effect on the CNS

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 Con’t
 Non H1-mediated effects
 Antimuscarinic activity of several first-generation
 The phenothiazines block AR, whereas
cyproheptadine is an antagonist at serotonin
receptors.
 Diphenhydramine, pyrilamine, and promethazine are
effective local anaesthetics

21
 Pharmacokinetics
 Rapidly absorbed following oral administration

 First-generation drugs enter the CNS readily, unlike 2nd

generations.

 Peak plasma concentration in 1-2 h, wide distribution

 Some extensively metabolised by Liver, 2nd generation agents

are metabolized by CYP3A4 (drug interaction)

 Many H1 antagonists have active metabolites.

 Active metabolites of hydroxyzine, terfenadine, and loratadine are available as
drugs (cetirizine, fexofenadine, and desloratadine, respectively
22
 Clinical Uses
 Allergic reactions
 Urticaria, allergic rhinitis (hay fever)= effective if given before
exposure. (2nd generations) Atopic dermatitis
 Not effective in bronchial asthma (involves several mediators besides
H1)
 1st & 2nd generation drug have same efficacy but vary in their tendency
to cause sedation.
 Motion Sickness and Vestibular Disturbances
 Diphenhydramine, promethazine, Dimenhydrinate, the piperazines
(cyclizine and meclizine) = greater efficacy. Scopolamine (H1 blocker is
the most effective)
 Nausea and Vomiting of Pregnancy
 Not Piperazine derivatives (teratogenic in rodents)
 Doxylamine promoted for this application

23
24
Clinical Uses of H1-Antihistamines
• Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (hives)
• Angioedema (swelling of the skin)
• Pruritus (atopic dermatitis, insect bites)
• Anaphylactic reactions (severe allergies)
• Nausea and vomiting (first generation H1-
antihistamines)
25
 Adverse Effects
 First-generation antihistamines
• Sedation, Antimuscarinic effects (dry mouth, urinary
retention)
• Dizziness, Tinnitus (ringing in the ear), Blurred vision
• In-coordination, Tremor

 Second-generation antihistamines
Doses above the usual therapeutic level can cause sleepiness
in certain individuals.
Cardiotoxicity (Arrhythmias

26
 Toxicity and drug interactions
• Lethal ventricular arrhythmias-Terfendine or
astemizole + Ketoconazole, itraconazole or
Erythromycin.
• H1- antagonists + CNS depressants
• C/I= driving or operating machinery

27
 Serotonin
 Synthesis
• Controlled by many factors
• Tryptophan is a precursor aa
 Transported to brain by carrier protein w/h also transports other aas
• Conc. Of tryptophan in brain
 Plasma conc of tryptophan
 Plasma conc of other aas

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 Receptors
 Largest NT receptor family
 About 7-subtypes are identified
 5HT1-4, have well defined functions
 All but 5HT3 are members of GPCRs and 5HT3 is ligand gated ion
channel (Na+ & K+)
 5HT1 receptors
5HT1B receptors; Found on the raphe nuclei of brain stem and Functions
as somatodendritic auto-receptor.
5HT1D receptors
– Act as auto-receptors on axon terminals
– Regulate
• Firing rate of DA containing cells and Release of DA

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 Con’t
• 5HT2 receptors
– Broadly distributed in the CNS
– 5HT2C are implicated in:
• Feeding behavior
• Susceptibility to seizure
• 5HT3 receptors
– Found in GIT, solitary tract & area postrema of CNS
– Participate in emetic response in both GIT & CNS
• 5HT4 receptors
– Widely distributed throughout the body
– Evoke secretion in the alimentary tract
– Facilitate peristaltic movement

30
 5HT receptor agonists
• 5HT1 receptor agonists
– Are indole derivatives
– Useful in treatment of acute migraine
• Includes:
– Sumatriptan, Zolmitriptan, Naratriptan & Nizatriptan
• Pharmacological properties
– Effect limited to 5HT1 receptors only
– Much more selective than ergot alkaloids
– Interact potently with 5HT1B & 5HT1D receptors
– Are inactive at
• α1, α2, β-adrenergic, dopaminergic, muscarnic & BDZ receptors

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 Con’t
• Mechanism of antimigraine activity
– Two hypotheses
• Cause constriction of intracranial blood vessels &
restore blood flow to the brain
• Modulate NT release from axon terminals
– Both 5HT1B & 5HT1D are presynaptic
autoreceptors
» Agonists may block the release of
proinflammatory neuropeptides at the
nerve terminal
» Accounts for their efficacy in acute
treatment of migraine

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Pharmacokinetics of Triptans
Drug Plasma Bioavailability metabolism T1/2
conc.
Sumatriptan 1-2hrs 14-17% MAO-A 1-2 hrs

12 mins 97%

Zolmitriptan 1.5-2 hrs 40% MAO-A 2-3 hrs

methylation
Naratriptan 2-3 hrs 70% CYP450 oxid. 6 hrs

Rizatriptan 1-1.5 hrs 45% MAO-A 2-3 hrs

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 Adverse reactions
• Minor side effects with acute treatment of migraine
– Rare but serious cardiac events:
• Coronary artery vasospasm
• Atrial & ventricular arthymia
• Myocardial infarction
– Most commonly experienced side effects:
• Pain, stinging
• Burning sensation
• Asthenia
• Flushing, drowsiness, nausea etc 34
 Contraindications
– Generally, ‘‘triptans’’ are contraindicated to patients with:
• History of ischemic or CADs; Cerebrovascular or peripheral vascular diseases
and Uncontrolled hypertension

– Naratriptan: C/I in severe renal or hepatic failure

– Rizatriptan: taken cautiously during renal or hepatic failure

– Sumatriptan, Rizatriptan & Zolmitriptan are C/I in patients taking

MAO inhibitors
• Clinical applications : Effective in acute treatment of migraine
• Not for prophylaxis of migraine, treat as soon as possible after onset of
migraine
• Oral dosage forms are most convenient to use

35
 5HT receptor antagonists
• 5HT antagonists
– Have widely differing chemical structures
– Newer agents are being explored for treatment of GIT cases
– Target 5HT2A/2C & 5HT3 receptors
• Katenserin
– Potently blocks 5HT2A and less potently 5HT2C receptors
– No significant effect on other 5HT receptors
– Has affinity for α1 & H1 receptors
– Lowers BP in patients with hypertension
• Comparable to β-antagonists & diuretics effect
• Reducing tone of both venous & arteries
• Effect related to α1 blocking activity not of 5HT2A/2C

36
 Con’t
– Inhibits 5HT induced platelet aggregation
– No severe side effects have been reported
– 50% BA, t1/2 = 12-25 hrs & metabolism is primary
mode of terminating its effect
• Clozapine
– 5HT2A/2C receptor blocker
– Also acts on dopamine receptors
– Atypical antipsychotic
• Reduce negative symptoms of schizophrenia
• Reduced extra pyramidal side effects

37
 Con’t
• Methysergid
– Blocks 5HT2A/2C receptors
– Inhibits vasoconstrictor & presser effects of 5HT
– Non selective
• Blocks 5HT1 receptors
• Therapeutic activity is result of 5HT2A/2C blockade
• Used in prophylactic treatment of migraine, diarrhea &
malabsorption
• Not useful for acute treatment of migraine
• GI disturbances, back pain, drowsiness, insomnia,
hallucinations

38
 Con’t
• 5HT3 receptor antagonists
– Includes Ondansetron, Granisetron & Dolasetron
– Used in treatment of chemotherapy induced
emesis
– Cancer treatment
• Causes release of 5HT from enterochromaffin cells
• Act on 5HT3A receptors on vagal nerves & CTZ
– Leads to vomiting

39
 Lipid derived autacoids
Eicosanoids
• Eicosanoids
– Arachidonate metabolites
– Not stored, synthesized & released up on need
– Pivotal role:
• Inflammation, Smooth muscle tone
• Hemostasis, Thrombosis
• Parturition, GIT secretion

40
 Biosynthesis
– Limited by availability of substrate
• Release of AA from membrane phospholipids
– D/f physical, chemical & hormonal stimuli
• Activate cPLA2
• Release AA from membrane phospholipids
– Once released, AA is metabolized to d/f products
• COXs= prostanoids
• LOXs = leukotrines
• CYP450 enzymes = epoxy & hydroxy derivatives

41
Synthesis of eicosanoids and sites of inhibitory effects of anti-inflammatory drugs

Membrane lipid
Corticosteroids
Phospholipase A2 -

Arachidonic acid

Cycloxygenase
Lipoxygenase
- NSAIDs

Hydroperoxides Endoperoxides
(HPETES) (PGG, PGH)

Leukotrienes Prostacyclin Thromoxane

(LTB, LTC ,LTD, LTE) (PGI) (TXA)
Prostaglandins
(PGE, PGF)
42
 Con’t
• Prostanoids
– Synthesized by consecutive activities of
• PGH synthetase-1 ( COX-1)
• PGH synthetase-2 ( COX-2)
– COX-1 & COX-2
• Constitutive Vs inducible activity
• House keeping Vs inflammation & cancer
• Differential sensitivity to NSAIDs
• Unique Vs coordinately regulated functions
– Involved in intercellular signaling
– Evidences show intracellular signaling, too

43
 Prostanoid receptors

• Classified into three clusters

 Relaxant receptors EP2, EP4, IP, and DP1, ↑ cAMP

 Contractile receptors EP1, FP, & TxA2, ↑ cytosolic

Ca2+

 EP3 can couple to both elevation of intracellular

calcium (Gq/11) and a decrease in cAMP (Gi)

44
 Roles of prostanoids
• Inflammation: PG E, I, Leukotrienes C4, D4
• Fever, pain: Prostaglandin E
• Regulation of blood pressure (PGE), blood clotting (PGE & PGI),
immune system modulation (PGE2)
• Thrombocyte aggregation: stimulated by thromboxane A2,
inhibited by PG E & I
- Uterine contraction: PGE2, PGF2
- Integrity of gastric mucosa: Prostaglandins E, F
- Regulation of blood flow and urine secretion in the kidney: PGE,
prostacyclin, thromboxane A
- Gastrointestinal motility: Prostaglandins E, F, I

45
 Clinical uses of eicosanoids

• NSAIDs & selective COX-2 antagonists

– Analgesics, antipyretic & anti-inflammatory agents
– Low dose aspirin is used in cardioprotection
• LT antagonists
– Useful in treatment of asthma
• The use of eicosanoids or eicosanoid derivatives
as therapeutic agents is limited
– Systemic administration associated with ADRs
– Very short half life
46
 Con’t
• Therapeutic abortion
– Systemic or intravaginal administration of PGE1
analog (Misoprostol) plus mifepristone
(progestrone antagonist) or methotrexate is very
useful in terminating early pregnancy
– Dinoprostone (PGE2)= during second trimester
• Gastric cytoprotection
– Several PG analogs suppress gastric ulceration
– Misoprostol
• Heals gastric ulcers as effective as H2 antagonists

47
 Con’t
• Ophtalmology
– Latanoprost (PGF2) for topical t/t of Glaucoma
– Bimatoprost, travoprost, and unoprostone are newer,
related drugs.
– These agents apparently increase the outflow of aqueous
humor, thus reducing intraocular pressure.
• Ductus arteriosus in infants (PGE1)
– To maintain until surgical correction can be
undertaken

48
 Con’t
• Impotence
– PGE1 (alprostadil) may be used in the treatment
of impotence, 1-3 hour erection in patients who
don’t have vascular sym disorder (inj. To
cavernosa)
• Pulmonary HTN
– Rare idiopathic disease affecting young adults
– Leads to right heart failure & is fatal
– Therapy with PGI2 (epoprostenol) delayed or
precluded the need for lung or heart transplant
49
 NSAIDs
• Chemically heterogeneous group of compounds
• Most of them are organic acids
• Share certain therapeutic actions & side effects
• Unlike aspirin, all are competitive inhibitors of COXs
• Well absorbed orally & highly bound to Plasma Pr.
• All are analgesics, antipyretic & anti-inflammatory
– Paracetamol
• Excreted by either
– Glomerular filtration or
– Tubular secretion

50
 Con’t
• MOA
– Inhibition of COXs  inhibit PG synthesis
– Aspirin differs from all other NSAIDs
• Irreversibly inhibit COXs
• So duration of aspirin effect depends on turn over rate
of the COXs
– Other NSAIDs are competitive inhibitors of COXs
• So duration of action depends on drug disposition

51
 Therapeutic effects of NSAIDs
• Pain/ analgesics
– Effective against pain of low to moderate intensity
– Much less efficacy than opioids
• No respiratory depression
• No dev’t of physical dependence
• Fever/ antipyretic
– Reduce fever but not temperature rise during exercise
– COX-2 PGs are responsible for rise in temperature
• Inflammation
– Chief clinical application
• Rheumatoid arthritis
• Osteoarthritis -Provide only pain relief not arrest disease progression
• Cancer chemoprevention
– Under active investigation
– Frequent use of aspirin showed 50% decrease in risk of colon cancer

52
 Adverse effects of NSAIDs therapy
• GI disturbances
– Anorexia, nausea, dyspepsia, abdominal pain etc.
• Results of induction of gastric or intestinal ulcers
– Ulceration
• Superficial to perforations
• Single or multiple point
• May be accompanied with blood loss/hemorrhage
• Increase in association with
– H. pylori, heavy alcohol consumption, concurrent use of GCs
– Selective COX-2 inhibitors have reduced GI SEs
• Antiplatelet aggregation
– Result of inhibition of TXA2 synthesis

53
 Con’t
• Renal & renovascular adverse effects
– Little effect on normal subjects
– Significant ADRs in patients with
• CHF, Hepatic cirrhosis & chronic kidney disease
– Retention of salt & water causing edema
• Pregnancy
– Prolongation of gestation by NSAIDs
– Increased risk of postpartum hemorrhage
• Hypersensitivity
– Some individuals are allergic to aspirin & NSAIDs

54
 Drug-Drug Interaction
NSAIDs
 with GCs increase risk of GI ulceration
 With ACEIs increase risk of hyperkalemia
• With Warfarin, increase risk of bleeding
– NSAIDs antiplatelet activity
– NSAIDs also interfere with plasma binding & metabolism of
warfarin
• Plasma protein binding
– NSAIDs with Warfarin, Sulfonyl urea, Methotrexate

55
 Respiratory drugs
Outline:
• Upper respiratory infection
• Expectorants and Antitussives Nasal
decongestants
• Lower respiratory infection
• Drugs used for Asthmatics
• Drugs used for COPD
• Anti TB

57
 Introduction
• Upper respiratory tract
infections (URI or URTI) are:
– illnesses caused by an acute infection which
involves the upper respiratory
tract including
the nose, sinuses, pharynx or larynx.
• This commonly includes:
– pharyngitis, laryngitis, Rhinitis, common
cold and their
complications: sinusitis, otitis media and
sometimes bronchitis (though bronchi are
generally classified as part of the lower
respiratory tract.)
58
 Treatment
• Treatment depends on the underlying cause.
– E.g antibiotics - effective if the infection is caused by
bacteria
• In the absence of clinical evidence of bacterial
infection, treatment remains entirely symptom-
based, with use of
– decongestants
– analgesics for headache, sore throat and muscle aches
– dextromethorphan for cough
• You can treat your symptoms at home by:
– taking over-the-counter painkillers such
as paracetamol or ibuprofen,
– drinking plenty of fluids- in an attempt to thin
respiratory secretions and resting.
59
 Con’t
Acetaminophen
• Inhibits prostaglandin synthesis in the CNS.
– This explains its antipyretic and analgesic properties.
• Has less effect on cyclooxygenase in peripheral tissues,
– which accounts for its weak anti-inflammatory activity.
Therapeutic uses
• is suitable substitute for the analgesic and antipyretic effects
of aspirin for those patients with:
– gastric complaints (gastrointestinal irritation)
– prolongation of bleeding time and
– those who do not require the anti-inflammatory action of
aspirin
60
 Con’t
• Product Name: SNIP
• Active Ingredient(s): Paracetamol 325mg,
Pseudoephedrine hydrochloride 15mg,
Chlorpheniramine maleate 1mg

– Paracetamol-------antipyretic, analgesic
– Pseudoephedrine----------decongestant
– Chlorpheniramine----------antihistamine

61
 Con’t
Treatment of Cough
• Cough is a protective reflex action,
caused by irritation in the throat
• Coughing is a symptom and, where possible,
therapy is directed to its etiology
• Cough may be useful or useless
– Useless (non-productive) cough should be suppressed
– Useful (productive) cough serves to drain the airway,
• its suppression is not desirable– unless it disrupts sleep

62
 Drugs for cough
Classified in to:
1. Antitussives (Cough centre suppressants)-- used for dry cough
(a) Opioids – (Codeine phosphate) …. obsolete
(b) Nonopioids - Dextromethorphan
2. Expectorants (Mucokinetics)-- used for productive cough
– (a) Bronchial secretion enhancers - Guaifenesin
– (b) Mucolytics - AcetyIcysteine
Antitussives (cough medications)
• They decrease the sensitivity of cough centers in the CNS to
peripheral stimuli (raise threshold of cough centre) or
• Act peripherally in the respiratory tract to reduce tussal
impulses
63
• Dextromethorphan—a synthetic derivative of
codeine
– Suppress the cough center (raises threshold of
cough centre)
– It does not have any analgesic(d-isomer) or
addictive potential, and it is less constipating
than codeine
– The antitussive action lasts for ~6 hours & is not
blocked by naloxone:
• therefore not exerted through opioid receptors.
– S/E: Dizziness, nausea, drowsiness, ataxia.
64
 Expectorants
• Expectorants (Mucokinetics) are drugs believed to
increase bronchial secretion or reduce its viscosity,
facilitating its removal by coughing.
• E.g:-Guaiphenesin, Saturated Solution of Potassium
Iodide, AcetyIcysteine, Bromhexine
A. Bronchial secretion enhancers: KI, Guaiphenesin,
balsum of Tolu, Vasaka, Ammonium chloride.
– KI is secreted by bronchial glands and can irritate
the airway mucosa.
– Guaiphenesin, vasaka, tolubalsum are plant
products which are supposed to enhance bronchial
secretion and mucociliary function while being
secreted by tracheobronchial glands
65
 Expectorants Cont’d
B. Mucolytics: Bromhexene, Acetyl cysteine, Carbocysteine
1. Bromhexine -- MOA - It depolymerises mucopolysaccharides
– It is particularly useful if mucus plugs are present.
– Side effects: rhinorrhoea, lacrimation, gastric irritation &
hypersensitivity.
2. AcetyIcysteine
– It opens disulfide bonds in mucoproteins present in sputum—
makes it less viscid,
3. Carbocisteine
– It liquefies viscid sputum in the same way as acetylcysteine

66
 DECONGESTANTS

• Reduce congestion, opening clogged nasal

passages
• Mechanisms of action:
1 agonists; produce localized vasoconstriction
on small blood vessels of nasal membrane.
• Clinical uses: in congestion associated with
allergic or non allergic rhinitis, hay fever and
to a lesser extent common cold.
• Drugs can be administered nasally or orally

67
 Decongestants Cont’d
• Classification:
 Short acting decongestant[orally]:
Phenylephrine
Phenylpropanolamine
 long acting decongestant[orally]:
Ephedrine
Pseudoephedrine,
Naphazoline
 long acting [topical]: Xylometazoline
Oxymetazoline
68
 Phenylephrine
• MOA--sympathomimetic drug which mimics the
actions of E or NE.
• Phenylephrine selectively binds to α1-adrenergic
receptors and cause blood vessels to constrict.
• Uses: Decongestant, hemorrhoids, pupil
dilatation, vasopressor and in priapism.
• Side effects: headache, reflex bradycardia,
excitability, restlessness and cardiac arrhythmias,
worsen Prostatic hyperplasia

69
 Ephedrine
• is an alkaloid found in various plants
• MOA:
The principal mechanism of action relies on its
indirect stimulation of the adrenergic receptor
system by increasing the activity of noradrenaline
at the postsynaptic α- and β-receptors.
Use:
 Prophylactically in chronic treatment of asthma.
 Increases alertness, decreases fatigue.
 For congestion of nasal & eustachian tubes.

70
 Adverse effects
 Cardiovascular: tachycardia, cardiac arrhythmias,
angina pectoris, vasoconstriction with hypertension
 Dermatological: flushing, sweating, acne vulgaris
 Gastrointestinal: nausea
 Genitourinary:
 decreased urination due to vasoconstriction of renal
arteries,
 difficulty urinating is common, as alpha-agonists such as
ephedrine constrict the internal urethral sphincter,
mimicking the effects of sympathetic nervous system
stimulation

71
 Xylometazoline
MOA:
• works by constricting the blood vessels in the nose.
• The decongestant effect is due to constriction of large
veins in the nose which swell up during the
inflammation of any infection or allergy of the nose.
• The smaller arteries are also constricted and this
causes the colour of the nasal epithelium to be visibly
pallor after dosage.
Uses:
• Relieving nasal congestion due to the common cold,
hay fever, other URT allergies, or sinus infection.
72
 Rhinitis
• Is inflammation of the nasal mucosa characterized
by two or more of the following symptoms
– nasal congestion, rhinorrhoea, sneezing & itchy nose
• divided into three main categories:
1. Infectious rhinitis
2. Allergic rhinitis is immunologic nasal response,
primarily mediated by immunoglobulin E (IgE).
3. Non-allergic rhinitis are rhinitis symptoms in the
absence of identifiable allergy, structure
abnormality or sinus disease. which include
vasomotor rhinitis, vascular rhinitis, perennial,
chronic and noninfectious perennial rhinitis.
73
 Histamine
• Release of histamine:
– The release of histamine may be the
primary response to some stimuli,
– Stimuli causing the release of histamine
from tissues include
• The destruction of cells as a result of cold,
bacterial toxins, bee sting venoms, or trauma.
• Allergies and anaphylaxis can also trigger
release of histamine

74
 Mechanism of action of histamine
• Histamine exerts its effects by binding to one or more of H1,
H2, H3, and H4 receptors
• H1 and H2 receptors are widely expressed and are the
targets of clinically useful drugs
• H1 receptors are important in producing smooth muscle
contraction and increasing capillary permeability
• Histamine promotes vasodilation by causing vascular
endothelium to release nitric oxide
• H2 receptors mediate gastric acid secretion
 Histamine is a chemical messenger that mediates a wide
range of cellular responses,
– allergic and inflammatory reactions,
– gastric acid secretion, and
– neurotransmission in parts of the brain
75
 H1 Antihistamines
• The term antihistamine refers to the classic H1-
receptor blockers
• The H1-receptor blockers can be divided into first-
and second-generation drugs
• The older first-generation drugs are still widely used
because they are effective and inexpensive.
• However, most of these drugs penetrate the CNS
and cause sedation.
• Furthermore, they tend to interact with other
receptors, producing a variety of unwanted adverse
effects
76
 1. Antihistamines
A. Diphenhydramine : 1st generation antihistamine

– MOA -- blocking effect of histamine at H1 receptor sites & reduction of

smooth muscle contraction.

– Use: treatment of the allergic rhinitis, hives, motion sickness, and

insect bites & stings.

– S/E:drowsiness, possibilities of motor impairment, dry mouth & throat

B. Fexofenadine HCl -- 2nd generation antihistamine.

MOA- histamine H1-receptor antagonist, not cross BBB & causes less
drowsiness.
Uses- in treatment of sneezing, rhinorrhea, itchy nose/palate/throat &
77
itchy/watery/red eyes.
 Con’t
C. Loratadine & Desloratadine
 are tricyclic antihistamine with selective H1 -antagonist action.
 Has a long-lasting effect can’t cross BBB -- does not cause drowsiness.
Uses: in sneezing, runny nose, itching & watery eyes & other allergic
symptoms such as hives
D. Cetirizine HCl is a racemic selective H1 receptor antagonist.
• Uses: treats itchy, red, and watery eyes, sneezing, runny, and itchy nose,
itching from hives.
• side effects: sleepiness, fatigue, or dizziness, headache, and dry mouth.
E. Azelastine HCl -- prescription antihistamine approved to treat nasal
congestion.

78
 2. cromolyn sodium
MOA: block a calcium channel essential for mast
cell degranulation, stabilizing the cell and
thereby preventing the release of histamine.
Uses: indicated in the management of patients
with mastocytosis, in diarrhea, flushing,
headaches, vomiting, urticaria, abdominal pain,
nausea, and itching in some patients.
Side effects: diarrhea, headache, abdominal pain,
irritability, muscle pain, nausea, trouble in
sleeping 79
 3. Anti-Leukotriene
• Equipotent to histamine-1 receptor antagonists but
with onset of action after 2 days
• Reduce nasal and systemic eosinophilia
Uses:simultaneous treatment of allergic rhinitis and asthma
4. Nasal Corticosteroids
• Most potent anti-inflammatory agents
• Effective in treatment of all nasal symptoms including
obstruction
• Superior to anti-histamines and anti-leukotienes
• First line pharmacotherapy for persistent allergic rhinitis
– Beclomethasone dipropionate, Budesonide,
Flunisolide, Fluticasone propionate, Mometasone
furoate, Triamcinolone acetonide
80
 Antibiotics
• When bacterial cause has been identified for
URTI, antibiotics should be given
• Classification of antibiotics based on their
proposed mechanism of action
– Cell wall synthesis inhibitors
– Protein synthesis inhibitors
– Plasma membrane-injuring agents
– Nucleic acid inhibitors
– Metabolic/enzyme inhibitors
81
 Penicillins
• They are among the most widely effective antibiotics
• The least toxic drugs known
• But increased resistance has limited their use.
Classification
• Based on their antimicrobial spectrum, penicillins can be
classified into 4 classes:
1. Natural penicillins: Penicillin G, Penicillin V
2. Anti-staphylococcal penicillins (penicillinase resistant
penicillins): Nafcillin, oxacillin, cloxacillin, dicloxacillin
3. Aminopenicillins: ampicillin, amoxicillin
4. Antipseudomonal penicillins: piperacillin, ticarcillin,
carbenicillin
82
 Natural penicillins
Absorption
Penicillin G
• Gastric juice at pH -2 rapidly destroys pen G
• Reduced acid secretion associated with aging accounts for better
absorption of pen G from GIT of older individuals
• Due to its acid labile nature, pen G is mostly administered by the
parenteral routes
• Can be used for treatment of mild to moderate upper
respiratory tract infections
Penicillin V
• is more stable in an acidic medium & is administered by the oral
route
• better absorbed from the gastrointestinal tract after oral
administration
83
 Aminopenicillins
• Have greater activity than pen G against gram-negative bacteria
 Enhanced ability to penetrate the gram-negative outer membrane
 Are inactivated by β-lactamases
 Are acid resistant & can be used orally
 Includes: ampicillin & amoxicillin
– Both have good oral bioavailability; ampicillin is also bioavailable after
intramuscular injection
• Amoxicillin oral therapy is appropriate for:
– Acute non serious bacterial infections like otitis media and sinusitis
– strep throat
– In multidrug regimens for eradication of H. pylori
– UTIs, lower respiratory tract infections
• Amoxicillin does not reach adequate concentrations in the CSF
– It is not appropriate for meningitis therapy

84
 Amoxicillin/clavulanic acid
• Amoxicillin--a β-lactam antibiotic
• Clavulanic acid-- a β-lactamase inhibitor.
• This combination restore efficacy against
amoxicillin-resistant bacteria that produce β-
lactamase.
Mechanism of action:
• Clavulanic acid is a suicide inhibitor,
covalently bonding to a serine residue in the
active site of the β-Lactamase.
• This inactivates the enzyme.

85
 β-Lactamase Inhibitor Combinations
• Several formulations combine a β -lactam antibiotic with a β-
lactamase inhibitor

Clavulanic acid
o It is combined with amoxicillin for oral administration
o AUGMENTIN
o and with ticarcillin for parenteral administrition
o TIMENTIN
Sulbactam
• combined with ampicillin for IV or IM use
• UNASYN
Tazobactam
• It has been combined with piperacillin as a parenteral preparation
• ZOSYN

86
 Asthma
• Asthma is an inflammatory disease of the airways
– characterized by episodes of acute
bronchoconstriction causing
• shortness of breath, cough, chest tightness, wheezing, and
rapid respiration
• The bronchoconstriction results from
1. Contraction of bronchial smooth muscle,
2. Inflammation of the bronchial wall, and
3. Increased mucous secretion
• The symptoms of asthma may be effectively
treated by several drugs,
• but no agent provides a cure for this obstructive
lung disease.
87
Drugs used for asthma

88
 Adrenergic agonists
• β2 agonists are potent bronchodilators that relax
airway smooth muscle.
• Most clinically useful β2 agonists have a rapid onset
of action (<30 minutes) and provide relief for 4 to 6
hours
• β2 Agonists have no anti-inflammatory effects, and
• They should never be used as the sole therapeutic
agents for patients with persistent asthma
• What is the advantage of dosing via inhalation?
– Adverse effects, such as tachycardia and hyperglycemia,
can be minimized
89
 Adrenergic agonists
• Pirbuterol, terbutaline, and albuterol are used for
quick relief
• Salmeterol and formoterol are long-acting β2 agonist
bronchodilators
– provide bronchodilation for at least 12 hours
– analogs of albuterol but differ by having a
lipophilic side chain, increasing the affinity of the
drug for the β2-adrenoceptor

90
 Corticosteroids
• Inhaled corticosteroids (ICS) are the drugs of first
choice in patients with any degree of persistent
asthma (mild, moderate, or severe)
• No other medications are as effective as ICS in the
long-term control of asthma

Inhaled steroids used in the mgt of chronic asthma

•Beclomethasone
•Flunisolide
•Triamcinolone
•Fluticasone
•Budesonide

91
 Corticosteroids
Actions on lung:
• ICS do not directly affect the airway smooth muscle.
• Instead, ICS therapy directly targets underlying
airway inflammation
– by decreasing the inflammatory cascade
(eosinophils, macrophages, and T lymphocytes),
reversing mucosal edema, decreasing the
permeability of capillaries, and inhibiting the
release of leukotrienes

92
93
• Drugs used to treat respiratory conditions can be
delivered
– Topically to the nasal mucosa,
– Inhaled into the lungs, or
– Given orally or parenterally for systemic
absorption.
• Topical delivery methods, such as nasal sprays or
inhalers, are preferred so as to target affected tissues
while minimizing systemic side effects

94
 Leukotriene antagonists
• Leukotriene (LT) B4 and the cysteinyl leukotrienes,
LTC4, LTD4, and LTE4, are products of the 5-lipoxygenase
pathway of arachidonic acid metabolism and part of the
inflammatory cascade
• Zileuton is a selective and specific inhibitor of 5-
lipoxygenase,
– prevent the formation of both LTB4 and the cysteinyl
leukotrienes.
• Zafirlukast and montelukast are selective, reversible
inhibitors of the cysteinyl leukotriene-1 receptor
– blocking the effects of cysteinyl leukotrienes
95
 Clinical role
• Used for prophylaxis of asthma
– They prevent bronchoconstriction and airway inflammation
• Used for chronic maintenance therapy
• Not effective in situations where immediate bronchodilation is
required
– They should not be used for acute bronchospasm
Cromolyn and nedocromil:
• are effective prophylactic agents
– That stabilize the membranes of mast cells and prevent
mediator release
• Not used for treating acute attacks of asthma
• Pre-treatment with cromolyn or nedocromil blocks allergen-
induced and exercise induced bronchoconstriction

96
 Cholinergic antagonists
• They block the vagally mediated contraction
of airway smooth muscle and mucus
secretion.
• Inhaled ipratropium, a quaternary derivative
of atropine, is useful in patients who are
unable to tolerate adrenergic agonists.

97
 Theophylline
• Methylxantine that increase cAMP by inhibiting the
enzyme phosphodiesterase
– Results in bronchodilation
• narrow therapeutic window,
• high side-effect profile,
• potential for drug interactions.
• Overdose may cause seizures or potentially fatal
arrhythmias.
• Theophylline is metabolized in the liver, is a CYP1A2
and 3A4 substrate, and interacts adversely with
many drugs.
98
DRUGS USED TO TREAT COPD
• It is a chronic, irreversible obstruction of air flow
• Smoking is the greatest risk factor for COPD
• The disease may respond to bronchodilators, such as
anticholinergic agents, β-adrenergic agents and
theophylline
• Therapy does not cure the disease or even
significantly slow its progress
• Treatment consists of a trial of β2-agonist or
ipratropium to assess any reversible component of the
disease, and is a reasonable first-line initial therapy for
all patients
• Glucocorticoids may be helpful in the treatment of
acute exacerbations in some patients 99
 Pneumonia
• Pneumonia refers to acute inflammation of the distal
lung-terminal airways, alveolar spaces, and interstisium.
• The most important pathogens which cause community
acquired pneumonia in immuno-competent adults
include Strep. Pneumoniae, followed by Mycoplasma
Pneumoniae, Chlamydia Pneumoniae, Legionella spp
and others.
• It is also important to remember that Pneumocystis
jiroveci and Mycobacterium Tuberculosis have now
become common causes of community acquired
pneumonia in immuno-compromised individuals
100
 Pneumonia cont..

• The most important symptoms include cough,

fever, chest pain and tachypnoea
• Initial empiric antibiotic therapy should be
broad and later on streamlined based on
results of examination and cultures of sputum,
endotracheal suction material and bronchial
lavage wash.

101
 Common drugs for t/t of pneumonia
I. Community acquired ambulatory patients (Mild
Pneumonia):
– Amoxicillin
– Erythromycin or Doxycycline or Procaine penicillin
II. Community acquired hospitalized patients (Severe
Pneumonia)
o The Antibiotic choice should be aimed at the most likely
causative agent
– A. Pneumonia due to common organisms:
• Benzyl penicillin PLUS Gentamicin
• Ceftriaxone or Erythromycin or Doxycycline
– B. Pneumonia due to Gram-negative bacteria
• Ampicillin PLUS Gentamicin
• Benzyl penicillin PLUS Gentamicin
– C. Pneumonia due to Staphyloccocus Aureus
• Cloxacillin
102
III. Hospital acquired pneumonias (Nosocomial
Pneumonias):
• The antibiotic choice should depend on the epidemiology and
susceptibility of local pathogens.
• Antimicrobials effective against gram-positives and gram-
negatives should be given in combination
– Cloxacillin PLUS Gentamicin
– Ceftazidime PLUS Gentamicin or Ceftriaxone PLUS
Gentamicin or Ciprofloxacin
• Specific cause known:
– 1. Staphylococcus aureus
• Cloxacillin
• If methicillin-resistant, Vancomycin PLUS Rifampicin
– 2. Pseudomonas aeruginosa
• Ceftazidime
• Ceftriaxone PLUS Gentamicin
– 3. Enterobacteriaceae
• Ceftriaxone PLUS Gentamicin
103
 Tuberculosis
• Is a leading infectious killer globally which is caused by
Mycobacterium tuberculosis

Risk factors
– Patients with underlying immune suppression
– Children under 2years of age & oldies above the age of 65
years
– HIV/AIDS patients, health professionals
– Individuals living in poorly ventilated areas & with
malnutrition

104
• Drugs used in the treatment of tuberculosis can be divided
into two major categories
First-line agents
• Have the greatest level of efficacy with an acceptable
degree of toxicity
• Includes: isoniazid, rifampin, ethambutol, streptomycin, &
pyrazinamide
• The large majority of patients with tuberculosis can be
treated successfully with these drugs

Second-line agents
• Are reserved for resistant cases of TB
• Are less efficacious & highly toxic than 1st line drugs
• Includes: moxifloxacin or gatifloxacin, ethionamide,
aminosalicylic acid, cycloserine, amikacin, kanamycin,
capreomycin & linezolid
105
 First-line anti-TB drugs

• All first-line anti-TB drug names have a standard

three-letter and a single-letter abbreviations:
– Ethambutol ( EMB or E)
– Isoniazid ( INH or H)
– Pyrazinamide (PZA or Z)
– Rifampicin (RMP or R)
– Streptomycin (SM or S)

106
 Multidrug therapy
• Strains of M. tuberculosis that are resistant to a
particular agent emerge during treatment with a
single drug.
• Therefore, multidrug therapy is employed when
treating tuberculosis in an effort to delay or prevent
the emergence of resistant strains
• Patient compliance is often low when multidrug
schedules last for 6 months or longer.
• One successful strategy for achieving better
treatment completion rates is directly observed
therapy, also known as DOT, in which patients take
their medication while being supervised and
observed 107
 The treatment strategy
• During the intensive phase
– is a short course of treatment- 2 months
– The drugs must be collected daily
– must be swallowed under the direct observation of a
health worker- DOTS
• During the continuation phase
– the drugs must be collected every month and
– self-administered by the patient

Example: 2 (RHZE) / 4RH

108
GI Pharmacology
OUT LINE :
Gastrointestinal disorder
Acid-peptic disorders
Peptic ulcer disorder/GERD/ H.pylori
Constipation
Anti diarrhea
Anti emetic drugs

109
 GASTROINTESTINAL DISORDERS
Acid-peptic disease
Gastroesophageal reflux disease (GERD)
Peptic ulcer disease (gastric & duodenal)
Stress-related mucosal injury
Constipation & diarrhea
Nausea & vomiting
Irritable bowel syndrome (IBS)
Inflammatory bowel disease (IBD)
110
 Acid peptic disease
Include
 Gastro esophageal reflux disease(GERD)
 Peptic ulcer (gastric & duodenal)
 Stress related mucosal injury
 In all this conditions mucosal erosion or ulceration arise
when causative effects like acid, pepsin, bile
overwhelm the defense factors of GI mucosa (mucus,
bicarbonates, prostaglandin, blood flow, etc.)

111
Peptic ulcer disease (PUD)
This is includes:
Duodenal ulcer
Gastric ulcer
– Causes:
• H. pylori infection
• NSAID use
• Pathologic gastric acid secretion
• Rare causes include herpes simplex infection,
• major physiologic stress (eg, critical illness, severe
burns)

112
 Regulation of Acid Secretion
 The parietal cell basolateral membrane has receptors for
three stimulants:
 Histamine (H2)
 Acetylcholine (M3)
 Gastrin (CCK-B/gastrin)
 Following binding, a second messenger is liberated
(Ca+, cyclic AMP)
 This second messenger activates protein kinases which
result in secretion of HCL whereby hydrogen ions are
secreted into the lumen in exchange for potassium ions by
action of the proton pump H+/K+ ATPase pump

113
Pathogenesis
 Imbalance between gastro-duodenal mucosal defence
mechanisms & the damaging forces
 Many factors can disrupt the balance
Activation of aggressive factors
Suppression of protective factors

 H. pylori : organism capable of disrupting the balance

114
Defensive Mechanisms
 Mucus
 Secreted by GI cells and form protective barrier
 HCO3: Neutralizes H+ ions that penetrate mucus
 Blood Flow: Ischemia can lead to cell injury
 Prostaglandins
 Stimulate mucus & HCO3 secretion
 Promote vasodilatation
 Maintaining blood flow
 Suppresses gastric acid secretion

115
Aggressive Factors
 Helicobacter pylori
 Gram –ve bacillus, produces urease
 Remains in GI tract for years
 Most people with PUD have H. pylori
 Duodenal ulcers more common with H. pylori
 NSAIDs (COX inhibitors)
 Inhibit biosynthesis of prostaglandins
 Irritate mucosa directly
 Acid & Pepsin
 Smoking: Delays ulcer healing

116
 Drug treatment of PUD & GERD
1. Anti-secretory
Proton pump inhibitors
Antihistamines
Anticholinergics
2. Antacids: Aluminium hydroxide, Magnesium trisilicate
3. Mucosal protecting agents: Colloidal bismuth cpds,
Prostaglandin analogs (misoprostol)
4. Anti-microbial Agents

117
 Drug treatment of PUD & GERD

Antacids

 They are weak bases

 Directly neutralize the acid  activity of acid & pepsin
 Reflex gastrin release  ↑acid secretion “acid
rebound’’
 Mainly indicated for simple dyspepsia & heartburn

118
 Commonly used antacids

 Magnesium antacids [Mg(OH)2 & Mg trisilicate]

o Fast onset, laxative effect, may cause diarrhea

(Osmotic laxative effects).

o Mg trisilicate adsorb HCl & pepsin (physical action),

neutralize HCl (chemical action)
Aluminum hydroxide [Al(OH)3 ]
 Slowly reacting antacid, long duration & constipation
 Al(OH)3 ↓ phosphate absorption  ↓ renal phosphate level
(used for t/t & prevention of renal phosphate stone)

119
 Drug treatment of PUD & GERD

 Combined antacids

Advantage

Fast [Mg(OH)2 ] & slow [Al(OH)3] acting components

yield fast as well as substantiated action

Mg salts are laxative while Al salts are constipating,

Gastric emptying is least affected & dose of each drug is

reduced

120
 Drug treatment of PUD & GERD
 E.g. Magaldrate (hydroxymagnesium aluminate
complex)
 In gastric acid, it is converted to Mg(OH)2 & Al(OH)3
 Dosage forms of antacids
Tablets (chewable) and Suspensions

 Systemic antacids : sodium bicarbonate

 Very water soluble

 Has risk of alkali and sodium over loads in patents

have cardiac and renal disease
121
Side Effects
 Osmotic Diarrhea-unabsorbed Mg salts
 Constipation-Aluminum salts
 Metabolic Alkalosis- absorption of unreacted
alkali
 Sodium overload- especially in patients with
heart/renal failure
 “Milk Alkali syndrome”- excess ingestion of
calcium and soluble alkali-like antacids,
especially sodium bicarbonate (baking soda)
over a prolonged period of time (Rare)

122
 Drug treatment of PUD & GERD
Antacids drug interactions

 Alter gastric pH

• ↓ absorption of drugs which needs acidic medium

e.g. Ketoconazole /antifungal /

 Chelation with other drugs forming insoluble complex  

absorption

e.g. Tetracycline, Fluoroquinolones, Digoxin - time gap (not less

than 2 hrs) is needed

123
 Drug treatment of PUD & GERD
Muscarinic antagonist
Drugs : Pirenzepine, Clindinium
MoA: inhibit muscarinic receptor on parietal
 Anticholinergics with anxiolytics can be used to treat
stress induced dyspepsia.
Eg. Librax® (clindinium bromide + chlordiazepoxide)
Adverse effects: Anticholinergic side effects (anorexia,
blurred vision, constipation, dry mouth, sedation)

124
 Drug treatment of PUD & GERD
Histamine H2 receptor blockers
Drugs
 Cimetidine (Prototype)
 Ranitidine
 Famotidine
 Nizatidine
 To day in clinical practice replaced by PPIs. And less
effective.

125
 Drug treatment of PUD & GERD
Pharmacokinetics
 Rapidly absorbed from intestine (1-3 hrs.)
 Cimetidine, Ranitidine & Famotidine undergo rapid 1st
pass metabolism (about 50%)
 Nizatidine has little first-pass metabolism
(bioavailability of almost 100%)
 Serum half life 1-4hrs and less protein bound.
 Clearance is both renal (the most ) & hepatic
 Dose reduction is required in patients with moderate to
severe renal & possibly severe hepatic insufficiency.
 All except nizatidine are also available for IV injection
126
 Drug treatment of PUD & GERD
 Pharmacodynamics
 MOA
 Reversible competitive antagonist of H2 receptor
 Direct stimulation of acid secretion by Ach & gastrin
reduced by H2 receptor blockers
 Inhibit nocturnal acid secretion  as Histamine is
responsible for nocturnal acid secretion(90%)
 Prolonged use  down regulation of receptors 
tolerance to these agents occurs
 All are equal in efficacy but differ in potency, (F > R/N
> C)
127
 Therapeutic uses
 Promote gastric & duodenal ulcer healing (6 – 8 wks
therapy
 To treat uncomplicated GERD
For patients with infrequent heartburn or dyspepsia
(< 3 times per week)
 To prevent bleeding from stress related gastritis
 Zollinger-Ellison syndrome
 Non ulcerative dyspepsia
 Ulcer caused by NSAIDs
128
 Adverse effects
 Diarrheal, headache, drowsiness, fatigue, muscular pain & constipation
 Less common: confusion, delirium, hallucinations, slurred speech (with
IV administration)
 Galactorrhoea in women ( due to ↑ed plasma prolactin level )
 Gynecomastia, reduced sperm count & impotence in men (with larger
dose and/or prolonged use of cimetidine)
Inhibits metabolism of estradiol by liver.

 Drug interaction
 Cimetidine inhibits several CYP450 isoenzymes
 Ranitidine interferes only minimally with hepatic metabolism of
other drugs.
 No significant drug interactions with Famotidine and Nizatidine.
 Antacids reduce absorption of all H2 blockers (2hr gap is required).
 Ketoconazole absorption is decreased by H2 blockers
129
 Proton pump inhibitors
Drugs
Omeprazole:(Prilosec) 10, 20, 40mg
PO/IV
 Lansoprazole: (Prevacid) 15, 30mg PO
 Rabeprazole: (Aciphex) 20mg PO
Pantoprazole: (Protonix) 40mg PO/IV
 Esomeprazole:(Nexium) 20mg, 40mg
PO/IV
 Only omeprazole available as a generic in US
130
 Drug treatment of PUD & GERD
MOA
 Prodrugs

 Are lipophilic weak bases  diffuse through membrane 

accumulate in acidic env’t of the canaliculi of the parietal cell 
react with thiophill sulfonamide cation  sulfonamides reacts
with H+/K+ATPase forming a covalent disulfide linkage 
Irreversible inactivation of the pump

 After diffusion in to parietal cells from blood, drugs get

concentrated in acidic PH (as charged drugs are not able to
diffuse back) then bind with the enzyme irreversibly

131
 Drug treatment of PUD & GERD

 Pharmacokinetics
The prodrugs are unstable in the presence of acid
Available as acid resistant enteric-coated formulation
Parental preparetion like Panto, lanso.
Should be given about 30 minute - 1hr before meals
 Rate of absorption may be reduced by food
 Reduce meal stimulated acid secretion
Undergo rapid 1st pass and hepatic metabolism
Oral is the most common route & the dose varies with
the type of PUD
132
 Drug treatment of PUD & GERD
 Clinical use
 GERD and PUD (duodenal ulcer-4wks therapy, gastric ulcer (6-
8wks therapy)
 As one component in H.Pylori eradication
 Aspirin induced ulcer provided that the use of aspirin is
continued FDA...Lansoprazole.

S/E:Nausea, abdominal pain, diarrhea, flatulence

 Sub acute myopathy, headache, skin rashes

 Hypergastrinimia is more frequent and more severe with proton

pump inhibitors than with H2-receptor antagonists.

 Deceased acidity may result in infection

133
 Drug treatment of PUD & GERD

 Drug interactions
 Decrease of acidity may alter absorption of drugs for
which intrgastric acidity is needed
e.g. ketokonazole, digoxin, vit B12,ampicillin,
iron salts
 Decrease the metabolism of
 Warfarin
 Cyclosporine
 Diazepam
 Increase metabolism of (cyp1A2) imipramine,
theophylline.

134
 Drug treatment of PUD & GERD

Mucosal protective agents

Gastroduodenal mucosa has a no of mechanisms to
protect itself from acid/pepsin
 Cell – cell tight junction  restrict back diffusion of
acid & pepsin
 Epithelial bicarbonate
 Mucosal prostaglandin
• Stimulate mucus & bicarbonate secretion
• Stimulate blood flow

135
 Drug treatment of PUD & GERD
 Prostaglandin analogue (Misoprostol)
Drug – misoprostol (methyl –PGE1 )

- prostaglandin and prostacyclin analogs

MOA: Bind EP3 receptors on parental cells and stimulate Gi path
way that decrease intracellular cAMP and gastric secretion.
Pharmacokinetics

Absorbed rapidly after oral administration and is hydrolysed

(de-esterfied to misoprostol acid) the active compound.

Metabolized by the liver & excreted mainly in the urine(free

acids)

Food and antacids decrease absorption. 136

 Cont…
 It have Both acid inhibitory & mucosal protective properties
(dual effects)
–  mucus secretion
–  HCO3- secretion
–  HCl secretion
– Vasodilation- HCl diffusion to blood

137
 Drug treatment of PUD & GERD

Clinical use
Prevention & treatment of NSAID induced ulceration(
FAD approved) but mostly not used ….Lansoprazole.
Treatment of PUD
Control of postpartum bleeding
But not commonly used b/c of high side effects &
multiple daily dosing…PPIs are more effective,
convenient & cheaper
Adverse effects
 Diarrhea with/out Abd pain and crams
 Exacerbation of IBD
 Utrine contractility &bleeing ( CI pregnancy) 138
 Drug treatment of PUD & GERD

 Sucralfate
 Salt of sucrose complexed to sulfated Al(OH)3
MOA: After exposure to gastric acid, the compound becomes
negatively charged, creating a viscous adherent complex
which is believed to inhibit back-diffusion of H+
 It forms viscous paste that selectively binds to ulcers
 Also causes direct reduction in pepsin activity & a slight
rise in tissue prostaglandin levels
 It has no acid-buffering capacity
Clinical use
– In ICU pts to prevent stress related gastritis
Adverse effects: Constipation, avoid in RF pts b/se AL overloads.
Drug interaction: BA of co administered medications
139
 Drug treatment of PUD & GERD

Colloidal Bismuth cpds

Drugs: colloidal bismuth sub citrate, subsalicylate
dinitrate
MOA: Form a protective coat on the ulcer base
USE :
 H. Pylori eradication
 Adsorb pepsin, prevent adherence of the bacteria
to the mucus
Adverse effect
 Small amount is absorbed  encephalopathy
 Blackening of stool & tongue
 High dose –salicylate toxicity.
140
 Drug treatment of PUD & GERD

H. Pylori
 Gram negative bacillus
 Uniquely adapted to survive in hostile environment
of stomach
 Able to attach to the epithelial cells of the stomach &
duodenum which stops them from being washed out
of the stomach
Once attached, the bacteria start to cause
damage to the cells by secreting degradative
enzymes, toxins & initiating a self-destructive
immune response
 Produce ammonia which maintain neutral
microenvironment around the bacteria
141
 Drug treatment of PUD & GERD

H. pylori Eradication
 >85% PUD caused by H. pylori
Combination antibiotic therapy
 Bismuth - Disrupts bacterial cell wall
 Clarithromycin - Inhibits protein synthesis
 Amoxicillin - Disrupts cell wall
 Tetracycline - Inhibits protein synthesis
 Metronidazole - Used often due to bacterial resistance to
amoxicillin and tetracycline, or due to intolerance

Triple Therapy - 7 -14 days treatment - Effective 80-85%

Proton pump inhibitor + amoxicillin/tetracycline + metronidazone/clarithomycin
Quadruple Therapy - as efficacious as triple therapy
- Add Bismuth to triple therapy
142
 Drug treatment of PUD & GERD
Drugs against H.pylori
 Initial treatment  triple therapy for 7 to 14 days
1. Omeprazole (20mg) bid
2. Clarithromycin (500mg) bid
3. Amoxicillin (1g) bid or [Metronidazole 500 mg bid]
 Quadruple treatment for Patients who failed to respond for initial
therapy (14days).
 PPI (BID)
 Metronidazole (QID)
 Tetracycline (QID)
 Bismuth subsalicylate (QID)

143
 Drugs used for constipation
 It is infrequency passage of stool which may be due to decrease in colon
motility or difficulty in evacuation.

Causes: Lack of dietary fiber, drugs, hormonal disturbances, neurogenic

disorders & systemic illnesses
 Insufficient fluid intake
 Medications that decrease motility:
Opioids Anticholinergics
Antihistamines
Foods:
 Alcoholic beverages Refined white flour products
 Dairy products Chocolate
144
 Con’t
Laxatives: induce evacuation of solid stool
Purgatives: induce evacuation of semisolid stool
Cathartics: induce evacuation of watery stool
Drugs/agents
1. Bulk forming laxatives
2. Stool surfactants/ softeners
3. Lubricants
4. Osmotic laxatives
5. Stimulant (irritant) laxatives
145
 Con’t
1. Bulk forming laxatives
 MOA: Indigestible, hydrophilic collides  bulky,
emollient gel  distend the colon  es peristalsis
e.g Methylcellulose, polycarbophil
1. S/E: No significant side effects
se flatulence & bloating
 Useful for treatment of
 Constipation
 Obesity
 Irritable colon disease

146
 Con’t
2. Stool surfactants/ softeners
 Lower the surface tension of the stool  mixing of
aqueous & fatty substance  soft stool & easily
defecated
 Also stimulate intestinal fluid & electrolyte secretion
(possibly by ↑ mucosal cAMP) & alter intestinal
mucosal permeability
 Docusate salts (oral & enema)
– Docusate sodium & docusate calcium
– They are anionic surfactants
Enema- evacuation the bowe

147
 Con’t
3. Lubricant/emollients
• Mineral oil (liquid paraffin): mixture of aliphatic hydrocarbons
– are indigestible
– On oral administration, the oil penetrates & softens the stool
• More slippery  stool slides easily
• Unwanted effects
–  fat soluble vitamins absorption
– Aspiration pneumonia (lipid pneumonitis)

148
 Con’t
4. Osmotic laxatives
Causes the intestine to retain more water
stool fluidity
4.1. Saline laxatives
Laxatives containing magnesium cations or
phosphate anions
4.2. Non digestible sugars & alcohols
Sorbitol , mannitol, Lactulose
4.3. Polyethylene Glycol-Electrolyte Solutions

149
 Con’t
5. Stimulant (irritant laxatives)
Have direct effects on enterocytes, enteric neurons, & GI
smooth muscle
Induce bowel movement by stimulating nerve endings in
the gut
Stimulate colonic fluid & electrolyte secretion
Drugs: diphenylmethane derivatives, ricinoleic acid &
anthraquinones
a) Castor oil (from caster bean)
Potent laxatives
Hydrolyzed to ricinoleic acid  stimulate intestine
Mainly used for cleansing the colon before procedure
150
 b) Diphenylmethane derivatives

Bisacodyl, glycerine, Phenolphthalein, Sodium picosulfate

 The diphenylmethanes can damage the mucosa & initiate an
inflammatory response in the small bowel & colon
Bisacodyl: tablets or suppository
Glycerin suppositories (900mg for child & 1800mg for adult)
c) Anthraquinonoid derivatives
 Aloe, cascara, Sena (found naturally in plants)
 Non-absorbable
 Can be administered orally or rectally
 Brown pigmentation of the colon (melanosis coli)

151
Diarrhea
 It is " too rapid evacuation of too fluid stools."
 It is roughly defined as greater than 250mg/day stool production
containing 70-95% water
 Since stool weight is largely determined by stool water, most
cases of diarrheal result from disorders of intestinal water &
electrolyte transport.
↑ed osmotic load within the intestine
Excessive secretion of electrolytes & water into the
intestinal lumen
Exudation of protein & fluid from the mucosa
Altered intestinal motility resulting in rapid transit (& ↓ed
fluid absorption)
 Severe diarrheal  dehydration & electrolyte imbalances
152
 Drugs Causing Diarrhea
 Laxatives  Cholinergics
 Antacids containing magnesium
 Bethanechol
 Antineoplastics
 Neostigmine
 Auranofin (gold salt)
 Antibiotics  Cardiac agents
– Clindamycin  Quinidine
– Tetracyclines  Digitalis
– Sulfonamides  Digoxin
– Any broad-spectrum antibiotic
 NSIDs
 Antihypertensives
– Reserpine  Prostaglandins
– Guanethidine  Colchicine
– Methyldopa
– Guanabenz
– Guanadrel

153
Treatment of diarrhea
1.Correction of fluid & electrolyte disturbance
 ORS
 IV preparations (if it is sever)
2.Anti infective
3.Adsorbents
4.Stimulation of intestinal opiate receptors
Each ORS sachet (powder) contains
Sodium chloride …………………… 3.5gm/lit
Trisodium citrate Dihydrate ……… 2.9gm/lit
Potassium chloride ………………… 1.5gm/lit
Glucose …………………………….20.0gm/lit
154
 ANTIDIARRHEAL AGENTS

Opioid agonists
Colloidal bismuth cpds
Kaolin & pectin
Bile salt–binding resins
Octreotide

155
 Con’t
Opioid agonists
Effects mediated through  - or -opioid receptors on enteric
nerves, epithelial cells & muscle
Effects on intestinal motility ( receptors), intestinal
secretion ( receptors), or absorption ( &  receptors)
Commonly used: loperamide, diphenoxylate & difenoxin
Act principally via peripheral -opioid receptors & are
preferred over opioids that penetrate the CNS
 Loperamide: as adjunct in almost all forms of chronic diarrheal disease

156
 Colloidal bismuth cpds
 Bismuth subsalicylate reduces stool frequency & liquidity in acute
infectious diarrhea
 This is due to salicylate inhibitory effect of intestinal prostaglandin action
& chloride secretion
 Bismuth has direct antimicrobial effects & binds enterotoxins (useful for
traveler's diarrhea)

Kaolin & pectin

 kaolin  naturally occurring hydrated magnesium aluminum silicate
(attapulgite)
 pectin  indigestible carbohydrate derived from apples.
 Both act as absorbents of bacteria, toxins & fluid
 ↓ stool liquidity and number
They may be useful in acute diarrhea but are seldom used on a chronic basis .

157
 Bile salt binding resins
 Conjugated bile salts are normally absorbed in the terminal ileum.
 Disease of the terminal ileum (eg, Crohn's disease) or surgical
resection  malabsorption of bile salts  colonic secretary
diarrhea.
 Bile salt binding resins may ↓ diarrhea caused by excess fecal bile
acids and bulking agents.
Drugs: Cholestyramine, Cholesterol
Adverse effects
 Bloating
 Flatulence
 constipation, fecal impaction
 Fat malabsorption ( in patient with diminished circulating
bile acid pools)
158
 Antiemetic's
 Vomiting is regulated centrally by the vomiting center
& the chemoreceptor trigger zone (CTZ)
-Both of which lie in the medulla
 The CTZ is sensitive to chemical stimuli & is the
main site of action of many emetic & antiemetic
drugs.
 The BBB in the neighborhoods of the CTZ is
relatively permeable
 The CTZ also regulates motion sickness (condition
caused by conflicting spatial signals arising from the
vestibular apparatus & the eye

159
 Con’t
Nausea: inclination to vomit
Vomiting: the ejection/expulsion of gastric content through
the mouth
 N & V are protective reflexes that prevent further
absorption from the GIT
 Causes of N & V
 Adverse effects of drugs
 Systemic disorder/infection
 Pregnancy
 Vestibular dysfunction
 Radiation / chemotherapy
 GI obstruction
160
The main neurotransmitters involved in
the control of vomiting
1. Histamine (H1 receptors)
2. Anticholinergics (M receptor)
3. Serotonin (5-HT3 receptor)
4. Dopamine (D2 receptor)
Drugs used for treatment of N & V
 Antihistamine (H1 blockers)
 Anti cholinergics
 Serotonine /5-HT3 receptor antagonists
 Neuroleptics (D2 blockers)
 Prokinetic drugs
 Adjuvant antiemetic's: Cannabinoids
161
 Anticholinergics
Drugs: scopolamine (hyoscine) oral or i.m.
Clinical use: In the prevention & treatment of
motion sickness; however, it has brief duration
of action
Adverse effects: sedation, dizziness, confusion,
dry mouth, urinary retention and other
anticholinergic side effects

162
 Antiemetics

Antihistamine (H1blockers)
Promethazine, diphenhydramine & dimenhydrinate
• Cyclizine & meclizine (less sedating & anticholinergic effect)
MoA: H1 histamine receptor antagonists
Clinical use
Mainly for treatment & prevention of motion sickness
To lesser extent in morning sickness & postoperative emesis
Adverse effects:
 Sedation, anti-muscarenic effects
 Nevertheless
 Excitation and convulsions in children, postural hypotension,
and allergic responses.
 The antihistaminic-anticholinergic antiemetics are the 1st drug of
choice for motion sickness
– Dopamine & 5HT3 antagonists are less effective
163
 Serotonin /5-HT3 receptor antagonists
Drugs: Ondansetron, Tropisetron & Dolasetron
MoA: Potent & selective 5-HT3 receptor antagonists
(on peripheral vagal nerve terminals & centrally in the CTZ)
 During chemotherapy that induces vomiting, mucosal enter
chromaffin cells in the GIT release serotonin, which stimulates 5-
HT3 receptors.
 This causes vagal afferent discharge, inducing vomiting
Clinical use:
 They are the most widely used drugs for chemotherapy induced
emesis and used to prevent / treat post-operative N & V
Adverse Effects: Headache ,dizziness and constipation
164
 Prokinetic drugs

• Metoclorpramide
• Domiperidone
• Cisapride
• Mosapride
• Tegaserod

165
 Metoclopramide
 ‘Gastric hurrying’ agent
Pharmacological effects +
 GIT
– ↑gastric peristalsis while relaxing the pylorus & 1st part of
duodenum → speeds gastric emptying
 CNS
– Effective antemetic acting on CTZ
– Blocks apomorphine induced vomiting
-Gastrokinetic action may contribute to antiemetic effect but it
does not have chlorpromazine like neuroleptic action.
MoA: dopaminergic & serotogenic antagonism
166
 Con’t
Clinical uses
 Antemetic
 Gastrokinetic: to facilitate gastric emptying
– For emergency general anesthesia (if the patient has taken food
with in 4hrs)
– To facilitate duodenal intubations
 Dyspepsia
Adverse effects
 GERD The drug is generally well tolerated
Sedation, dizziness, loose stool
Long term use may cause
parkinsonism, galactorrhea &
gynecomastia
167
 Con’t
• NB. It should not be used to augment lactation though the
amount of milk is small as the baby may develop loose
motion, & other adverse effect
Adjuvant antiemetic
 Corticosteroids (Dexamethasone)- augment the
efficacy of other primary antiemtics (Metoclopramide
& ondasetron) for highly emetogenic regimens & for
cisplatin induced delayed emesis
 Benzodiazepines (Diazepam or lorazepam )- Used as
adjuvant to metoclopramide
 Cannabinoids (Dronabinol) -Synergistic action with
phenothiazine
 Read about pharmacology of IBD??????
168
Thank

You
169