1. Ipratropium2. Antiallergic ttt

Lecture 3

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Ipratropium bromideInhalation anticholinergic drug given as aerosol.

The 2nd choice bronchodilator after sympathomimetics.

Mechanism:

Muscarinic (M3) antagonist, decreasing IP3 & free Ca++→:

1. Bronchodilatation.

Attenuation of bronchial circadian rhythm.

↑nocturnal vagal stimulation is important in bronchial asthma.

2. ↓bronchial mucous secretions. They may become more viscid.

Beneficial in bronchorrhea.

3. ↑mucociliary clearance.

Advantages:

1. Higher potency & less systemic adverse effects than atropine

due to specific M3 blocking (pharmacodynamic) & inhalation route (pharmacokinetic).

2. Longer duration than β2 agonists. Used twice daily.

3. May be combined with β2 agonists in acute attacks (→potentiation).

4. May be combined with inhaled steroids in acute attacks (→potentiation).

Disadvantages:

1. Used as monotherapy for prophylaxis (mild action & delayed onset).

2. Antimuscarinic effects as dryness of mouth may occur.

3. Tolerance: blocks M2 autoreceptors →↑ Ach release.

Tiotropium (once daily) is similar to ipratropium, but:

1. Has longer duration due to slow dissociation from M3 receptors.

2. Less tolerance: M2 antagonism is insignificant due to rapid dissociation.

Mast cell stabilizers

3) Ketotifen

Mechanism:

1. Stabilizes eosinophil, basophil & neutrophil cell membrane beside mast cell , inhibiting release of allergic mediators specially SRS-A.

2. Anticholinergic, antihistaminic and antiserotonin.

Advantages:

1. Long duration.

2. Oral.

3. Potent in children. Used more commonly in children.

Disadvantages:

1. Sedation(antihistaminic).

2. Dryness of mouth (anticholinergic).

Dose: 1mg orally twice daily for several weeks.

Leukotriene inhibitors

Less effective than steroids (act only on leukotrienes).

A) Leukotriene (LTD4 receptor) antagonists

Mechanism:

Leukotriene (LTD4 receptor) antagonist. They inhibit spasmogenic effect of leukotrienes and reduces allergic responses.

Uses: moderate bronchial asthma caused by allergy, exercise, cold exposure & aspirin – induced asthma.

For maintenance and prophylaxis.

1 . MontelukastMechanism & uses:…………

Very commonly used.

Of top ten selling drugs in pediatrics (country….year…).

Given once daily in the evening.

Adverse effects:

1. Increase liver enzymes.

2. Dyspepsia & headache.

3. Neuropsychiatric disorders as sleep disorders, aggressive behavior

& suicidal tendency.

2. Zafirlukast

Used orally twice daily away from meals.

Adverse effects:

As montelukast +:

1. Enzyme inhibitor.

2. Decrease absorption by food.

B) Lipoxygenase inhibitors

Zileuton: inhibits lipoxygenase →↓leukotriene synthesis.

Given orally, 4 times daily.

Adverse effects are similar to zafirlukast.

OmalizumabMechanism:

A monoclonal antibody which binds to IgE receptors.

It affects early and late allergic & inflammatory phases responses.

Uses:

Severe resistant (even to large dose of steroids) cases with inadequate control.

Given by SC injection every 2 – 4 weeks.

Disadvantages:

1. Expensive.

2. Hypersensitivity reactions as anaphylaxis.

3. Upper respiratory tract infection.

Recently, anti- IL-5 therapy.

Glucocorticoids

Mechanism:

1. antiinflammatory: reduce airway edema & obstruction by ↓capillary permeability. They ↓transcription of genes coding for many pro-inflammatory and other proteins e.g. cytokines, phospholipase A2 & COX. Also they cause apoptosis of some inflammatory cells.

2. Inhibition of phospholipase A2 decreases leukotrienes & PGs.

3.↑ cAMP decreases histamine release.

4. Destruction of antigens (proteins) (catabolic).

5. Inhibition of antigen antibody reactions.

6. Immunosuppressant: decrease antibodies and cytokines by reduction of B & T lymphocytes respectively.

7.↑ Epinephrine synthesis.

GlucocorticoidsLecture 4

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Uses

A) Chronic bronchial asthma.

Inhalation steroids (preferred to minimize systemic adverse effects) may be used as monotherapy.

They may be also combined (for some period) with inhalation selective β2 agonists to increase β2 receptors number and sensitivity. They also increase transcription of genes coding for β2 receptors and some anti-inflammatory proteins. So they antagonize tolerance and down regulation of β receptors produced by β2 agonists.

Also may be combined with ipratropium bromide or tiotropium.

Triple therapy of inhalation steroids, long acting β2 agonists + tiotropium is commonly used.

Inhalation steroids are now the preferred therapy for all forms of persistent asthma in all age groups. More effective than bronchodilators.

In morning & nocturnal asthma they reduce bronchial circadian rhythm.

For prevention, inhalation steroids are most effective when given in late afternoon. More effective when given twice daily than once daily.

They have flat dose - response curve. So small doses are preferred.

Adequate response onset is 12 hours, significant clinical response after 2 weeks. Full effect takes longer periods.

Response variations due to gene variant.

Systemic steroids are used for 3-10 days, with no tapering of doses. Usually avoided as long - term controller.

B) Status asthmatics & severe asthma. Parenteral preparations are used.

Adverse effects

12. Inhalation steroids cause:

a. Oropharyngeal candidiasis (fungal infection) due to immunosuppression. This is minimized by mouth wash after inhalation.

b. Cough.

c. Hoarseness of voice.

d. Large dose → systemic adverse effects.

Systemic adverse effects:

1. Cushing syndrome. Adrenal suppression on withdrawal.

2. Immunosuppression , infections.

3. Hyperglycemia.

4. Edema, hypokalemia & hypertension.

5. Osteoporosis.

6. Peptic ulcer.

PreparationsA) Inhalation: to decrease systemic toxicity.

1. Beclomethasone.

2. Budesonide.

3. Fluticasone. Of top ten selling drugs in pediatrics.

4. Mometasone.

5. Ciclesonide is prodrug, inhaled steroid, activated in bronchial epithelial cells,

passes to circulation where it is tightly bound to serum proteins →↓systemic effects.

Less frequent candidiasis.

B) Parenteral:

1. Dexamethasone.

2. Hydrocortisone Na hemisuccinate.

C) Oral:

1. Betamethasone.

2. Dexamethasone.

3. Prednisolone.

Prophylactic therapy in asthmaBy controllers (preventers);

1. Long acting bronchodilators as selective β2 agonists (e.g. salmeterol), ipratropium, tiotropium & theophylline.

2. Mast cell stabilizers.

3. Leukotriene inhibitors.

4. Inhaled steroids.

5. Omalizumab.

6. Antimicrobials: Used only occasionally and in selected cases.

Mainly macrolides which are effective against chlamydia & mycoplasma responsible for most bronchial infections.

Treatment of status asthmaticus

1. Hospitalization.

2. Correction of water, electrolyte & acid base balance.

3. Hydrocortisone Na hemisuccinate by IV infusion 100mg.

4. Aminophylline (IV slowly).

5. If no response a short acting selective ß2 agonist is added.

6. Supportive drugs. e.g. O2, antimicrobials, expectorants….

Bronchodilators in hypertensives1. Selective β2 agonists.

2. Celiprolol. Β1 antagonist & partial β2 agonist.

3. Ipratropium bromide & tiotropium.

4. Theophylline.

5. Ca++ channel blockers.

They decrease Ca++ influx in bronchial muscles→ bronchodilatation.

They also decrease release of allergic mediators (Ca++ dependent).

In pregnancy safest: inhaled budesonide & salbutamol.

Top 10 selling drugs in pediatrics

(in country…year….)

1. Antibiotics: amoxicillin (or +...), azithromycin & cephalosporins.

2. Salbutamol.

3. Montelukast.

4. Corticosteroids: mometasone, fluticasone.

5. Paracetamol & ibuprofen.

Factors ↑asthma

1. Comorbidity by allergic rhinitis & sinusitis.

2. Upper respiratory tract infection.

3. Obesity.

4. GERD.

Precautions

1. Avoid allergens.......

2. For exercise - induced asthma: warming up before exercise and covering mouth & nose during cold weather. Montelukast is used. Pretreatment with salbutamol 5 minutes before exercise.

3. Yearly influenza vaccination and pneumococcal vaccination (once before & once after age of 65 years).

4. Avoid drugs.....

5. Use selective β blockers in lowest effective dose.

6. Paracetamol < 1gm instead of NSAIDs.

CoughLecture 5

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Coughi.e. forcible expulsion of foreign body or gas out of respiratory tract.

A protective reflex to get rid of ... microbes, allergens, … more nocturnal.

A universal symptom of many important diseases.

Center : cough center, above RC.

Afferents: vagal, with central synapses via NMDA receptors fromrespiratory tract (mechanoreceptors above and chemoreceptors below),heart, stomach & ear.

Efferents: via phrenic & intercostal nerves to diaphragm & intercostal muscles.

Types of cough

Dry cough: useless and harmful (treated by antitussives).

Productive cough: useful cough (treated by expectorants & mucolytics).

Chronic cough (> 3 weeks): e.g. postnasal drip, asthma or GERD.

A)Treatment

Antitussives are used when cough is unproductive, distressing, painful, exhausting, increasing airway damage or causing morbidity as:

a. Sleep disturbances.

b. Chest pain.

c. Hernia.

d. Urinary incontinence.

e. Neuropsychiatric disorders.

Expectorants are used to get rid of excessive thick bronchial secretions

B)Adjuvants (new antitussive approach)Have some antitussive activity and also specific action in treatment of cough in different clinical diseases.

1)Upper respiratory tract infection (URTI) & common cold.

ttt. Lecture 6.

2)Upper airway syndrome (postnasal drip syndrome). Chronic, mainly sinusitis.

ttt. antihistaminics (1st generation due to multiple receptor block) & decongestants (α1 agonists).

3)Bronchial asthma & COPD.

Selective β2 agonists, M3 antagonists & theophylline: ↑ mucociliarytransport.

Inhaled steroids: anti-inflammatory.

4)Allergic : Anihistaminics & inhaled steroids.

5)GERD : proton pump inhibitors (PPIs) & H2 antagonists.

Antitussives

Central : ↓ cough c. Peripheral

A) Opioids

Narcotic Non-narcotic

(mild addictive)

1. Codeine 1. Dextromethorphan.

2. Dihydrocodiene 2. Propoxyphen.

more potent . 3. Noscapine.

B) Non opioids:

1) Carbetapentane.

2) Benzonatate.

3) Caramiphen (also bronchodialtor).

1- Cabetapentane:

local anesthetic &

atropine like .

2- Benzonatate: local

anesthetic, blocks

stretch receptor in

pulmonary alveoli

preventing afferent

stimuli stimuli for

cough reflex .

3- Dimulcents :

increase mucous

secretion forming a

Mild addictive opioid antitussivesAdvantages:

1. Potent cough center depressant.

2. Mild analgesic.

Disadvantages:

1. Mild narcotic addictive.

2. Constipation.

3. ↓ciliary activity.

Non addictive opioid antitussives Preferred:

1.Potent cough center depressant.

2. Less sedation & addiction.

3. Less constipation.

New antitussivesCough receptors stimulation increases glutamate release

in nucleus tractus solitarius leading to NMDA receptors stimulation.

This is potentiated by neurokinins.

1) NMDA antagonists. e.g. memantine.

2) Neurokinin antagonists.

3) GABA receptor agonists.

4) Leukotriene receptor antagonists.

5) Local anesthetics as inhaled lidocaine.

1 – 3 are central. 4 & 5 are peripheral.

Expectorantsi.e. drugs liquefying sputum (bronchial secretion) by ↓ viscosity &

↑ volume causing its expulsion out by cough reflex easily.

Used in bronchitis, bronchial asthma & emphysema.

A) Aromatic (stimulant) expectorants:

Mechanism:

1. Stimulation of bronchial mucus glands →↑ sputum volume (directly).

2. Stimulate repair & healing of destroyed epithelium in respiratory tract. 3. Antiseptic. 4. Deodorant.

Volatile oils as menthol, tr. tolu. & benzoin by inhalation via water vapor.

B) Na & K acetate or citrate, tr. ipecac & ammonium chloride or carbonate.

Mechanism: reflex stimulation of bronchial mucus glands (by irritation of gastric mucosa).

C) K iodide:Mechanism:

1. Excretion via bronchial gland → direct stimulation.

2. Irritate gastric mucosa → reflex stimulation of bronchial glands.

3.↑ Proteolytic activity of enzymes in sputum (mucolytic).

Adverse effects:

1. Bronchospasm (respiratory tract irritation).

2. Spread of TB (dissolves fibrous tissue).

3. GIT irritation.

4. Iodism: rhinorrhea, lacrimation, salivation &↑bronchial secretions.

5. Hypothyroidism.

6. Allergy.

Contraindications:1. Acute bronchitis (↑↑ bronchial secretions).

2. Bronchial asthma. 3. TB bronchitis.

4. Hypothyroidism. 5. Allergy.

Mucolyticsi.e. drugs which break mucus & ↓ sputum viscosity usually without affecting its volume.

Uses are similar to those of expectorants but in cases with thick sputum.

(1) Bromhexine:

Mechanism:

Depolymerization of mucopolysaccharides reducing sputum viscosity.

Adverse effects: mild GIT irritation.

(2) Carbocysteine:

Mechanism:

1. It breaks disulfide bonds of thick mucus reducing viscosity.

2. ↓ mucus glands hyperplasia & ↓ sputum volume .

3. It protects mucus membrane against infection.

(3) Acetyl cysteine:

Mechanism:

Disrupts disulfide bonds in thick sputum → ↓ viscosity.

Uses:

1. As mucolytic: oral & by inhalation.

2. Paracetamol toxicity (→ SH to liver).

Adverse effects :

1. Bronchospasm if by inhalation.

2. GIT irritation if oral.

3. Inactivates penicillin.

4. Allergy.

URTILecture 6

Prof Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Upper respiratory tract infection

(URTI)

i.e. Pharyngitis & tonsilitis, sinusitis and otitis media.

Also, laryngitis, tracheitis & bronchitis.

Aetiology

Mainly by respiratory viruses; 90%, 98% & 50% in pharyngitis &

tonsilitis, sinusitis and otitis media respectively.

Self-limited, without antibiotics within 7 days (85%), 14 days (80%) and

24 hours (60%) respectively.

Antibiotic ttt usually causes repeated attacks in the future.

Delayed antimicrobial therapy decreases suppurative complications as

immediate therapy.

Manifestations of viral URTI↑ number of:

1.Scratchy or sore throat & painful swelling.

2.Nasal congestion, rhinorrhea & sneezing, sinus pain &

tenderness.

3.Conjunctivitis: congestion, redness & lacrimation.

4.In lower part of URT: Cough (dry or mucus productive),

hoarseness of voice.

5. Fever, headache, body (myalgia, arthralgia) aches,

malaise ,..

1 – 4: local. 5: systemic.

Treatment of viral URTI

1. Rest in moist warm air, warm fluids, salt water gargle &

saline nasal drops.

2. Paracetamol; for systemic manifestations (…….).

3. Antihistaminics: decrease congestion & secretions,

adjuvant antitussive. Also sedative.

4.Decongestants: as pseudoephedrine (↑BP & HR) & α1

agonists (↑BP) orally & nasally for short period except in

CV diseases.

5. Antitussives, expectorants & honey (in warm water).

Bacterial URTIa. +ve cocci : str. pyogenes, str. pneumonia & staph. aureus.b. -ve bacillii: H influenza.

ManifestationsRapid onset , localized , severe & getting worse.

1. Less number of (1 – 4) & most are mild except one of them.2. Impaired swallowing, severely inflamed tonsils with exudate, swollen tender anterior

cervical lymph nodes.3. Purulent nasal discharge or facial pain > 3 days.4. Ear pain.5. Productive cough….mucopurulent…6. Dyspnea.7. Systemic:……..

Clinical scoreBy increase number of these:a. No antibiotics (least number).b. 2 days delayed antibiotics.c. Immediate antibiotics.

Treatment of bacterial URTI

Pharyngitis, tonsilitis

Amoxicillin 500 mg/ 8 hours (or + clavulanic acid) or (before meals)

phenoxymethyl penicillin for 7-10 days (2 days after clinical cure).

In penicillin allergy:

A) Mild allergy : cephalosporins.

B) Severe allergy: macrolides.

1.Clarithromycin : 250 - 500 mg/ 12 hours for 7-10 days.

2. Azithromycin : 500 mg /day for 3 days.

3. In children : erythromycin for 5 days.

4. In pregnancy : erythromycin 250 - 500 mg/ 6 hours for 5 days.

Otitis media

Similar to pharyngitis and clavulanic acid is added.

Therapy duration ?

Acute sinusitis

1st line: amoxicillin for 7-10 days.

Doxycycline (for sinuses penetration) and

clindamycin (against anerobes) are commonly used.

Intensive care in suspected complications as sepsis, intracranial

or intraorbital.

Chronic bacterial sinusitis

Similar, but for 14 days and clavulanic acid is added.

Community acquired Pneumoniaa. +ve cocci: str. pneumonia, str. py.& staph. aureus.b. -ve bacillii: legionella & H influenza. c. Mycoplasma & Chlamydia.d. Anerobic bacteria.e. Fungi (in low immunity).

ttt.

1. Macrolides ( & new classes).

2. Penicillins combinations.

3. Cephalosporins.

1-3 for a.

4. Fluoroquinolones. For b.

5. Doxycycline. For c.

6. Anerobic infection ttt. for d.

7. Antifungal ttt. for e.

Empiric ttt with broad spectrum antibiotics is started, after culture ttt is

continued by narrow spectrum antimicrobials according to pathogens.

Nosocomial pneumoniaa. - ve bacilli ; Enterobacteriacease ( E coli, proteus, enterobacter &

citrobacter) and pseudomonus. b. MRSA ,VRSA & staph. aureus.c. Bacteroides (anerobic infection).

Treatment

Gram –ve bacteria1. Extended spectrum & Penicillinase resistant penicillins.2. Cephalosporins (3rd generation injections).3. Fluroquinolones.4. Carbapenems. IV or IM.5. New classes similar to macrolidesa. Streptogramins: By IV infusion.b. Linezolid : oral & IV.

Anerobic infection 1. Clindamycin. 2. Some cephalosporins. 3. Carbapenems IV or IM.

TBLecture 7

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

TBWe give combinations between 3 drugs in 1st 3 months and then 2 drugs

to be changed every 2 months for 1 year? to:

1. ↓ resistance.

2. ↑anti TB potency.

3. ↓dose of each.

4. ↓toxicity.

First Line Drugs

1) INH (isoniazid)

Mechanism

Antimetabolite. ↓synthesis of mycolic acid & phospholipid of TB wall.

Tuberculocidal.

Spectrum: TB only.

Potent and is given in most combinations.

Pharmacokinetics

Lipophilic.

1- Regularly absorbed orally, so given orally.

2- Passes BBB. So effective in TB meningitis &…...

3- Metabolized in liver, so may be toxic to liver.

Hepatic CL, dose & t1/2 are affected by liver function.

4- Excreted changed by kidney, so not toxic to kidney.

Uses

All types of TB including, open, closed, fibrous, caseous, TB meningitis and TB affecting serous cavities as pleura & peritoneum. It affects intra & extracellular bacilli.

Also prophylactic.

Adverse effects1.Pharmacogenetic defect:

In slow acetylators there is ↓metabolism→↑ INH which competes with

pyridoxine (B6) & ↓GABA synthesis→ polyneuropathy & CNS stimulation.

Treatment: pyridoxine 100 mg.

2. Liver damage in rapid acetylators.

3. Bone marrow depression.

4. CNS symptoms

5. Enzyme inhibition.

6. Hemolytic anemia.

7. Hypersensitivity reactions.

8. Resistance.

Dose: Tablets 300 mg once daily

or 900 mg twice weekly.

2) RifampinMechanism

Transcription inhibitor, inhibits DNA - dependent RNA polymerase

→↓m RNA synthesis.

Pharmacokinetics

Lipophilic : similar to isoniazid………..

Excreted mainly in bile (enterohepatic circulation).

Spectrum

Broad spectrum (Page …).

+ TB, leprosy & viruses.

Uses

1. All types of TB including …. (as INH).

2. Meningitis (miningococcal + H. influenza), also for carrier.

Not preferred in other infections to avoid resistance

Adverse effects

1.Liver damage.

2.Bone marrow depression.

3.Enzyme induction.

4.Red urine & sweat (by its metabolites).

5.Superinfection.

6.Avitaminosis B & K.

7.Hypersensitivity reactions.

8.Flu: influenza - like manifestations by large dose.

*Resistance develops rapidly by mutation.

Dose: Tablets 600mg / day on morning

or twice weekly in short course (6 months).

3) EthambutolMechanism:

↓ cell wall synthesis in TB by ↓ polymerization of arabinoglycan.

Also ↓transfer of mycolic acid into cell wall.

Disruption of cell barrier → penetration of lipophilic drugs.

Tuberculostatic.

Pharmacokinetics:

Lipophilic (…….), but renal clearance.

Uses: an additive drug to delay resistance.

Adverse effects:

Optic nerve damage (retrobulbar neuritis).

Resistance by mutation.

Dose: 15mg /kg, once daily.

4) PyrazinamideTuberculocidal.

Pharmacokinetics:

Lipophilic.

Uses:

Combined with INH & rifampin to reduce resistance.

Adverse effects:

1. Hepatotoxicity.

2. GIT upset.

3. Gout.

4. Fever.

Second Line DrugsUsed in combination with one of 1st line drugs if resistanceor toxicity develops.

1.Streptomycin:Mechanism: Binds to 30s ribosomal subunit → misreading of genetic code → altered protein synthesis. Bactericidal but Tuberculostatic.

Spectrum: Mainly T.B + Gram –ve bacilli. Also +ve cocci.

Pharmacokinetics: Lipophobic. Not absorbed orally (give IM). Ineffective in meningitis, not metabolized in liver, renal clearance (excreted unchanged by kidney). No hepatotoxicity, dose is not affected by liver dysfunction.

Adverse effects: ototoxicity & nephrotoxicity.

Uses: TB open type & extracellular bacilli. Also renal & urinary tract TB (excreted unchanged).

2. Ethionamide:

Adverse effects:

1.GIT upset.

2.Neurological (ttt by vitamin B6).

3.Hepatotoxicity.

3. Aminoglycosides as capreomycim.

4. Cycloserine:

Adverse effects:

CNS toxicity in 25%, so + pyridoxine.

5. Fluroquinolones:

Ciprofloxacin 750mg/12hours.

Levofloxacin 500 mg/day.

Moxifloxacin (preferred).

6. Rifampin analogs :

Rifabutin & rifapentine.

AntihistaminicsLecture 8

Professor Ahmed Shaaban

Professor of Pharmacology &

Senior Consultant of Endocrinology

Histamine1)Actions mediated via H1 receptors

A) Storage in mast cells, basophils &… → allergy & inflammation.

Gq - linked:

1. Smooth muscle contraction e.g. bronchi & intestine.

2. VD (via EDRF).

3. Increase secretions.

B) Chemical transmitter in CNS & NANC.

1.CNS stimulation & vomiting.

2. Neuroendocrine control.

3. CVS regulation.

4. Pain.

5. Role in mood, arousal, body weight & temperature regulation.

2) Via H2 receptorsGs – linked.

1.↑Hcl secretion.

2. Mild allergic.

3. CNS: Neuroendocrine control.

3) H3 receptorsMay be involved in ttt of sleep disorders, obesity & psychiatric disorders.

How to antagonize histamine actions?

• a. In severe anaphylaxis :

1. Epinephrine : physiological antagonist to histamine.

2. Glucocorticoids : potent antiallergic & antiinflammatory.

b. In mild allergy: antihistaminics. Competitive H1

antagonists.

c. Prophylaxis: mast cell stabilizers as cromolyn sodium,

nedocromil & ketotifen.

• d. H2 antagonists: ↓Hcl secretion and also ↓allergic

reactions.

Antihistaminics (H1 antagonists)1st generation

Lipophilic.

PharmacodynamicsCompetitive antagonists to H1 receptors. Some new preparations are also inverse H1 agonists.Block H1, M1, M3, α1 & 5-HT2 receptors (Gq- linked) & Na+ channels →:1. Antiallergic (H1).2. Sedation (H1).3. Antiemetic (H1).4. Atropine –like (M3 & M1).5. Antiparkinsonism (M1).6. α1 blocker → e.g. hypotension.7. 5- HT blocker.8. Local anesthetic (block neuronal Na+ channels).9. Antiarrhythmic (block cardiac Na+ channels).

Adverse effects1. Sedation (H1). Drowsiness & dizziness are more common in old patients.

Also impairment of cognitive & motor function.

2. Dry mouth & retention of urine (M3, atropine- like).

3. Postural hypotension (α1 blocker).

4. Excitation in children (H1).

5. Paradoxically, excitation in adults (H1).

6.Topically (& also orally) may → allergy (H1).

7. Cardiotoxicity by quinidine (↓) & atropine – like (↑) adverse effects.

8. Hepatotoxicity: more by 1st generation.

Contraindications1.Prostatic hypertrophy (atropine -like).

2.Glaucoma (atropine -like).

3.Liver diseases (lipophilic).

4.Epilepsy ?.

Preparations

1st generation

Lipophilic. Crosses BBB.

e.g. cyproheptadine, chlorpheniramine, diphenhydramine.

2nd generation

1. Lipophobic. Does not pass BBB.

2. More specific H1 antagonist.

3. Less autonomic effects.

4. More potent.

5. Used mainly in allergy.

6. Less sedative.

7. Longer duration.

8. Cardiotoxicity. Specially when combined with enzyme inhibitors.

e.g. loratadine & cetirizine.

3rd generation

Less likely to pass BBB.

Active metabolites of 2nd generation drugs without cardiotoxicity.

e.g.

1.Fexofenadine: metabolite of terfenadine.

2.Desloratadine.

UsesUsually for short term therapy.

1.Allergy as rhinitis (congestion, sneezing, rhinorrhea), conjunctivitis

(itchy or watery eyes) & urticaria.

Commonly used in URT congestion, allergy, common cold, influenza…By:

a. ↓congestion. b. ↓secretions. c. antitussive. d.↑sleep hours.

e. Chronic allergy increases URTI risk (viral → bacterial).

Ineffective in asthma because several mediators are involved &….

2. Motion sickness, vomiting of pregnancy, vestibular disturbances

as vertigo and Meniere,s syndrome.

3. Parkinsonism.

4. Insomnia (OTC drug).

H2 antagonists1.Ranitidine. 2. Famotidine.

Mechanism1. H2 receptors are linked via Gs proteins to adenyl cyclase .

H2 antagonists are reversible competitive H2 blockers leading to decrease

intracellular cAMP particularly in parietal cells.

2 -H pylori suppression by ranitidine.

Famotidine is more potent than ranitidine, but ranitidine has higher efficacy due

to H pylori suppression .

USES

1- DU :

2- GU :

3- GERD:

4- Functional dyspepsia.

5- Upper GIT bleeding .