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Autacoids and autacoid antagonists Histamine ,prostaglandins & serotonin are called autacoids.

Autacoid come from greek: autos(self) & akos(medicinal agent or remedy). They are defined as local hormone i.e. they are released from tissues upon which they act. They differ from hormone in that they are produced by many tissues rather than specific endocrine glands.(autacoids produced byselfs & they act locally) -Histamine Synthesis: it is synthesized from amino acid histidine. * It present with high amounts in lungs, skin, GIT (sites where inside meet the out side). It present in concentration in mast cells & basophilis.

-These mast cells are especially rich at sites of potential tissue injury i.e. skin, lungs, liver, GIT etc (on site where we have contact b/t external & internal compartment) -In mast cells and basophils, histamine is complexed in intracellular granules with acidic protein. *Release: is it may be primarily in response to some stimuli as a mediator of inflammation & allergic reactions.

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-Stimuli causing histamine release include destruction of cells as a result of cold, bacterial toxins, bee sting venoms or trauma. "why we see redness on our hands when we scratch it?" Ans:due to histamine release on the skin Release of histamine occurs through: A- Immunologic reactions: (antigen-antibody reaction) The mast cells and basophiles, which are previously sensitized by exposure to the antigen, contain antibodies (IgE) attached to their surface membranes. Re-exposure to the antigen results in antigen-antibody reaction on the walls of these cells. Influx of calcium ions and Degranulation of the mast cells and basophiles and release of histamine by exocytosis. *if an asthmatic patient expose to allergen (cat) this allergen will bind to IgE antibody & stimulate the release of histamine from mast cell & on asthmatic patient this will produce asthmatic attach as immunological response -Histamine is released from mast cells during an allergic response Receptor-induced exocytosis triggered by: -Antigen binding to cell-bound IgE ( immediate or type I hypersensitivity)

If the release is localized to respiratory passages it may result in bronchoconstriction. If localized to the skin it results in itching, urticaria(redness & swelling).

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But if generalized release of histamine it may result in anaphylactic shockcharacterize by: -bronchconstriction -angioedema -vasodilatation reflex tachycardia B- Non-immunologic activation: It is IgE-independent Activation may occur by: 1-Drugs: morphine, d-tubocurarine. 2-Mechanical: cold air, exercise, and mechanical injury of mast cells. Allergies & anaphylaxis trigger histamine release. Its also plays an important physiological role in control gastric acid secretion & as neurotransmitter. Histamine is metabolised by histaminase &/or by methylating enzyme imidazole N-methyltransferase
Histamine is metabolized by methylation and oxidation and secreted in the urine
CH2CH2NH2

HN

N CH2CH2NH2
CH3N N

Histamine

N-Methylhistamine
CH2COOH

CH3N

N-Methylimidazole Acetic Acid

Mechanism of action of histamine: It acts on specific receptors * H1-receptors occurs at postsynaptic sites: -Smooth muscle - Exocrine glands - Brain - Endothelium * H2-receptors occurs at postsynaptic sites: -Gastric mucosa(on parietal cell which secrete gastric acied) - Heart, Mast cells * H3-receptors occurs at prestsynaptic sites:
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-Nerve endings & - Brain, inhibit the release of neurotransmitters(autoregulatory effect) . Effects of histamine: 1.production of nasal & mucus secretion (H1) 2. Bronchial smooth muscle (H1) bronchoconstriction. 3. Sensory nerve endings (H1) cause itching & pain. 4. Stomach (H2) gastric acid secretion. 5. Heart (H1& H2) rate & force of contraction. 6.Arterioles (H1& H2) vasodilatation. 7. Capillaries (H1) vasodilatation & permeability result in redness, wheal formation & flare triple response. - On the skin: Intradermal injection of histamine produces a characteristic "Triple response: A) Red spot "Flush", due to V.D of small blood vessels. B) Then a localized edematous 'Wheal' due to increased capillary permeability. C) Then a red irregular Flare surrounding the wheal (due to local arteriolar dilation resulting in V.D in surrounding area). Pain sensation and itching. *important figure :
Actions of histamine

pharmacology for dentistry

The pathological role of histamine: 1.As a stimulation of gastric acid secretion (treated by H2 antagonists).
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2. As a mediator of type 1 hypersensitivity reactions(anaphylaxis) Antihistamines: They are classified into H1-blockers & H2-blockers. H1-blockers: (selective) Are absorbed from the GIT. Can also be given parenterally & topically. Most of them appear widely distributed throughout the body, but some do not penetrate the BBB(will give adverse effect if reach cns) Are most effective when use prophylactically. Most of the them are metabolized extensively in the liver. It may cross placenta. H1-blockers are divided in to first &second generation First generation H1-blockers: Are the older. Still widely used because they are effective & inexpensive. Penetration to the CNS cause sedation. Interact with other receptors producing a variety of unwanted side effects. Example: chlorpheniramine, promethazine, meclizine, diphenhydramine *elerphine : it is antihistamine which have sedation effect when taken because it penetrate BBB so it can be given to treat ansomia Second generation H1-blockers: Are specific for H1 receptors. Do not penetrate the BBB so they show less CNS toxicity. E.g. loratadine & fexofinadine show the least sedation. Other example: cetirizine. **Additional effects of H1-blockers: 1.CNS sedation, dizziness & fatigue. 2.Anticholinergic effect dry mouth, urinary retention, tachycardia 3.- blocking effect postural hypotension, reflex tachycardia. 4. Antiserotonin effect appetite

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*important figure:

-Clinical uses of H1-blockers: 1. For allergic reactions including allergic rhinitis, urticaria, insect bites. DRUGS That lack sedative or muscarinic antagonist actions( e.g. cetirizine or fexofinadine) are preferred. 2. As antiemetics for prevention of motion sickness or other causes of nausea. Muscarinic receptor antagonist actions of some antihistamines (e.g. diphenhydramine, meclizine, cyclizine) are most effective agents. *meclizine, cyclizinecure vomiting during pregnancy 3. For sedation: some H1 antagonists (e.g. promethazine, diphenhydramine) are strong sedatives & may be used for this action. The use of first generation H1 antihistamines is contraindicated in treatment of individuals working in jobs where wakefulness is critical. -Other preparations: Cyproheptedine has potent antiserotonin gain in weight. Loratidine has long duration of action once daily dosing {homework Q} "if u have an old male patient & he develop common flew u are looking to give him antihistamine..if he told u that he have prostate hyperplasia..or glaucoma..Which type of antihistamine is contraindicated??"

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S/Es: some adverse effects observed with first generation antihistamines

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-Agents that inhibit the release of histamine from mast cells: * Mast cell stabilizers -Cromolyn Sodium -Nedocromil Sodium * Inhibits antigen-induced bronchospasm and mast cell degranulation Used prophylactically to treat mild to moderate asthma With regular use reduces airway hyperreactivity H2-blockers: -These drugs produce their action by blocking histamine H2 receptors gastric acid secretion. -Example: Cimetidine, ranitidine. Question??? What are the mechanisms that can inhibit or antagonize the effects of histamine??? 1-blocking histamine receptor 2-inhibit histamine release by mast cell stabilizer 3-dr Saied that u will find it on this luc

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Pharmacology of the Respiratory Tract What is bronchial asthma? It is chronic inflammatory disorder of airways In susceptible individuals, this inflammation causes recurrent episodes of: 1.Wheezing (worse at early morning & night) 2.Breathlessness 3.Chest tightness 4.Cough *it may cause cough only -These episodes are associated with wide spread airflow obstruction that is often reversible -Airflow obstruction in asthma is due to bronchoconstriction resulting from: 1.contraction of bronchial smooth muscle 2.Inflammation of the bronchial wall 3. mucus secretion -The inflammatory changes in the airways associated with bronchial hyper-responsiveness (abnormal sensitivity to stimuli).

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-Comparison of bronchi of normal & asthmatic individuals:

*normal airway tube: normal bronchioles which enhance airflow *inflamed airway tube: constricted & inflamed bronchioles & increase on epithelial thickness mucus hyper secretion which cause obstruction

*not for memorizing:

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- Stimuli that cause asthmatic attack: (trigger factor) Allergens: e.g. animal dander, pollen Exercise Cold air Respiratory tract infection Environment Tobacco smoke Drug induced: NSAIDs especially Aspirin, -blockers *the classification is important to give proper medication:
Classification of asthma
Stage Symptoms Long-term control Quick relief of symptoms
Short acting 2 agonists.

Mild intermittent Mild persistent

2 /week

No medication

>2 /week but not daily

dose of ICS

Short acting 2 agonists.

Classification of asthma
Stage Symptoms Long-term control Quick relief of symptoms

Moderate persistent

Daily to medium Short acting symptoms dose of ICS& 2 agonists.


long acting 2 agonists.

Severe persistent

Cont. symptoms Throughout the day

dose of ICS & oral CS& long acting 2 agonists

Short acting 2 agonists.

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)*ICS = inhaled corticosteroids ) -THE GOALS OF ASTHMA MANAGEMENT: 1- Achieve and maintain control of symptoms 2- Prevent asthma exacerbations & develop acute sever asthma 3- Maintain pulmonary function as close to normal as possible 4- Avoid adverse effects from asthma medications 5- Prevent development of irreversible airflow limitation 6- Prevent asthma mortality that happened on acute cases if its not controlled probably Approaches to treatment: -Determine precipitating factors & avoid them if possible (avoid cause) -Bronchodilator to reverse the bronchospasm -Anti-inflammatory agents to inhibit or prevent the inflammatory components & the hyperactivity of the bronchi A. Bronchodilators: They are 1st line drug & include: 1.2-receptor agonists (1st choice of bronchodilators) 2.Methylxanthines 3.Muscarinic receptor antagonists "can we use epinephrine on bronchial asthma?" Ans: it is effective but it stimulate B1 receptor & this will lead to tachycardia 1.Selective 2-agonists: These drugs are usually given by inhalation (preferable) of aerosol, powder, or nebulized solution or may be given orally or by injection (for emergency) 2 categories of 2 adrenoceptor agonists:
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Short Acting Agents(4-6 hours)& fast onset of action: Salbutamol, Terbutaline. They are usually used on "as needed" basis to control symptoms of acute attack Taken by inhalation

-Long Acting Agents(12 hour) but delay onset of action: Salmeterol, Formeterol *They are not used "as needed" but are given regularly twice daily *as prophylaxis (prevent bronchospasm at night or with exercise) *S/Es: The unwanted effects of 2-adrenoceptor agonists result from systemic absorption (if they given systemically & parentally or oraly: 1.Tachycardia 2.Tremor 3.Hyperglycemia *Salbutamol oral side effects :taste changes, teeth discoloration Salmeterol oral side effects: Dental pain, throat dryness {patient must rinse his mouth even with water after uptake }

2. Methylxanthines: These are 3 pharmacologically active naturally occurring substances: Theophylline, Caffeine & Theobromine. The one which employed in clinical medicine is Theophylline & Aminophylline (Theophylline salt) Theophylline is given orally in sustained-release preparation; Aminophylline can be given I.V. infusion (slowly) to treat status asthmaticus. -Has narrow therapeutic index (10-20mg/mL) so: Dont combine oral & I.V. Before giving I.V. Theophylline, always ask if the patient is already taking Theophylline orally Monitor for signs of toxicity: vomiting, headache, tachycardia Obtain Theophylline serum concentration
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Clinical uses of theophylline: 1. as second line drug, in addition to steroids, in patients whose asthma does not respond to 2 agonists. 2. Intravenously in acute sever asthma.

S/Es: 1.CNS excitation, tremor, nervousness 2.Tachycardia. 3.Nausea & vomiting. D/D interaction: possible theophylline toxicity ( metabolism) if used with erythromycin,ciprofloxacin,clarithromycin "hepatic enzyme inhibitor . "theophylline metabolized by liver so lf it taken with some hepatic enzyme inhibitor it will inhibited & toxicity increased " 3.Muscarinic Antagonists: The main compound used specifically as anti-asthmatic is Ipratropium It is quaternary derivative given by aerosol, it is not well absorbed thus the possibility of systemic S/E is minimal S/Es: 1.Cough 2.Dryness of mouth -Clinical uses: 1.As bronchodilator in some patients with bronchospasm precipitated by 2-receptor antagonists 2.As an adjunct to 2-agonists & steroids Q:why do we use ipratropuim in management of bronchospasm induced by B blocker? Like propanolol which is a nonselective B blocker?? Ans: already the receptor is busy by propanolol if for example sulbetamol used it will not find any empty receptor to bind with & produce bronchodilatation soo we use another mechanism by blocking muscaranic receptor

Done by : salam ahmad Al-bataineh & hebah r3d Ramadneh


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