the 14 fatal or near fatal

reactions occurred in patients

with known asthma (grade C).
It is not clear if this is related
to the severity of the
underlying asthma.
Auto-injectors
Who should be prescribed
 Adrenaline (epinephrine) is the recommended first line treatment for patients with anaphylaxis. This review discusses the safety and efficacy of adrenaline in the treatment of anaphylaxis in the light of currently available evidence. A pragmatic approach to use of adrenaline auto-injectors is suggested.
 Anaphylaxis is the clinical syndrome representing the most severe systemic allergic reactions. Mediator release results in smooth muscle contraction, vasodilation, increased vascular permeability, and activation of vagal pathways, leading to the classic features of anaphylaxis, including urticaria and angioedema, bronchoconstriction and hypotension. Owing to the nature of anaphylaxis there are few controlled clinical trials, and therapeutic recommendations are based on clinical observation and animal models. We look at the current evidence for the use of
adrenaline (epinephrine) in anaphylaxis, including its safety and route and timing of administration. We also discuss adrenaline auto-injectors and their role in patients with anaphylaxis.
 Methods
 We searched Medline using the key words adrenaline, anaphylaxis, epinephrine, and Epipen, and articles from the authors' personal collection. When necessary we accessed cross references and related articles. Evidence has been graded, where possible (see bmj.com). Only studies with clinical outcomes have been classified (see table on bmj.com); those showing in vitro improvements have not been graded.
 Anaphylaxis
 Anaphylaxis is a severe, life threatening systemic reaction that can affect all ages. The clinical syndrome may involve multiple target organs, including skin, respiratory, gastrointestinal, and cardiovascular systems. The essential underlying mechanism is the presence of biologically active chemical mediators released from mast cells or basophils.1 If this occurs in the context of a classic IgE mediated reaction from previously sensitised mast cells or basophils then anaphylactic reaction is the preferred term. Degranulation of mast cells or basophils may also
occur in non-IgE mediated mechanisms, and these reactions are termed anaphylactoid reactions. Clinically it is not possible to distinguish the two, and treatments for both mechanisms are identical. Invalid assumptions of an anaphylactoid cause have led to fatal re-exposure.2
 Summary points
 Anaphylaxis is a severe life threatening reaction that can affect all age groups
 The severity of previous reactions does not predict the severity of subsequent reactions
 Intramuscular adrenaline is the first line treatment for anaphylaxis, with intravenous adrenaline reserved for unresponsive anaphylaxis or circulatory collapse
 Early use of adrenaline in anaphylaxis is associated with improved outcomes
 Any patient with a systemic allergic reaction should be considered for an adrenaline auto-injector, depending on risk of further reactions
 There is a clear need to improve education of both patient and physician on the use of and indications for adrenaline auto-injectors
 Anaphylaxis occurs in an acute and unexpected manner. The true incidence is unknown. Epidemiological studies have shown differing results owing to differences in both definitions of anaphylaxis and the population groups studied. A retrospective population based study in Olmsted County, United States showed an incidence of 21 cases per 100 000 person years.3 A retrospective study in a UK accident and emergency department suggested an incidence of between 1 in 2300 and 1 in 1500 attendances, and retrospective analysis in a US emergency
room has shown an incidence of 1 in 1100 attendances.4,5 Most data for the incidence have been derived from hospital databases, and it is widely believed anaphylaxis is under-recognised and under-reported.5-7 Anaphylaxis remains an important cause of mortality. Of 164 fatal reactions identified between 1992 and 1998 in the United Kingdom, around half were iatrogenic.8 Of the non-iatrogenic causes, half were related to venom (for example, wasp sting) and most of the remainder to food.
 Adrenaline has physiological benefits in the treatment of anaphylaxis: stimulation of α adrenoceptors increases peripheral vascular resistance thus improving blood pressure and coronary perfusion, reversing peripheral vasodilation, and decreasing angioedema. Stimulation of β1 adrenoceptors has both positive inotropic and chronotropic cardiac effects. Stimulation of β2 receptors causes bronchodilation as well as increasing intracellular cyclic adenosine monophosphate production in mast cells and basophils, reducing release of inflammatory mediators.9
 However, given the speed of onset, the often unexpected occurrence and rapid response to treatment, there are few controlled clinical trials in acute anaphylaxis, and this is unlikely to change. Most treatment recommendations have therefore been based on clinical observation, interpretation of the pathophysiology and, to an extent, animal models.9 w1
 Adrenaline
 Is adrenaline safe?
 Adrenaline is the recommended first line treatment in anaphylaxis (fig 1).10 Confusion arises because systemic allergic reactions can be mild, moderate, or severe. For example, generalised angioedema and urticaria without airway involvement would not be described as anaphylaxis. A good working definition is that an anaphylactic reaction involves one or both of the two severe features: respiratory difficulty (which may be due to laryngeal oedema or asthma) and hypotension (which may present as fainting, collapse, or loss of consciousness).
Inappropriate use of adrenaline may be dangerous. Most adverse events with adrenaline usage occur when it is given in overdose or intravenously. Those particularly at risk include elderly patients and patients with hypertension, arteriopathies, or known ischaemic heart disease.7,8,10 w2 w3 As there are no controlled trials there is no way to estimate the risk in relation to benefit. Based on the current evidence, the benefit of using appropriate doses of intramuscular adrenaline far exceeds the risk (grade C). It should be stressed that adrenaline is not
contraindicated in individuals with underlying ischaemic heart disease, as the decrease in filling pressure due to anaphylaxis is likely to result in further coronary ischaemia (grade C).1  Careful monitoring and avoidance of adrenaline overdose is necessary in these patients.
 Fig 1
 Algorithm for the treatment of anaphylaxis. Reproduced with permission of UK Resuscitation Council
 What is the best route for administering adrenaline?
 Subcutaneous and intramuscular routes 
 The correct route of administration and dose of adrenaline has been under debate. One study showed that subcutaneous administration of adrenaline was associated with a striking difference in the time of maximum plasma adrenaline concentrations of children compared with the intramuscular route (average time: intramuscular group, 8 minutes; subcutaneous group, 34 minutes).11  The average maximum plasma concentration was also significantly higher for the intramuscular group than for the subcutaneous group, and this has been shown elsewhere
(grade B).11,12
 Inhaled adrenaline 
 Studies using inhaled adrenaline by way of a pressurised aerosol have given conflicting results.w4-w6 One report showed that adrenaline was present systemically after an inhaled 3 mg dose but not after 1.5 mg and that the clinical effect was less pronounced and shorter lasting than by subcutaneous injection.w4 Other studies have shown the reverse.w6 No direct comparisons have been made between the inhaled and intramuscular route. Such findings have only been shown in healthy volunteers and have, as yet, not been confirmed in patients during
anaphylaxis.
 Intravenous route 
 Intravenous adrenaline has been associated with the induction of fatal cardiac arrythmias and myocardial infarction. Major adverse effects usually occur when adrenaline has been given too rapidly, inadequately diluted, or in excessive dose (grade C).1,2,8,9 Such published reports often fail to state clearly that other factors, including hypoxia, acidosis, or the direct action of inflammatory mediators, may be, at least in part, responsible for the cardiovascular complications. Given all of this, the intravenous route should be reserved for those with unresponsive
anaphylaxis. This includes any patient who deteriorates despite receiving intramuscular adrenaline or those in whom there is doubt about the circulation. It should only be given in a resuscitation area during electrocardiography by medical staff who are trained in its use (grade C).7
 What dose of adrenaline is appropriate?
 Some disagreement exists about the recommended dose of adrenaline. Although almost all of the literature agrees on 0.01 mg/kg in infants and children, North American guidelines suggest a dose in adults of 0.3-0.5 ml of adrenaline diluted 1:1000 (0.3-0.5 mg), whereas European literature suggests 0.5-1.0 mg.13 w1 w7 No comparative trials have been conducted. For most patients only one dose is needed, although repeat doses may be given at five minute intervals until symptoms improve.
 Does adrenaline have any important drug interactions?
 Anaphylaxis may be made worse by β blockers, and these drugs decrease the effectiveness of adrenaline (grade C).14 Paradoxically the dose of adrenaline should be halved owing to the increased risks associated with unopposed stimulation of α adrenoceptors and reflex vagotonic effects, including bradycardia, hypertension, coronary artery constriction, and bronchoconstriction.15 β Blockers, including eye drops containing them, should therefore be withdrawn and substituted in any patient who is considered at risk of anaphylaxis.16 Tricyclic
antidepressants and monoamine oxidase inhibitors potentiate adrenaline and increase the risk of cardiac arrhythmias. The dose of adrenaline should be halved in these patients (grade C). Cocaine sensitises the heart to catecholamines (as does uncontrolled hyperthyroidism), and adrenaline is therefore relatively contraindicated (grade C).10
 When should adrenaline be given?
 Evidence in the literature suggests that a poor outcome from anaphylaxis is associated with late administration of adrenaline. In a series of 13 fatal and near fatal anaphylactic reactions over a 14 month period, only two of the six patients who died received adrenaline within the first hour compared with six of the seven survivors (grade C).17 In a retrospective study of 27 patients with anaphylaxis occurring outside hospital, all those treated within 30 minutes recovered compared with two deaths in those in whom treatment was delayed by more than 45
minutes (grade C).18 One study showed that whereas adrenaline was used in the treatment of 62% of fatal reactions it was used in only 14% before cardiac arrest (grade C).8  This may, however, be due in some part to both the speed of reactions and the availability of treatment. As a result current guidelines suggest adrenaline should be given as soon as possible.19
 Which patients have the worst outcomes?
 The severity of previous reactions does not determine the severity of future reactions, and subsequent reactions could be the same, better, or worse. The unpredictability depends on the degree of allergy and the dose of allergen.8,20 A series of paediatric anaphylaxis showed that in two of the three fatal reactions and five of the six near fatal reactions, the previous allergic event had not required urgent hospital intervention (grade C).19 Studies have also shown a significant increased risk of near fatal and fatal reactions in patients with coexistent asthma.17,19  In
one study, 13 of the 14 fatal or near fatal reactions occurred in patients with known asthma (grade C). It is not clear if this is related to the severity of the underlying asthma.
 Auto-injectors
 Who should be prescribed adrenaline auto-injectors?
 Studies have shown that only 50-75% of patients prescribed auto-injectors for self administration of adrenaline carry them around at all times.21-24 w8 Of these, only 30-40% were able to correctly demonstrate how they would administer adrenaline to themselves. A retrospective analysis showed that only 29% of children with recurrent anaphylaxis were treated with their adrenaline auto-injector.25 The subsequent need for adrenaline and admission to hospital was reduced in those patients who did receive the appropriate dose by auto-injector (grade C).25
 Adrenaline auto-injectors proved unsuccessful in nine of 14 patients with severe reactions, either due to unavailability (n = 4), rapidity of reaction (n = 1), incorrect dose (n = 1), or despite correct treatment (n = 2) (grade C).8 In another study, 23% (n = 22) of adult patients admitted that they would probably not be brave enough to self administer adrenaline—half would seek medical assistance and the other half would ask another person.22
 Studies in primary and secondary care have shown that most doctors are themselves uncertain about the correct method for use of auto-injectors.24 w8 Only instruction provided by an allergy specialist has been shown to have any effect on proper injection technique (grade C).23,24 Patients need to be aware about expiry dates for their auto-injectors, although studies have shown adrenaline content and bioavailabilty in outdated auto-injectors.w9 Instruction by a physician familiar with auto-injectors and regular review of technique and reinforcement of the
issues surrounding their use is therefore vital for these patients (fig 2). Current opinion on prescription of auto-injectors is divided. American opinion suggests that all patients with an episode of major allergy should be prescribed an auto-injector.13,15 In the United Kingdom some people believe auto-injectors are over-prescribed.22 Current UK paediatric guidelines suggest auto-injectors should be given only to patients with previous severe reaction or reactions involving the airway.21 Given that current evidence supports the relative safety of intramuscular
adrenaline, and early administration is associated with an improved survival, any patient with a systemic allergic reaction should be a candidate for adrenaline by auto-injector. The prescription of auto-injectors, however, needs to be targeted to those most likely to use the adrenaline and in whom the benefit outweighs the risk. We propose an algorithm for identifying patients who may benefit from an adrenaline auto-injector (fig 3). Further careful epidemiological research is needed to clarify who benefits most from such treatment.
 . Bronchial Asthma • Asthma as an inflammatory illness • Accounting 5000 deaths/ year in USA • Asthma is common disorder and it is characterized by airway inflammation and hyperresponsiveness to stimuli that produce bronchoconstriction. These stimuli include cold air, exercise, a wide variety of allergens and emotional stress. – Extrinsic asthma: It is mostly episodic, less prone to status asthmaticus. – Intrinsic asthma: It tends to be perennial, status asthmaticus is more common.
 3. Pathophysiology of asthma
 4. Chronic obstructive pulmonary diseases (COPD) • Incudes chronic bronchitis and emphysema – chronic bronchitis: cough associated with inflammation of the bronchioles – Emphysema: permanent destruction and enlargement of the airspaces distal to the bronchioles • COPDs results airway obstruction, dyspnea, ↓ blood O2 concentrations and ↑blood CO2 concentrations. • Risk factor of COPD: Smocking and old age • Treatment: Bronchodilators and long time oxygen therapy.
Antibiotics can be used to treat acute exacerbations caused by bacterial infections.
 5. Bronchial Asthma: Treatment approaches • Prevention of antigen antibody reaction: Avoidance of antigen, hyposensitization • Neutralization of IgE: Omalizumab • Suppression of inflammation and bronchial hyper reactivity: Cotricosteroids • Prevention of release of mediators: Mast cell stabilizers • Antagonism of released mediators: Leukotriene antagonists, antihistamines, platelet aggravating factor (PAF) antagonist • Blacked of constrictor neurotransmitter: Sympathomimetics •
Directly acting bronchodilators: Methylxanthines
 6. Classification • Bronchodilators – β Sympathomimetics: Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formoterol, Ephedrine. – Methylxanthines: Theophylline (anhydrous), Aminophylline, Choline theophyllinate, Hydroxyethyl theophylline, Theophylline ethanolate of piperazine, Doxophylline. – Anticholinergics (muscarnic receptor antagonist): Ipratropium bromide, Tiotropium bromide. • Leukotriene antagonists: Montelukast, Zafirlukast. • Mast cell stabilizers: Sodium
cromoglycate, Ketotifen. • Corticosteroids – Systemic: Hydrocortisone, Prednisolone and others. – Inhalational: Beclomethasone dipropionate, Budesonide, Fluticasone propionate, Flunisolide, Ciclesonide. • Anti-lgE antibody: Omalizumab
 7. Bronchodilators Stimulates 2-adrenergic receptors of bronchi 2-agonists Anticholinergic drugs Smooth muscle relaxation reduce tonus of vagus Methylxanthines inhibit phosphodiesterase 2-agonists: treatment of acute asthmatic attacks Muscarinic antagonist: Less useful in asthma, used for treat COPDs Methylxanthines: Long-term/ prevent bronchoconstriction
 8. Sympathomimetics • The selective β2 agonist is the primary bronchodilators used in the treatment of asthma/ acute asthmatic attacks. • β2 adrenergic receptor agonists stimulates the beta receptor, increasing the cAMP concentration in smooth muscle and causing bronchodilatation. It also increase the conductance of large Ca2+- sensitive K+ channels in airway smooth muscle, leading to membrane hyperpolarization and relaxation. • The selective β2 agonist relax the bronchial
smooth muscle without affecting cardiac function. In higher doses selective β2 agonist increasing the heard rate by stimulating the cardiac β1-receptor. The selective β2 agonist produce hypertension to patient those receiving digitalis. • Types: – Long-acting β2 adrenergic receptor agonists (Salmeterol; formoterol) – Short-acting β2 adrenergic receptor agonists (albuterol, levalbuterol, metaproterenol, terbutaline, and pirbuterol )
 9. Sympathomimetics • Salbutamol: – Selective β2 agonists with less cardiac side effects – Inhaled salbutamol produce bronchodililation within 5-min and the action lasts for 2-4 h. – Used for acute asthmatic attack. Not suitable for prophylaxis – Side effect: Palpitation, restlessness, nervousness, throat irritation and ankle edema. – Metabolism: metabolized in gut; oral bioavailability is 50%. – Duration of action: oral salbutamol acts 4-6 h. – Dose: 2-4 mg/ oral; 0.25- 0.5 mg/ i,.p., or
s.c.,; 100-200 μg/ inhalation • Terbutaline: – Similar to salbutamol; regular use dose not reduce bronchial hyper-reactivity – Dose: 5 mg/ oral; 0.25 mg/ i,.p., or s.c.,; 250 μg/ inhalation Cont.,
 10. Sympathomimetics • Bambuterol: – Biocarbamate ester of prodrug of terbutaline – Slowly hydrolyzed in plasma and lung by pseudocholinesterase to release the active drug over 24 h. It also reversely inhibits pseudocholinesterasein a dose dependent mannor. – Used in chronic bronchial asthma in a singe evening dose of 10-20 mg/ oral. • Salmeterol: – First long acting selective β2 agonists with slow onset of action – Twice daily for maintain the therapy/ nocturnal asthma, but not
for acute asthma – Concurrent use of inhaled glucocorticoid with salmeterol is advised for patient with persistent asthma. – COPD: equivalent to inhaled anticholinergics in COPD. Reduce breathlessness by abolishing the reversible component of airway obstruction. • Formoterol: – Long acting selective β2 agonists which acts 12 h when inhaled. – Compare to salmeterol it has a faster onset of action (with in 10 min) Cont.,
 11. Methylxanthines • Theophylline and its derivatives are most commonly used for the treatment of COPD and asthma. • Caffeine, theophylline and theobromine are naturally occurring xanthine alkaloids which have qualitatively similar actions. • Mechanism of action: – Methylxanthines inhibits cyclic nucleotide phosphodiesterase (PDEs), thereby preventing conversion of cAMP and cGMP to 5’-AMP and 5’-GMP, respectively. Inhibition of PDEs will lead to an accumulation of
intracellular cAMP and cGMP. Bronchodilataion, cardiac stimulation and vasodilatation occur when cAMP level rises in the concerned cells. Theophylline and related methylxanthines are relatively nonselective in the PDE subtypes inhibitor. – Theophylline is a competitive antagonist at adenosine receptors. Adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from human lung mast cells. Methylxanthines inhibits the
adenosine action thereby casing bronchodilataion.
 12. Methylxanthines • Mechanism of action: Bronchodilation Bronchial tone Muscarinic antagonist Acetylcholine Adenosine Theophylline cAMP ATP AMP Adenylyl cyclase Phosphodiesterase (PDE) Theophylline Beta agonist
 13. Methylxanthines • Pharmacological action: • CNS: – Stimulant; affects higher center. – Caffeine 150-200 mg produce a sense of wellbeing, alertness, beats boredom, allays fatigue and improve performance and increase the motor activity. Caffeine is more active than theophylline in producing these effects. – Higher dose cause nervousness, restlessness, panic, insomnia and excitements. – Still higher dose cause tremors, delirium and convulsions. Theophylline is more toxic than
caffeine. – Stimulates medullary vagal, respiratory and vasomotor centers. – High dose: Vomiting and gastric irritation and CTZ stimulation. Cont.,
 14. Methylxanthines • Pharmacological action: • CVS – Stimulates the heart and increase force of contraction. Increase the heart rate (direct action) but decrease it by vagal stimulation- net effect is variable. – Tachycardia; increased cardiac output; increased cardiac work – High dose: cardiac arrhythmias – Effect on blood pressure is variable and unpredictable. Usually a rise in systolic and fall in diastolic BP is observed. • Vasomotor center and direct cardiac stimulation- tends to raise
BP • Vagal stimulation and direct vasodilatation- tends to lower BP • Smooth muscles: – Relaxation – Theophylline is more potent and slow, sustained dose related bronchodilatation – Increase vital capacity – Direct action due to adrenergic stimulation – Biliary spasm is relived, but the effects on intestines and urinary tract is negligible. – Theophylline is more potent; caffeine has minimal actions. Cont.,
 15. Methylxanthines • Pharmacological action: • Kidney – Mild diuretics – Inhibiting tubular reabsorption of Na+ and water – Increasing vascular blood flow and g.f.r. – Theophylline is more potent; caffeine has minimal actions. • Skeletal muscles: – Caffeine enhance contractile power. In high dose it increases release of Ca+ from sarcoplasmic reticulum by direct action. – Twitch response at low doses. – Caffeine facilitates neuromuscular transmission by increasing Ach release. •
Stomach: – Enhance secretion of acid and pepsin – Gastric irritation (more with theophylline) Cont.,
 16. Methylxanthines • Pharmacological action: • Metabolism – Increase BMR. – Plasma free fatty acid levels are increased. • Mast cells and inflammatory cells: – Theophylline inhibits the release of histamine and other mediators form mast cells and active inflammatory cells. Cont.,
 17. Pharmacological actions of Methyl xanthines CNS Stimulation Increase motor activity Improve the performance CVS Stimulate the heart Increase the force of contraction High dose: cardiac arrhythmias BP: effect is variable Stimulation of Vegas stimulation: ↓ BP Vasomotor center : ↑ BP Smooth muscle Relaxation Lungs vital capacity- increased Biliary spasm: relieved Kidney Mild diuretics (Inhibiting reabsorption of Na+ & H2O) Increase the renal blood flow Increase the g.f.r. Mast
cell Inhibit the release of histamine Stomach Enhance the secretion of acid, Pepsin Metabolism Increase BMR It has variable physiological actions
 18. Methylxanthines- Theophylline • Pharmacokinetics: – Absorption: Absorbed orally; rectal absorption form suppositories is erratic. – Distribution: All tissues; cross BBM; crosses placenta and is secreted in milk; 50% plasma protein bound – Metabolism: Metabolized in liver (CYPP1A2) by demethylation and oxidation. – Excretion: Excreted in urine; 10 % of total administration excreted unchanged form. Elimination rat various considerably with age (age dependent excretion). – Adult
t1/2 is around 7-12 h. Children elimination is much faster (t1/2 3-5 h); In premature infants has prolonged t1/2 (24-36 h). – In higher dose pharmacokinetics changes form first order to zero order.
 19. Methylxanthines- Theophylline Cont., • Adverse effects: – Narrow margin safety – CVS and CNS stimulant; ADRs not dependent to dose; GIT distress – Children are more liable to developed CNS toxicity – Rapid i.v injection cause- precordial pain, syncope and sudden death Bronchodilatation
 20. Methylxanthines- Theophylline • Interactions: – Theophylline metabolism decreased by smoking, phenytoin, rifampicin, phenobarbitone and charcoal broiled meat meal., which increases the parenthesis. – Erythromycin, ciprofloxacin, cimetidine, oral contraceptives and allopurinol inhibits CYP1A2 and increasing the theophylline plasma concentraction; dose should be reduced to 2/3. – Theophylline reduce the effects of phenytoin, lithium. – Theophylline enhance the effects of
furosemide, sympathomimetics, digitalis, oral anticoagulants and hypoglycemics. • Indications: – Primarily used to treat chronic obstructive lung disorders and asthma. – Also used to treat apnea Cont.,
 21. Anticholinergics Ipratropium/ tiotropium (derivative of atropine) • Parasympathetic activation/ release of ACh cause bronchoconstriction and increase mucus secretion. • Blocking the action of ACh by anticholinergic drugs produce bronchodilation and also reduce the volume of respiratory secretion. • Less effective than sympathomimetic. • Inhaled ipratropium/ tiotropium are choice of bronchodilator choice in COPD. • Tritropium produce longer duration of action than ipratropium
• ADR: Dry mouth, respiratory tract discomfort
 22. Leukotriene antagonists Montelukast, Zafirlukast • Both are having similar action and clincial utility • Block the cys-leukotrienes C4, D4 and E4 (LTC4, LTD4, LTE4) • Alternative for inhaled glucocorticoids • Prophylactic therapy for mild, moderate asthma; not used for terminating asthma. • Both are very safe drugs and ADRs are few (headache, rashes); eosinophilia and neuropathy are infrequent. Few cases Churg-Strauss syndrome (vasculitis with eosinophilia) have been reported. •
Dose: Montelukast 10 mg OD, Zafirlukast 20 mg BD
 23. Leukotriene antagonists • Mechanism of action of leukotriene antagonist, antiinflammatory drugs Cont., Bronchoconstriction, I nflammation, increase d mucus Bronchoconstriction, Infla mmation, Pain Block by steroidal antiinflammatory drugs Block by nonsteroidal antiinflammatory drugs Block by Leukotriene antagonists
 24. Corticosteroids • Corticosteroids are not bronchodilator; benefit by reducing bronchial hyperreactivity, mucosal edema and by suppressing inflammatory. • Inhaled glucocorticoids are partially absorbed and because of their systemic AEs oral glucocorticoids are usually reserved for patients with severe persistent asthma. • Systemic steroid therapy – Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids. – Status asthmaticus/ acute asthma exacerbation: ‘’’
 25. Corticosteroids Inhaled steroids • High topical and low systemic activity (due to poor absorption/ fast pass metabolism). • Inhaled steroids are not recommended for patient with mild or episodic asthma. High dose inhaled steroids are beneficial for advanced COPD with frequent exacerbations. • Systemic steroid therapy – Sever chronic asthma: Not contorted by bronchodilator and inhaled steroids. – Status asthmaticus/ acute asthma exacerbation: ‘’’
 26. Mast cell stabilizers Sodium cromoglycate, Ketotifen • Inhibits degranulation of mast cell by trigger stimuli and prevent the release of histamine, LTs, PAF, interleukins etc. from mast cells. Inhibition of mediator release by cromolyn is through blockade of calcium influx in mast cells. • Long time therapy reduce cellular inflammatory response. • It is not histamine antagonist/ bronchodilator- ineffective in asthmatic attack. • Pharmacokinetic: – Not absorbed orally. It is administered as
an aerosol through metered dose inhaler delivering 1 mg per dose; 2 puffs 4 times a day – Not popular- production of cough and bronchospasm because of particulate nature of the inhalation. – Small fraction of the inhaled drug is absorbed systemically and excreted unchanged form in urine and bile.
 27. Mast cell stabilizers • Use: – Bronchial asthma: Sodium. Cromoglycate is used as a long term prophylactic in patients not adequately controlled by inhaled bronchodilators. Alternative for inhaled steroids in mild to moderate asthma but not severe cases. – Allergic rhinitis: Cromoglycate is not nasal decongestant, regular prophylactic use as a nasal spray produces symptomatic improvement in many patients. – Allergic conjunctivitis: Regular use as eye drops is benificial in some
chronic cases Cont., Adverse effect (cromoglycate): Bronchospasm Throat irritation Cough, headache Arthralgia, rashes and dysuria Rarely nasal congestion Adverse effect (Ketotifen): Generally well tolerated Sedation and dry mouth Dizziness, nausea and weight gain
 28. Anti-lgE antibody: Omalizumab • recombinant DNA-derived monoclonal antibody • Selectively binds to human immunoglobulin E (IgE) and decrease binding affinity of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils, reduce allergic response. • Omalizumab may be particularly useful for treatment of moderate to severe allergic asthma in patients who are poorly controlled with conventional therapy. • Due to the high cost of the drug, limitations on
dosage, and limited clinical trial data, it is not currently used as firstline therapy.
NSAIDs have following group of drugs  Analgesic  Antipyretic  Antiinflammatory 2

3. Classification A. Nonselective COX inhibitors (traditional NSAIDs) 1. Salicylates: Aspirin 2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen. 3. Anthranilic acid derivative: Mephenamic acid 4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac. 5. Ox PHARMACOLOGICALACTIONSicam derivatives: Piroxicam, Tenoxicam. 6. Pyrrolo-pyrrole derivative: Ketorolac 7. Indole derivative: Indomethacin. 8. Pyrazolone derivative: phenylbutazone, Oxyphenbutazone 3

4. B. Preferential COX-2 inhibitors Nimesulide, Meloxicam, Nabumeton. C. Selective COX-2 inhibitors Celecoxib, Etoricoxib, Parecoxib. D. Analgesic-antipyratics with poor antiinflammatory action 1. para aminophenol derivatives: Paracetamol 2. Pyrazolone derivative: Metamizol, Propiphenazone. 3. Benzoxazocine derivative: Nefopam 4

5. Mechanism of action of NSAIDs 1. Antiinflammatory effect  due to the inhibition of the enzymes that produce prostaglandin H synthase (cyclooxygenase, or COX), which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclin. 5

6.  Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue.  This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2. 6
7. 2. Analgesic effect A. The analgesic effect of NSAIDs is thought to be related to:  the peripheral inhibition of prostaglandin production  may also be due to the inhibition of pain stimuli at a subcortical site. B. NSAIDs prevent the potentiating action of prostaglandins on endogenous mediators of peripheral nerve stimulation (e.g., bradykinin). 7

8. 3. Antipyretic effect  The antipyretic effect of NSAIDs is believed to be related to:  inhibition of production of prostaglandins induced by interleukin-1 (IL-1) and interleukin-6 (IL-6) in the hypothalamus  the “resetting” of the thermoregulatory system, leading to vasodilatation and increased heat loss. 8

9. NSAIDs and Prostaglandin (PG) synthesis inhibition  NSAIDs blocked PG generation.  Prostaglandins, prostacyclin (PGI2), and thromboxane A2(TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase.  Cyclooxygenase (COX) exists in COX-1 and COX-2 isoforms.  COX -3 has recently been identified 9
10.  Cyclooxygenase (COX) is found bound to the endoplasmatic reticulum. It exists in 3 isoforms: • COX-1 (constitutive) acts in physiological conditions. • COX-2 (inducible) is induced in inflammatory cells by pathological stimulus. • COX-3 (in brain). 10

11. Nonselective COX inhibitor Salicylates Aspirin:  Aspirin is Acetylsalicylic acid converts to salicylic acid in body, responsible for action. 11
12. PHARMACOLOGICALACTIONS 1. Analgesic, antipyretic, antiinflammatory actions:  Aspirin is a weaker analgesic than morphine type drugs.  Aspirin 600 mg < Codeine 60 mg < 6 mg Morphine  it effectively relieves inflammation, tissue injury, connective tissue and integumental pain, but is relatively ineffective in severe visceral and ischaemic pain.  The analgesic action is mainly due to obtunding of peripheral pain receptors and prevention of PG-mediated sensitization of nerve endings.  No sedation, subjective effects, tolerance or physical dependence is produced.  Aspirin resets the hypothalamic thermostat and rapidly reduces fever by promoting heat loss, but does not decrease heat production.  Antiinflammatory action is exerted at high doses
(3-6 g/ day or 100 mg/kg/ day) 12
13. 2. Metabolic effects:  significant only at antiinflammatory doses  Cellular metabolism is increased, especially in skeletal muscles, due to uncoupling of oxidative phosphorylation increased heat production.  There is increased utilization of glucose blood sugar may decrease (especially in diabetics) and liver glycogen is depleted.  Chronic use of large doses cause negative N2 balance by increased conversion of protein to carbohydrate. Plasma free fatty acid and cholesterol levels are reduced. 13
14. 3. Respiration:  Effects are dose dependent.  At antiinflammatory doses, respiration is stimulated by peripheral (increased C02 production) and central (increased sensitivity of respiratory centre to C02) actions.  Hyperventilation is prominent in salicylate poisoning. Further rise in salicylate level causes respiratory depression; death is due to respiratory failure. 14

15. 4. Acid-base and electrolyte balance:  Antiinflammatory doses produce significant changes in the acid-base and electrolyte composition of body fluids.  Initially, respiratory stimulation predominates and tends to wash out C02 despite increased production ….respiratory alkalosis, which is compensated by increased renal excretion of HCO3̄; (with accompanying Na+, K+ and water).  Still higher doses cause respiratory depression with C02 retention, while excess C02 production continues…. Respiratory acidosis . 15

16. 5. CVS:  Aspirin has no direct effect in therapeutic doses.  Larger doses increase cardiac output to meet increased peripheral O2 demand and causes direct vasodilatation.  Toxic doses depress , vasomotor centre: BP may fall. Because of increased cardiac work as well as Na+ and water retention,  CHF may be precipitated in patients with low cardiac reserve. 16

17. 6. GIT:  Aspirin and released salicylic acid irritate gastric mucosa, cause epigastric distress, nausea and vomiting.  It also stimulates CTZ. 7. Urate excretion:  Aspirin in high dose reduces renal tubular excretion of urate 17
18. 8. Blood:  Aspirin, even in small doses, irreversibly inhibits TXA2 synthesis by platelets. Thus, it interferes with platelet aggregation and bleeding time is prolonged to nearly twice the normal value.  long-term intake of large dose decreases synthesis of clotting factors in liver and predisposes to bleeding; can be prevented by prophylactic vit K therapy. 18

19. Pharmacokinetics  Aspirin is absorbed from the stomach and small intestines.  Its poor water solubility is the limiting factor in absorption: microfining the drug particles and inclusion of an alkali (solubility is more at higher pH) enhances absorption.  Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other tissues to release salicylic acid which is the major circulating and active form.  It slowly enters brain but freely crosses placenta.  The metabolites are excreted by glomerular filtration as well as tubular secretion. 19

20. Uses of Aspirin  As analgesic (300 to 600 mg during 6 to 8 h) for headache, backache, pulled muscle, toothache, neuralgias.  As antipyretic in fever of any origin in the same doses as for analglesia. However, paracetamol and metamizole are safer, and generally preferred.  Acute rheumatic fever. Aspirin is the first drug of choice. Other drugs substitute Aspirin only when it fails or in severe cases. Antirheumatic doses are 75 to 100 mg/kg/24 h (resp. 4–6 g daily) in the first weeks.  Rheumatoid arthritis. Aspirin a dose of 3 to 5 g/24 h after meal is effective in most cases. Since large doses of Aspirin are poorly tolerated for a long time, the new NSAIDs (diclofenac, ibuprofen, etc.) in depot form are preferred. 20
21.  Aspirin therapy in children with rheumatoid arthritis has been found to raise serum concentration transaminases, indicating liver damage. Most cases are asymptomatic but it is potentially dangerous.  An association between salicylate therapy and “Reye’s syndrome”, a rare form of hepatic encephalopathy seen in children, having viral infection (varicella, influenza), has been noted.  Aspirin should not be given to children under 15years unless specifically indicated, e.g. for juvenile arthritis (paracetamol is preferred).  Postmyocardial infarction and poststroke patients: By inhibiting platelet aggregation in low doses (100 mg daily) Aspirin decreases the incidence of reinfarction. 21

22. 22

23. Adverse effects 1. Gastrointestinal effects  most common adverse effects of high-dose aspirin use (70% of patients):  nausea  vomiting  diarrhea or constipation  dyspepsia (impaired digestion)  epigastric pain  bleeding, and ulceration (primarily gastric). 23

24.  These gastrointestinal effects are thought to be due to: 1. direct chemical effect on gastric cells or 2. decrease in the production and cytoprotective activity of prostaglandins, which leads to gastric tissue susceptibility to damage by hydrochloric acid. 24
25.  The gastrointestinal effects may contraindicate aspirin use in patients with an active ulcer.  Aspirin may be taken with prostaglandins to reduce gastric damage.  Decrease gastric irritation by:  Substitution of enteric-coated or timed-release preparations, or  the use of nonacetylated salicylates, may decrease gastric irritation. 25

26. 2. Hypersensitivity (intolerance)  Hypersensitivity is relatively uncommon with the use of aspirin (0.3% of patients); hypersensitivity results in:  rash  bronchospasm  rhinitis  Edema, or  an anaphylactic reaction with shock, which may be life threatening.  The incidence of intolerance is highest in patients with asthma, nasal polyps, recurrent rhinitis, or urticaria.  Aspirin should be avoided in such patients. 26
27.  Cross-hypersensitivity may exist:  to other NSAIDs  to the yellow dye tartrazine, which is used in many pharmaceutical preparations.  Hypersensitivity is not associated with:  sodium salicylate or  magnesium salicylate. 27

28.  The use of aspirin and other salicylates to control fever during viral infections (influenza and chickenpox) in children and adolescents is associated with an increased incidence of Reye’s syndrome, an illness characterized by vomiting, hepatic disturbances, and encephalopathy that has a 35% mortality rate.  Acetaminophen is recommended as a substitute for children with fever of unknown etiology. 28

29. Miscellaneous adverse effects and contraindications  May decrease the glomerular filtration rate, particularly in patients with renal insufficiency.  Occasionally produce mild hepatitis  Prolong bleeding time.  Aspirin irreversibly inhibits platelet COX-1 and COX-2 and, thereby, TXA2 production, suppressing platelet adhesion and aggregation.  The use of salicylates is contraindicated in patients with bleeding disorders  Salicylates are not recommended during pregnancy; they may induce:  postpartum hemorrhage  premature closure of the fetal ductus arteriosus. 29

30. Drug interactions Drugs Result Diuretics Decrease diuresis Beta-blockers Decrease antihypertensive effect ACE inhibitors Decrease antihypertensive effect Anticoagulants Increase of GI bleeding Sulfonylurea Increase hypoglycemic risk Cyclosporine Increase nephrotoxicity GCS Increase of GI bleeding Alcohol Increase of GI bleeding 30
31. PROPIONIC ACID DERIVATIVES  Ibuprofen was the first member  The analgesic, antipyretic and antiinflammatory efficacy is rated somewhat lower than high dose of aspirin.  All inhibit PG synthesis, naproxen being the most potent; but their in vitro potency tor this action does not closely parallel in vitro antiinflammatory potency.  Inhibition of platelet aggregation is short-lasting with ibuprofen, but longer lasting with naproxen. 31

32.  Ibuprofen:  In doses of 2.4 g daily it is equivalent to 4 g of Aspirin in anti- inflammatory effect.  Oral ibuprofen is often prescribed in lower doses (< 2.4 g/d), at which it has analgesic but not antiinflammatory efficacy. It is available in low dose forms under several trade names (e. g. Nurofen® – film-tabl. 400 mg).  A topical cream preparation is absorbed into fascia and muscle. A liquid gel preparation of ibuprofen provides prompt relief in postsurgical dental pain.  In comparison with indometacin, ibuprofen decreases urine output less and also causes less fluid retention.  It is effective in closing ductus arteriosus in preterm infants, with much the same efficacy as indometacin. 32

33.  Flurbiprofen:  Its (S)(-) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect TNF-α and NO synthesis.  Hepatic metabolism is extensive. It does demonstrate enterohepatic circulation.  The efficacy of flurbiprofen at dosages of 200–400 mg/d is comparable to that of Aspirin and other NSAIDs for patients with rheumatoid arthritis, gout, and osteoarthritis.  Flurbiprofen i.v. is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. 33

34. Adverse effect  Ibuprofen and all its congeners are better tolerated than aspirin.  Side effects are milder and their incidence is lower.  Gastric discomfort, nausea and vomiting, though less than aspirin or indomethacin, are still the most common side effects.  Gastric erosion and occult blood loss are rare.  CNS side effects include headache, dizziness, blurring of vision, tinnitus and depression.  Rashes, itching and other hypersensitivity phenomena are infrequent.  They are not to be prescribed to pregnant woman and should be avoided in peptic ulcer patient. 34

35. Pharmacokinetic and interactions  Well absorbed orally.  Highly bounded to the plasma protein (90-99%).  Because they inhibit platelet function, use with anticoagulants should, nevertheless, be avoided.  Similar to other NSAIDs, they are likely to decrease diuretic and antihypertensive action of thiazides, furosemide and β blockers.  All propionic acid derivatives enter brain, synovial fluid and cross placenta. They are largely metabolized in liver by hydroxylation and glucuronide conjugation and excreted in urine as well as bile. 35

36. Uses  Ibuprofen is used as a simple analgesic, and antipyretic in the same way as low dose of aspirin. It is particularly effective in dysmenorrhoea. In which the action is clearly due to PG synthesis inhibition.  It is available as an over-the-court drug.  Ibuprofen and its congeners are widely used in rheumatoid arthritis, osteoarthritis and other musculoskeletal disorders.  They are indicated in soft tissue injuries, vasectomy, tooth extraction, postpartum and postoperatively: suppress swelling and inflammation. 36
37. Anthranilic acid derivative  Mephenamic acid:  An analgesic, antipyretic and weaker antiinflammatory drug, which inhibits COX as well as antagonises certain actions of PGs.  Mephenamic acid exerts peripheral as well central analgesic action. 37

38.  Adverse effects:  Diarrhoea is the most important dose-related side effect. Epigastric distress is complained, but gut bleeding is not significant.  Skin rashes, dizziness and other CNS manifestations have occurred.  Haemolytic anaemia is a rare but serious complication.  Pharmacokinetics:  Oral absorption is slow but almost complete. It is highly bound to plasma proteins-displacement interactions can occur; partly metabolized and excreted in urine as well as bile. Plasma t1/2 is 2-4 hours.  Uses:  Mephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong antiinflammatory action is not needed. It is quite effective in dysmenorrhoea. It may be useful in some cases of rheumatoid and osteoarthritis but has no distinct
advantage. 38

39. Aryl-acetic acid derivatives  Diclofenac:  An analgesic-antipyretic antiinflammatory drug, similar in efficacy to naproxen. It inhibits PG synthesis and is somewhatCOX-2 selective. The antiplatelet action is short lasting. Neutrophil chemotaxis and superoxide production at the inflammatory site are reduced.  Adverse effects of diclofenac are generally mild epigastric pain, nausea, headache, dizziness, rashes. Gastric ulceration and bleeding are less common. Reversible elevation of serum aminotransferases has been reported more commonly; kidney damage is rare.  A preparation combining diclofenac and misoprostol (PGE1) decreases upper GI ulceration but may result in diarrhoea.  Diclofenac is among the most extensively used NSAID; employed in
rheumatoid and osteoarthritis, bursitis, ankylosing spondylitis, toothache, dysmenorrhoea, post-traumatic and postoperative inflammatory conditions- affords quick relief of pain and wound edema. 39

40.  Aceclofenac:  A somewhat COX-2 selective congener of diclofenac having similar properties. Enhancement of glycosaminoglycan synthesis may confer chondroprotective property. 40

41. Oxicam derivatives  Piroxicam:  It is a long-acting potent NSAID with antiinflammatory potency similar to indomethacin and good analgesic- antipyretic action.  It is a reversible inhibitor of COX; lowers PG concentration in synovial fluid and inhibits platelet aggregation-prolonging bleeding time.  In addition, it decreases the production of IgM rheumatoid factor and leucocyte chemotaxis. 41

42.  Pharmacokinetics:  It is rapidly and completely absorbed  99% plasma protein bound;  Largely metabolized in liver by hydroxylation and glucuronide conjugation;  Excreted in urine and bile;  Plasma t1/2 is long nearly 2 days.  Adverse effects:  The g.i. side effects are more than ibuprofen, but it is better tolerated and less ulcerogenic than indomethacin or phenylbutazone; causes less faecal blood loss than aspirin. Rashes and pruritus are seen in < 1% patients. Edema and reversible azotaemia have been observed.  Tenoxicam:  A congener of piroxicam with similar properties and uses. 42
43. Pyrrolo-pyrrole derivative  Ketorolac:  A novel NSAID with potent analgesic and modest antiinflammatory activity.  In postoperative pain it has equalled the efficacy of morphine, but does not interact with opioid receptors and is free of opioid side effects.  it inhibits PG synthesis and relieves pain by a peripheral mechanism.  rapidly absorbed after oral and i.m. administration.  It is highly plasma protein bound and 60% excreted unchanged in urine.  Major metabolic pathway is glucuronidation.  plasma t1/2 is 5-7 hours. 43

44.  Adverse effects:  Nausea, abdominal pain, dyspepsia, ulceration, loose stools, drowsiness, headache, dizziness, nervousness, pruritus, pain at injection site, rise in serum transaminase and fluid retention have been noted.  Use:  Ketorolac is frequently used in postoperative, dental and acute musculoskeletal pain: 15-30 mg i.m. or i.v. every 4-6 hours (max. 90 mg/day).  It may also be used for renal colic, migraine and pain due to bony metastasis.  Continuous use for more then 5 days is not recommended. 44

45. Indole derivative  Indomethacin:  It is a potent antiinflammatory drug with prompt antipyretic action.  Indomethacin relieves only inflammatory or tissue injury related pain.  It is a highly potent inhibitor of PG synthesis and suppresses neutrophil motility.  In toxic doses it uncouples oxidative phosphorylation (like aspirin).  Pharmacokinetics:  Indomethacin is well absorbed orally  It is 90% bound to plasma proteins, partly metabolized in liver to inactive products and excreted by kidney.  Plasma t1/2 is 2-5 hours. 45

46.  Adverse effect:  A high incidence (up to 50%) of GI and CNS side effects is produced: GI bleeding, diarrhoea, frontal headache, mental confusion, etc.  It is contraindicated in machinery operators,  drivers, psychiatric patients, epileptics, kidney  disease, pregnant women and in children. 46

47. PREFERENTIAL COX-2 INHIBITORS  Nimesulide:  weak inhibitor of PG synthesis and COX-2 selectivity.  Antiinflammatory action may be exerted by other mechanisms as well, e.g. reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and TNFa release, free radical scavanging, inhibition of metalloproteinase activity in cartilage.  The analgesic, antipyretic and antiinflammatory activity of nimesulide has been rated comparable to other NSAIDs.  It has been used primarily for short-lasting painful inflammatory conditions like sports injuries, sinusitis and other ear-nose-throat disorders, dental surgery, bursitis, low backache, dysmenorrhoea, postoperative pain, osteoarthritis and for fever. 47

48.  Nimesulide is almost completely absorbed orally, 99% plasma protein bound, extensively metabolized and excreted mainly in urine with a t1/2 of 2-5 hours.  Adverse effects of nimesulide are gastrointestinal (epigastralgia, heart burn, nausea, loose motions), dermatological (rash, pruritus) and central (somnolence, dizziness). 48
49. SELECTIVE COX-2 INHIBITORS  They cause little gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA2 Production by platelets (COX-I dependent); do not inhibit platelet aggregation or prolong bleeding time but reduce PGI2 production by vascular endothelium.  It has been concluded that selective COX-2 inhibitors should be used only in patients at high risk of peptic ulcer, perforation or bleeds. If selected, they should be administered in the lowest dose for the shortest period of time. Moreover, they should be avoided in patients with history of ischaemic heart disease/ hypertension/ cardiac failure/ cerebrovascular disease, who are predisposed to CV events. 49

50.  Celecoxib:  It exerts antiinflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX- 1 activity in gastroduodenal mucosa . Platelet aggregation in response to collagen exposure remained intact in celecoxib recipients and serum TXB2 levels were not reduced. Though tolerability of celecoxib is better than traditional NSAIDs, still abdominal pain, dyspepsia and mild diarrhoea are the common side effects. Rashes, edema and a small rise in BP have also been noted.  Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with a t1/2 of 10 hours. It is approved for use in osteo- and
rheumatoid arthritis in a dose of 100-200 mg BD. 50
 51.  Etoricoxib:  This newer COX-2 inhibitor has the highest COX-2 selectivity. It is suitable for once-a-day treatment of osteo /rheumatoid / acute gouty arthritis, dysmenorrhoea, acute dental surgery pain and similar conditions, without affecting platelet function or damaging gastric mucosa. The t1/2 is 24 hours. Side effects are dry mouth, aphthous ulcers, taste disturbance and paresthesias.  Parecoxib:  It is a prodrug of valdecoxib suitable for injection, and to be used in postoperative or similar short-term pain, with efficacy similar to ketorolac. 51
  atenolol
 1. Synthesis of atenolol and its impurity Name: manthan prabhu Synthesis of atenolol and its impurity 11/2/2017 1
 2. INTRODUCTION ◦ Atenolol is a selective β1 receptor antagonist, a drug belonging to the group of beta blockers, a class of drug primarily used in cardiovascular diseases. ◦ Introduced in 1976,
Atenolol was developed as a replacement for propranolol in the treatment of hypertension. ◦ It works by slowing down the heart and reducing its workload. O NH2 O NH OH CH3 CH3 11/2/2017 2
 3. HISTORY Dr. James Black 1st trade name O OH NH CH3 CH3 PROPRANALOL NH CH3 CH3 OH PRONETHALOL 11/2/2017 3
 4. BETA BLOCKER ◦ Beta blocker, also written β-blocker, is a class of medications that are particularly used to manage cardiac arrhythmias, and to protect the heart from a second heart attack
(myocardial infarction ) after a first heart attack (i.e. secondary prevention) ◦ They are also widely used to treat hypertension. 11/2/2017 4
 5. •Beta blockers are competitive antagonists that block the receptor site for the endogenous Catecholamine epinephrine (adrenaline) and nor epinephrine (noradrenalin) on adrenergic Beta
receptor, of the sympathetic nervous system, which mediates the fight or fight-response. NH CH3 OH OH OH OH OH NH2 OH ADRENALINE NORADRENALIN 11/2/2017 5
 6. ◦ Three known types of beta receptor are β1, β2, β3 receptor. ◦ β1 –adrenergic receptor : are located mainly in the heart and kidney. ◦ β2 – adrenergic receptor : are located mainly in the lungs,
gastrointestinal tract , liver, uterus, vascular smooth muscles, and skeletal muscle. ◦ β3 -adrenergic receptor : are located in fat cells. 11/2/2017 6
 7. MODE OF ACTION  Atenelol is a beta – adrenergic blocking agent that blocks the effects of adrenergic chemicals, for example, adrenaline or epinephrine, released by nerves of sympathetic
nervous system.  One of the important function of beta- adrenergic nerves is to stimulate the heart muscle to beat more rapidly. By blocking the stimulation by these nerves, atenelol reduces the
heart rate and is useful in treating abnormally rapid heart rhythm.  Atenelol also reduces the force of contraction of heart muscle and lowers the blood pressure.  Atenelol is useful in treating
angina. 11/2/2017 7
 8. 11/2/2017 8
 9. MEDICINAL USES : The use of beta blocker around time of cardiac surgery decrease the risk of heart dysrhythmias(irregular heart beats). These are given during the congestive heart failure.
Hypertension. Long QT syndrome. (disorder of heart electrical activity) Acute myocardial infarction. Ventricle tachycardia. [Fast heart rhythm that starts in the lower part of
heart( ventricals)] Supraventricular tachycardia. 11/2/2017 9
 10. 11/2/2017 10 SIDE EFFECTS :  Dizziness  Tiredness  Drowsiness  Depression  Nausea  Shortness of breath
Alpha blockers
1. ALPHA BLOCKERS Dr.RENJU.S.RAVI MD
2. A 46 year old women presented with severe headache, palpitation and sweating. O/E – BP-150/90 mm Hg , Heart rate- 88/min Abdominal palpation elicited a rise in BP of 210/120 mm Hg, HR of 122 /min with severe headache and profuse sweating. Likely diagnosis?
3. OVERVIEW FUNCTIONS OF ALPHA RECEPTORS CLASSIFICATION GENERAL EFFECTS INDIVIDUAL DRUGS
4. Alpha adrenergic receptor antagonists Drugs that inhibit the interaction of Norepinephrine, Epinephrine and other sympathomimetic drugs with alpha adrenergic receptors.
5. 5
6. FUNCTIONS OF ALPHA RECEPTORS α1  Smooth muscle contraction  Vasoconstriction  Gland – ↓ secretion  Gut – relaxation  Heart – arrhythmia  Eyes – pupillary dilatation α2  Inhibition of transmitter release  Vasoconstriction  Decreased central sympathetic flow  Decreased
insulin release  Platelet aggregation
7. CLASSIFICATION NON SELECTIVE IRREVERSIBLE – Phenoxybenzamine REVERSIBLE – Phentolamine SELECTIVE
8. CLASSIFICATION SELECTIVE α1 Prazosin Terazosin Doxazosin Tamsulosin Alfuzosin Urapidil Indoramin SELECTIVE α2 Yohimbine Idazoxan Rauwolscine
9. GENERAL EFFECTS  Vasodilatation  Decreased tone of smooth muscle in bladder trigone, sphincter and prostate  Increased Intestinal motility  Miosis  Contraction of vas deferens and related organs
10. INDIVIDUAL DRUGS 1) PHENOXYBENZAMINE  Haloalkylamine  Greater affinity to α1 receptors
11. Actions:  Forms strong covalent bonds with α receptors  Reflex tachycardia ;Fall in BP is mainly postural  Shifts blood from pulmonary to systemic system  Penetrates BBB
12. Pharmacokinetics  IV / Oral  Accumulates in adipose tissue Uses:  Pheochromocytoma  Hypertension  Shock  Peripheral vascular disease (PVD)
13. PHENOXYBENZAMINE Adverse effects Orthostatic hypotension Tachycardia Vertigo Sexual dysfunction
14. 2) PHENTOLAMINE  Non selective  Equally blocks α1 & α2 receptors  Short acting Uses  Pheochromocytoma  Hypertension  Erectile dysfunction
15. Adverse Effects  Hypotension  Arrhythmias  Nasal congestion and headache  Abdominal pain, nausea and exacerbation of peptic ulcer
16. α1 SELECTIVE BLOCKERS 1) PRAZOSIN  Quinazoline Actions:  Vasodilatation → postural hypotension  First dose effect – fainting & dizziness  Inhibits phosphodiesterase
17. Pharmacokinetics  Orally effective  Highly plasma protein bound  Metabolized in liver and excreted in bile Uses  Hypertension  BPH  CCF
18. PRAZOSIN 18 Peripheral Blood vessel Bladder neck Prostate With α1 Blocker Without α1 Blocker
19. 2) TERAZOSIN  Chemically and pharmacologically similar to prazosin  More water soluble, higher oral bioavailability and longer plasma t ½  Duration of action extends beyond 18 hours, once daily dosing  Use – More popular than prazosin in BPH
20. 3) DOXAZOSIN  Congener of prazosin with similar pharmacological profile.  t ½ - 20 hours  Duration of action – 36hrs.  Use – BPH and hypertension.
21. 4) TAMSULOSIN  Uroselective (α1A) alpha blocker.  No CVS side effects like Postural hypotension BP/HR changes at low doses  Use – BPH (dose of 0.4mg/day)  ADR – dizziness and impaired ejaculation
 22. SUMMARY  Important in management of Pheochromocytoma BPH Hypertension PVD  ADR Postural hypotension, reflex tachycardia Nasal stuffiness, sexual dysfunction
Calcium channel blockers
1. Calcium channel blockers Symposium on : Antihypertensive drugs.. Presented by : AASHNA DHINGRA Roll no. 03
2.  INTRODUCTION  CLASSIFICATION  MECHANISM OF ACTION  PHARMACOLOGICAL ACTIONS  PHARMACOKINETICS  USES  ADVERSE EFECTS  CONTRAINDICATIONS Layout of
the presentation :
3. INTRODUCTION.. also known as calcium antagonists.  prevent calcium from infiltrating the cells of the heart and blood vessel walls. relaxes and widens blood vessels of the heart within the arterial walls,
promoting lowered blood pressure. may also slow the heart rate, relieve chest pressure and control an irregular heartbeat.
4.  they are first line antihypertensive drugs.  the onset of antihypertensive action is quick.  monotherapy with CCBs is effective in about 50% of the hypertensives.  can also be used for treating angina.
5.  PHENYLAKYLAMINES Verapamil Very  1,4-DIHYDROPYRIDINES  Nifedipine Nice  BENZOTHIAZEPINES Diltiazem
6. 1,4 dihydopyrimidines are selective for the arteriolar beds. The phenylalkylamines and benzothiazepines are selective for the atrioventricular node.
7. Short-acting • nifedipine, dilatiazem, verapamil Long-acting • amlodipine, felodipine, isradipine, nicardipine, nisoldipine,
8. Mechanism of action.. O Calcium channels are of 5 subtypes- L, N, T, P, and R. o L-type in cardiac and smooth muscle cells.

9. Moa : CCBs block voltage sensitive L- type Ca channels by binding to specific site on the α-1 subunit. Prevent entry of Ca into cell. No excitation-coupling reaction in heart and vascular smooth muscles.
10.  Increase the time that Ca2+ channels are closed.  Relaxation of the arterial smooth muscle.  Significant reduction in afterload.  Coronary vasodilatation. PHARMACOLOGICAL ACTIONS..

11. PHARMACOKINECTICS..  well absorbed through Git.  first pass metabolism.  highly bound to plasma proteins.  metabolised in liver.  excreted through urine.
12. USES OF CCBs.. 1. angina pectoris – Due to decrease in myocardial oxygen consumption, and dilatation of coronary arteries. 2. supraventicular arrhythmias – because of its depressant action on S-A and A-V nodes. 3.
hypertension – they control blood pressure by their vasodilatory effect. 4. Migraine 5. raynaud’s phenomenon – due to their vasodilatory property.
13. ADVERSE EFFECTS..  Postural hypotension  palpitation  reflex tachycardia  edema  dizziness  constipation  sedation  A-V block  headache  fatigue  lowered B.P.
 14. CONTRAINDICATIONS o Heart failure o Bradycardia o Atrioventricular block. O Dihydropyridine calcium-channel blockers should not be used in people with uncontrolled heart failure.
Antihypertensive drugs
1. Antihypertensive Drugs S. Parasuraman, M.Pharm., Ph.D., Senior Lecturer, Faculty of Pharmacy, AIMST University
2. Etiology of Hypertension • A specific cause of hypertension established in only 10–15% of patients. • Patients in whom no specific cause of hypertension are said to have essential or primary hypertension. • Patients with a specific etiology are said to have secondary hypertension. • Genetic factors, psychological stress, and environmental and dietary factors as contributing to the development of hypertension. The heritability of essential hypertension is estimated to be about 30%.
3. Classification of hypertension on the basis of blood pressure JNC 7; 2003
4. Normal Regulation of Blood Pressure According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR) • BP = CO × PVR
5. Blood pressure is maintained by • Moment-to-moment regulation of cardiac output and peripheral vascular resistance exerted at three anatomic sites arterioles, postcapillary venules (capacitance vessels), and heart. • Kidney • Baroreflexes mediated by autonomic nerves (combination with humoral mechanisms, including the renin-angiotensin-aldosterone system) • Local release of vasoactive substances
6. Antihypertensive agents • Diuretics – Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide – High ceiling: Furosemide, Torsemide, ethacrynic acid. – K+ Sparing: Spironolactone, Amiloride • ACE inhibitors – Captopril, Enalapril, Lisinopril, Perindopril, Ramipril, Fosinopril, etc. • Angiotensin (AT1 receptor) blockers: Losartan, Candesartan, Irbesartan, Valsartan, Telmisartan • Direct renin inhibitor: Aliskiren • β Adrenergic blockers: Propranolol, Metoprolol, Atenolol, etc.
7. Antihypertensive agents • Calcium channel blockers – Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine, Lacidipine, etc. • β + α Adrenergic blockers: Labetalol, Carvedilol • α Adrenergic blockers: Prazosin, Terazosin, Doxazosin, Phentolamine, Phenoxybenzamine • Central sympatholytics: Clonidine, Methyldopa • Vasodilators – Arteriolar: Hydralazine, Minoxidil, Diazoxide – Arteriolar + venous: Sodium nitroprusside • Others: Adrenergic neurone blockers (Reserpine, Guanethidine, etc.), Ganglion blockers (Pentolinium, etc.)
8. Sites of action of the major classes of antihypertensive drugs
9. Diuretics • Thiazide diuretics: Thiazide diuretics, such as hydrochlorothiazide and chlorthalidone, lower blood pressure initially by increasing sodium and water excretion. Thiazide diuretics can induce hypokalemia, hyperuricemia and, to a lesser extent, hyperglycemia in some patients.
10. Diuretics • Loop diuretics: • Inhibitors of epithelial sodium transport at the late distal and collecting ducts (furosemide, and ethacrynic acid) or antagonizing aldosterone receptor (spironolactone, and eplerenone) and reduce potassium loss in the urine. • Aldosterone antagonists have the additional benefit of diminishing the cardiac remodeling that occurs in heart failure.
11. Diuretics • Loop diuretics: • The loop diuretics act promptly by blocking sodium and chloride reabsorption in the kidneys, even in patients with poor renal function or those who have not responded to thiazide diuretics. Loop diuretics cause decreased renal vascular resistance and increased renal blood flow.
12. Diuretics • K+ Sparing: • potassium-sparing diuretics (spironolactone, and eplerenone) are competitive antagonists that either compete with aldosterone, or directly block epithelial sodium channel (amiloride).
13. ACE inhibitors Renin Inhibitors ACE Inhibitors Angiotensin blockers
14. ACE inhibitors • The ACE inhibitors, are recommended as first-line treatment of hypertension in patients with a variety of compelling indications, including high coronary disease risk or history of diabetes, stroke, heart failure, myocardial infarction, or chronic kidney disease.
15. ACE inhibitors • ACE is also responsible for the breakdown of bradykinin, a peptide that increases the production of nitric oxide and prostacyclin by the blood vessels. Both nitric oxide and prostacyclin are potent vasodilators.
16. ACE inhibitors • ACE inhibitors decrease angiotensin II and increase bradykinin levels. Vasodilation is result of decreased vasoconstriction (from diminished levels of angiotensin II) and enhanced vasodilation (from increased bradykinin). • By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention. • ACE inhibitors reduce both cardiac preload and afterload, thereby decreasing cardiac work.
17. ACE inhibitors Comparative features of some ACE inhibitors
18. ACE inhibitors Adverse effects of ACE inhibitors: • The adverse effect profile of all ACE inhibitors is similar. Captopril is well tolerated by most patients, especially if daily dose is kept below 150 mg. • Hypotension: An initial sharp fall in BP occurs especially in diuretic treated and CHF patients • Hyperkalaemia • Cough • Rashes, urticaria • Angioedema
19. ACE inhibitors Adverse effects of ACE inhibitors: • Dysgeusia/ parageusia • Foetopathic • Headache, dizziness, nausea and bowel upset • Granulocytopenia and proteinuria (rare ADR) • Acute renal failure
20. ACE inhibitors Advantages of ACE inhibitor: • Free of postural hypotension, electrolyte disturbances, feeling of weakness and CNS effects • Safety in asthmatics, diabetics and peripheral vascular disease patients • Long-term ACE inhibitor therapy has the potential to reduce incidence of type 2 diabetes in high risk subjects • No rebound hypertension on withdrawal
21. ACE inhibitors Advantages of ACE inhibitor: • No hyperuricaemia, no deleterious effect on plasma lipid profile • ACE inhibitors are the most effective drugs for preventing sudden cardiac death in post-infarction patients. However, they are less effective for primary prophylaxis of MI and for preventing left ventricular hypertrophy.
22. Uses of ACE inhibitors • Hypertension: – The ACE inhibitors are first line drugs in all grades of hypertension, but the angiotensin receptor blockers (ARBs) have now surpassed them in popularity. – Essential hypertension respond to monotherapy with ACE inhibitors and majority of the rest to their combination with diuretics or beta blockers.
23. Uses of ACE inhibitors • Congestive Heart Failure (CHF): ACE inhibitors cause both arteriolar and venodilatation in CHF patients; reduce afterload as well as preload. • Myocardial infarction: Long-term ACE inhibitor therapy reduces recurrent MI. • Prophylaxis in high cardiovascular risk subjects: ACE inhibitors are protective in high cardiovascular risk subjects even when there is no associated hypertension or left ventricular dysfunction. ACE inhibitors may improved endothelial function.
24. Uses of ACE inhibitors • Diabetic nephropathy: Prolonged ACE inhibitor therapy has been found to prevent or delay end- stage renal disease in type I as well as type II diabetics. • Nondiabetic nephropathy: ACE inhibitors reducing proteinuria by decreasing pressure gradient across glomerular capillaries as well as by altering membrane permeability. • Scleroderma crisis: The marked rise in BP and deterioration of renal function in scleroderma crisis is mediated by Ang II. ACE inhibitors produce improvement and are life saving in this condition.
25. Angiotensin antagonists (ARBs) • Angiotensin antagonists: losartan, candesartan, valsartan, telmisartan, olmesartan and irbesartan. • Their pharmacologic effects of ARBs are similar to those of ACE inhibitors. • ARBs produce arteriolar and venous dilation and block aldosterone secretion, thus lowering blood pressure and decreasing salt and water retention. • ARBs do not increase bradykinin levels. • ARBs may be used as first-line agents for the treatment of hypertension, especially in patients with a compelling indication of diabetes, heart failure, or chronic kidney disease.
26. Direct renin inhibitor • A selective renin inhibitor, aliskiren directly inhibits renin and, thus, acts earlier in the renin– angiotensin–aldosterone system than ACE inhibitors or ARBs. • It lowers blood pressure about as effectively as ARBs, ACE inhibitors, and thiazides. Aliskiren should not be routinely combined with an ACE inhibitor or ARBs. • Aliskiren can cause diarrhea, especially at higher doses, and can also cause cough and angioedema, but probably less often than ACE inhibitors. • Aliskiren is contraindicated during pregnancy.
27. β-adrenergic blockers • β-adrenergic blockers are mild antihypertensives and do not significantly lower BP in normotensives. In stage 1 cases of hypertensive patients (30 – 40%), β- adrenergic blockers are used alone.
28. β-adrenergic blockers Propranolol • Propranolol is a first β blocker showed effective in hypertension and ischemic heart disease. • Propranolol has now been largely replaced by cardioselective β blockers such as metoprolol and atenolol. • All β-adrenoceptor-blocking agents are useful for lowering blood pressure in mild to moderate hypertension. • In severe hypertension, β blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators.
29. β-adrenergic blockers Metoprolol & Atenolol • Metoprolol and atenolol, which are cardioselective, are the most widely used β blockers in the treatment of hypertension. • Metoprolol is atenolol is inhibiting stimulation of β1 adrenoceptors. • Sustained-release metoprolol is effective in reducing mortality from heart failure and is particularly useful in patients with hypertension and heart failure. • Atenolol is reported to be less effective than metoprolol in preventing the complications of hypertension.
30. β-adrenergic blockers Other beta blockers • Nadolol and carteolol, nonselective β-receptor antagonists • Betaxolol and bisoprolol are β1-selective blockers • Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity. These drugs are particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease.
31. β-adrenergic blockers Other beta blockers • Nadolol and carteolol, nonselective β-receptor antagonists • Betaxolol and bisoprolol are β1-selective blockers • Pindolol, acebutolol, and penbutolol are partial agonists, ie, β blockers with some intrinsic sympathomimetic activity. These drugs are particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease.
32. β-adrenergic blockers Other beta blockers • Labetalol, Carvedilol, & Nebivolol have both β- blocking and vasodilating effects. • Esmolol is a β1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia or when there is concern about toxicity such as aggravation of severe heart failure.
33. α-Adrenergic blockers Prazosin, terazosin, and doxazosin • Prazosin is a prototype α1-adrenergic blocking agent. • Terazosin and doxazosin are long-acting congeners of prazosin • Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. Other alpha-adrenoceptorblocking agents • phentolamine (reversible nonselective α-adrenergic antagonist) and phenoxybenzamine (non-selective, irreversible alpha blocker) are useful in diagnosis and treatment of pheochromocytoma.
34. Centrally acting adrenergic drugs Clonidine • Clonidine acts centrally as an α2 agonist to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery. This leads to reduced total peripheral resistance and decreased blood pressure. At present, it is occasionally used in combination with a diuretic. Methyldopa • It is an α2 agonist that is converted to methylnorepinephrine centrally to diminish adrenergic outflow from the CNS. It is mainly used for management of hypertension in pregnancy, where it has a record of safety.
35. Vasodilators • Hydralazine/Dihydralazine and minoxidil not used as primary drugs to treat hypertension. These vasodilators act by producing relaxation of vascular smooth muscle, primarily in arteries and arterioles. This results in decreased peripheral resistance. • Both agents produce reflex stimulation of the heart, resulting in the competing reflexes of increased myocardial contractility, heart rate, and oxygen consumption. • Hydralazine is an accepted medication for controlling blood pressure in pregnancy induced hypertension. This drug is used topically to treat male
pattern baldness.
36. Treatment of hypertension • Hypertensive emergency: It is rare but life- threatening condition (systolic BP >180 mm Hg or diastolic BP >120 mm Hg with evidence of impending or progressive target organ damage such as stroke, myocardial infarction). • A variety of medications are used, including calcium channel blockers (nicardipine and clevidipine), nitric oxide vasodilators (nitroprusside and nitroglycerin), adrenergic receptor antagonists (phentolamine, esmolol, and labetalol), the vasodilator hydralazine, and the dopamine agonist fenoldopam.
37. Treatment of hypertension • Resistant hypertension: It is defined as blood pressure that remains elevated despite administration of an optimal three-drug regimen that includes a diuretic. The most common causes of resistant hypertension – poor compliance – excessive ethanol intake – concomitant conditions (diabetes, obesity, sleep apnea, hyperaldosteronism, high salt intake, metabolic syndrome) – concomitant medications (sympathomimetics, nonsteroidal anti-inflammatory drugs, or antidepressant medications) – insufficient dose/ drug
38. Treatment of hypertension • Summary of WHO-ISH and British Hypertension Society (BHS) 2004, guidelines – Except for stage II hypertension, start with a single most appropriate drug – Follow A B C D rule (A—ACE inhibitor/ARB; B—β blocker; C—CCB, D—diuretic). While A and (in some cases) B are preferred in younger patients (<55 years), C and D are preferred in the older (> 55 years) for the step I or monotherapy. – Initiate therapy at low dose; if needed increase dose moderately. – If only partial response is obtained, add a drug from another complimentary class
or change to low dose combination
39. Treatment of hypertension • Summary of WHO-ISH and British Hypertension Society (BHS) 2004, guidelines – If no response, change to a drug from another class, or low dose combination from other classes – In case of side effect to the initially chosen drug, either substitute with drug of another class or reduce dose – Majority of stage II hypertensives are started on a 2 drug combination
40. Treatment of hypertension in patients with concomitant diseases
41. Combinations to be avoided Combination Possible effects An α or β adrenergic blocker with clonidine Apparent antagonism of clonidine action has been observed. Hydralazine with a dihydropyridine (DHP) or prazosin haemodynamic action Verapamil or diltiazem with β blocker bradycardia, A-V block can Methyldopa with clonidine or any two drugs of the same class
 42. Antihypertensives & pregnancy Antihypertensives to be avoided during pregnancy Antihypertensives found safer during pregnancy ACE inhibitors, ARBs: Risk of foetal damage, growth retardation. Hydralazine Methyldopa Diuretics: increase risk of foetal wastage, placental infarcts, miscarriage, stillbirth. Dihydropyridine CCBs: if used, they should be discontinued before labour as they weaken uterine contractions. Nonselective β blockers: Propranolol cause low birth weight, decreased placental size, neonatal bradycardia and hypoglycaemia. Cardioselective β blockers
and those with ISA, e.g. atenolol, metoprolol, pindolol, acebutolol: may be used if no other choice. Sod. Nitroprusside: Contraindicated in eclampsia. Prazosin and clonidine-provided that postural hypotension can be avoided.
Nifedipine is a calcium channel blocker in the dihydropyridine subclass. It is primarily used as an antihypertensive and as an anti-anginal medication. FDA-approved indications include chronic stable angina, hypertension. It also has other off-label indications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of nifedipine, so providers can direct patient therapy successfully in instances where nifedipine provides a benefit to patient care.

Objectives:

Identify the mechanis m of action of nifedipine.

Discuss the therapeutic mechanism of action of nifedipine.

Summarize the adverse event profile associated with nifedipine therapy.

Review the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with nifedipine.

Access free multiple choice questions on this topic.

Indications

Nifedipine is a calcium channel blocker that belongs to the dihydropyridine subclass. It is primarily used as an antihypertensive and antianginal medication.

FDA Approved Indications[[1][2][2][3][4][5][6]

Chronic stable angina – Nifedipine reduced the frequency of angina and increased the mean exercise time in the IMAGE trial. Reflex tachycardia may limit its effectiveness; the addition of a beta-blocker can overcome this limitation. A long-acting formulation is preferred (extended-release).

Vasospastic angina – It can be used as a second line of treatment.

Hypertension – May be used as monotherapy or in combination with several different medications to manage hypertension (such as ACE inhibitor, ARB, thiazide diuretic).

Off-label Uses [7] [8] [9] [10] [11]

Raynaud phenomenon

Severe hypertension during pregnancy and post-partum hypertens ion

High altitude pulmonary edema

Pulmonary arterial hypertension (group 1)

Achalasia

Distal ureteric calculi

Tocolysis
M echanism of Action

During the depolarization phase of smooth muscle cells, there is an influx of calcium ions through voltage-gated channels. Nifedipine inhibits the entry of calcium ions by blocking these voltage-dependent L-type calcium channels in vascular smooth muscle and myocardial cells. Reduced intracellular calcium reduces peripheral arterial vascular resistance and dilatation of coronary arteries, leading to a reduction in sys temic blood pressure and increased myocardial oxygen delivery. Nifedipine thus has hypotensive and antianginal properties.

Adminis tration

Nifedipine is available in both immediate and extended-release preparations. Its initial marketing was in a short-acting, immediate-release formulation that required multiple daily dosing. These preparations caused rapid vasodilation followed by reflex sympathetic activation, resulting in side effects such as headaches, palpitations, and flushing. These side effects led to the launch of extended-release preparations, which have shown to have a sustained 24-hour anti-hypertensive effect and fewer side effects.

Extended-release preparations are available in 30, 60, and 90 mg tablets. Dosage adjustments should ideally occur at 7- to 14-day intervals. The same total daily dosage should apply when switching from immediate to extended-release preparations. Patients may take immediate-release formulations without regard to meals . A few specific extended-release preparations require ingestion on an empty stomach.

Immediate-release preparations have an onset of action within 20 minutes with a plasma half-life of about 4 to 7 hours. Extended-release preparations have an approximate duration of action of about 24 hours. It undergoes hepatic metabolism via the CYP3A4 pathway. Extended-release preparations have a bioavailability of up to 89% relative to the immediate-release formulation. Bioavailability significantly increases in patients with liver failure necessitating dosage adjustment (due to reduced clearance of the medication).

Recommended Dosages

Chronic Stable Angina

Immediate-release: 10 to 20 mg three times daily; maximum dose of 180 mg per day

Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day

Vasospastic Angina

Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day

Hypertension

Extended-release: 30 or 60 mg daily; maximum dose of 120 mg per day

Hypertensive Emergency During Pregnancy or Postpartum Period

Immediate-release: 10 mg; may repeat with a 20 mg dose in 20 minutes

Adverse Effects

Adverse effects present in about 20 to 30% of patients prescribed nifedipine. These are primarily the result of the vasodilatory properties of nifedipine.

The mos t common adverse effects include flushing, peripheral edema, dizziness, headache. Tolerance is better with the extended-release preparations than the immediate-release preparations of nifedipine. Hypersensitivity reactions, such as pruritus, urticaria, and bronchospasms, are relatively rare. Abrupt discontinuance of the drug after prolonged use may lead to rebound hypertension or angina.

Contraindications

Absolute Contraindication

Hypersensitivity to nifedipine or its components

ST-elevation myocardial infarction [12]

Relative Contraindication

Severe aortic stenosis

Unstable angina

Hypotension

Heart failure

M oderate to severe hepatic impairment

In patients with unstable angina/non-STEM I, the use of immediate-release nifedipine is not a recommendation except with concomitant beta-blockade.[13] Immediate-release preparations of nifedipine (sublingually or orally) should be avoided in patients within hypertens ive emergencies and urgencies as it is neither safe nor effective.[14] In cardiogenic shock, the heart cannot pump effectively, and this situation is exacerbated by inhibiting the influx of calcium ions into cardiac cells.[13] In severe aortic stenosis, nifedipine can cause ventricular collapse and dysfunction. In unstable angina, nifedipine causes a reflexive increase in cardiac contractility, which increases myocardial oxygen demand and worsens the ischemia. Nifedipine can exacerbate hypoperfusion to vital organs in patients with severe hypotension.[13] Furthermore, patients with hepatic impairment may not be able to metabolize nifedipine, leading to a longer half-life, putting them at an increased risk of toxicity and side effects.

M onitoring

In general, there is no required laboratory monitoring for patients taking nifedipine. Since nifedipine is an antihypertensive medication, clinicians and patients should regularly measure blood pressure to achieve target levels. Patients should undergo monitoring for adverse side effects such as peripheral edema, dizziness, flushing.

Toxicity

Treatment of overdos e varies with the amount taken, duration since ingestion, age and, co-morbidities of the patient. Initial assessment involves securing airway, breathing, circulation, appropriate blood work, including testing for coingestants. Early consultation with poison control/ toxicology should be a priority.

An overdose of nifedipine can lead to systemic vasodilation, severe hypotension, and reflex tachycardia. Prolonged systemic hypotension can progress to shock and even death. Activated charcoal at a dose of 1 g/kg is useful if the patient presents within 1 to 2 hours of ingestion. Whole bowel irrigation should be a consideration with extended-release preparations or large quantity ingestion. Nasogastric lavage is usually ineffective. Intravenous fluid resuscitation, calcium salts, and vasopressor therapy with dopamine or norepinephrine usually alleviate the hypotension. Administration of high-dose insulin is an option as it has been shown to lower mortality and improve hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes require continuous monitoring. For intentional ingestion, psychiatric cons ultation is also necessary. Patients presenting with an overdose of immediate-releas e preparations need observation for 4 to 7 hours. For extended-release preparations, 24 hours of telemetry observation is ideal.

No specific antidote is available.

Enhancing Healthcare Team Outcomes

All interprofessional healthcare team members should be familiar with the indications and contraindications of nifedipine. This includes all clinicians (including specialis ts, NPs, and Pas), nurses, and pharmacists. The drug can cause severe hypotension, and thus it is recommended that the dosing undergo titration from an initial low dose. Long-term patient monitoring is necessary to determine its effectiveness. Sublingual preparations are no longer recommended agents for hypertensive emergencies or urgencies due to lack of efficacy data and numerous severe adverse events such as an uncontrollable decrease in blood pres sure, reflex tachycardia, and cerebral ischemia/infarction.

 Given the risks, prescribing/ordering clinicians should strive to work with the interprofessional team when using nifedipine. Pharmacists should have involvement to verify dosing, particularly with the dosing differences between release formulations. They also need to conduct medication reconciliation to alert the team to any potential drug-drug interactions. Nurses will be administering the drug inpatient and are on the front lines for observing both treatment effectiveness as well as adverse events, which they should report to the clinician immediately. This collaborative interprofessional approach between clinicians, nursing, and pharmacy will better advance patient outcomes with nifedipine therapy.
GLAUCOMA
2. GLAUCOMA Glaucoma : is a group of eye diseases in which the optic eye nerves is damaged leading to irreversible loss of vision, in the most cases this damage is due to increase pressure within the eye .
3. GLAUCOMA caused by : - increased intraocular pressure / ocular hypertension (high pressure of fluids “aqueous humor” within the eye), complication: - possible optic nerve damage.
4. liquid aqueous humor: produced by ciliary bodies, flows into posterior chamber, flows through pupil, flows into anterior chamber, drained by trabecular meshwork.
5. In a healthy eye the rate of secretion is balanced with the rate of drainage. In glaucoma, the drainage canal is partially or completely blocked, fluids build up in the eye chamber leading to increased pressure.
6. GLAUCOMA There are two type of glaucoma open angel and closed angle glaucoma . Open angle glaucoma (chronic glaucoma) is caused by partial blockage of the drainage canal . Closed angle glaucoma ( acute glaucoma )is caused by sudden or complete blockage of aqueous humor drainage the pressure
within the eye.
7. GLAUCOMA open /wide-angle glaucoma 1) degeneration & obstruction of trabecular meshwork. 2)reducing drainage of aqueous humor 3)increased resistance & chronic buildup of pressure in the eye. Close/narrow-angle glaucoma 1)complete closure of iridocorneal angle. 2)reducing flow of aqueous
humor from posterior chamber to anterior chamber. 3)increased resistance & acute pressure in the eye.
8. –The aim is to lower intra-ocular pressure –Topically (B-blockers, parasympathomimetics) OR systemic (carbonic anhydrase inhibitors, osmotic diuretics) –First line therapy: B-blocker, prostaglandin analoges, alpha 2 agonist and carbonic anhydrase inhibitor .
9. Treatment of open angle glaucoma B-blockers:  First choice of treatment.  MOA: block beta receptors in the ciliary epithelium and reduce the secretion of aqueous humour.  Side effects: bradycardia, headache, dyspnea.
10. Treatment of open angle glaucoma prostaglandin analoges:  Are used topically to lower intra-ocular pressure.  Examples: travoprost , bimatoprost , latanoprost . Alpha 2 agonist:  Example : brimonidine .
11. Treatment of open angle glaucoma Carbonic anhydrase inhibitors :  Used with the previous medications.  MOA: reduce production of aqueous humour.  Side effects: confusion, drowsiness, nausea.
12. Treatment of open angle glaucoma parasympathomimetics:  MOA: facilitate ocular drainage by constricting the pupil and pulling open the meshwork.  Side effects: blurred vision, brow ache, itching.  Pilocarpine eye drop  carbachol
13. Treatment of open angle glaucoma  Eye drops contain tow medications.
14. Treatment of closed angle glaucoma  Should be started within 24 -48 hours .  If it is delayed : - adhesion may form between the iris and the cornea. – the ocular meshwork may be damaged. – leads to chronic closed angle glaucoma then loss vision (absolute glaucoma).
15. Treatment of closed angle glaucoma  parasympathomimetics : e.g. pilocarpine.  carbonic anhydrase inhibitors : e.g. acetazolamide.  osmotic diuretics : e.g. mannitol and urea (IV), glycerol or isosorbide (orally).  prostaglandin : which is used topically to lower intra- ocular pressure.
16. Treatment of closed angle glaucoma Osmotic diuretic :  Used in the short-term management of glaucoma prior to surgery.  MOA: reduce vitreous volume and cause marked reduction in intra-ocular pressure.  Side effects: oral dryness, ocular dryness, headache, dizziness.
17. – Usually we start with the non-surgical treatment if it was not effective, we go to laser therapy and lastly we go to surgical treatment. – But in emergency cases (closed-angle glaucoma) the surgery is the first choice.
18. Surgical treatment of glaucoma Patient who have had a previous ocular surgery there is a high failure rate, due to formation of scar tissue. We can give injection of anti-proliferative agent such as fluorouracil, that has been shown to reduce the failure rate of surgery. (S/E: increased epithelial toxicity and
conjunctival wound leaks).
19.  After the surgery we give antibacterial and anti- inflammatory drugs, on the afternoon of the same day of the surgery , we measure the ocular pressure and if we observe that the pressure started to rise (20 mmHg instead of 15 mmHg), we give anti-glaucoma drug, but we have to be careful not to mix them
with the post- operative drugs, we give them in different times. OR we give Diamox® tablets after the surgery as an anti- glaucoma agent. Surgical treatment of glaucoma
20.  Anti-bacterial agents:  Dexacol®: eye drops (Chloramphenicol,Dexamethasone) Steroidal antibacterial drug.  Zymar®: ophthalmic solution (Gatifloxacin-fluoroquinolone): Antibacterial that is active against pathogens that are resistant to other antibiotics. Post-operative agents
21.  Anti-inflammatory agents:  Nevanac® (Nepafenac 0.1%): non-steroidal anti-inflammatory drug (NSAID).  Pred Forte® (Prednisolone acetate): steroidal anti-inflammatory drug. Surgical treatment of glaucoma
 22.  Martindale, The extra pharmacopoeiua, the thirty-first edition. Referances
Myasthenia Gravis RVS Chaitanya koppala
2. INTRODUCTION  Myasthenia gravis (MG) is a complex, autoimmune disorder in which antibodies destroy neuromuscular connections.  Causes problems with the nerves that communicate with muscles.  Affects the voluntary muscles of the body, especially the eyes, mouth, throat, and limbs.
3.  Characterized by weakness and rapid fatigue of any of the muscles under the voluntary control.  The cause of myasthenia gravis is a breakdown in the normal communication between nerves and muscles.  No cure for myasthenia gravis, but treatment can help relieve signs and symptoms – such as weakness of arm or leg muscles, double vision, drooping eyelids, and difficulties with speech, chewing, swallowing and breathing.
4. TYPES OF MYASTHENIA GRAVIS Three types of MG in children:  Congenital MG – Very rare non-immune form of MG that is inherited as an autosomal recessive disease.  Symptoms of congenital MG usually begin in the baby’s first year and are life-long.  Transient neonatal MG – Between 10 and 20 percent of babies born to mothers with MG may have a temporary form of MG.  Neonatal MG usually lasts only a few weeks, and babies are not at
greater risk for developing MG later in life.  Juvenile MG – This auto-immune disorder develops typically in female adolescents.  It is a life-long condition that may go in and out of remission. About 10 percent of MG cases are juvenile-onset.
5. SYMPTOMS  Babies with neonatal MG may be weak, with a poor suck, and may have respiratory difficulty. A few babies may need the help of a mechanical breathing machine if their respiratory muscles are too weak to breathe on their own.  Congenital MG symptoms may begin in the first year, with generalized weakness in the arms and legs, and delays in motor skills such as crawling, sitting, and walking  Juvenile MG symptoms may begin gradually over
weeks or months. The child may become excessively tired after very little activity, and begin to have problems chewing and swallowing. Drooping eyelids may be so severe that the child cannot see.
6. Eye muscles In more than half the people who develop MG, their first signs and symptoms involve eye problems:  Drooping of one or both eyelids (ptosis)  Double vision (diplopia), which may be horizontal or vertical  Blurred vision, which may come and go
7. Face and throat muscles In about 15 percent of people with myasthenia gravis, the first symptoms involve face and throat muscles, which can cause difficulties with:  Speaking. The speech may be very soft or sound nasal, depending upon which muscles have been affected.  Swallowing. May choke very easily, which makes it difficult to eat, drink or take pills. In some cases, liquids may come out of the nose.  Chewing. The muscles used for chewing may wear
out halfway through a meal, particularly if eating something hard to chew, such as sugarcane.  Facial expressions. Family members may note “lost smile” if the muscles that control facial expressions are affected.
8. Arm and leg muscles  Myasthenia gravis can cause weakness in arms and legs, but this usually happens in conjunction with muscle weakness in other parts of the body – such as eyes, face or throat.  The disorder usually affects arms more often than legs.  If it affects legs, may waddle when walking. Normal dumbbell Weakness dumbbell
9. When to see a doctor If having trouble with:  Breathing  Seeing  Swallowing  Chewing  Walking
10. CAUSES  Myasthenia gravis may be inherited, genetic disease, acquired by babies born to mothers with MG  Nerves communicate with the muscles by releasing chemicals, called neurotransmitters, which fit precisely into receptor sites on the muscle cells.  In myasthenia gravis, immune system produces antibodies that block or destroy many of the muscles’ receptor sites for a neurotransmitter called acetylcholine.  With fewer receptor sites available, muscles
receive fewer nerve signals, resulting in weakness.

11. Chemicals messengers, called neurotransmitters, fit precisely into receptor sites on your muscle cells. In myasthenia gravis, certain receptor sites are blocked or destroyed, causing muscle weakness.
12.  It’s believed that the thymus gland, a part of the immune system located in the upper chest beneath the breastbone, may trigger or maintain the production of these antibodies.  Large in infancy, the thymus is small in healthy adults. But, in some adults with myasthenia gravis, the thymus is abnormally large.  Some people also have tumors of the thymus.  Usually, thymus gland tumors are noncancerous.
13. Thymus gland, a part of your immune system located in the upper chest beneath the breastbone, may trigger or maintain the production of antibodies that result in the muscle weakness common in MG.
14. Factors worsening MG  Fatigue  Illness  Stress  Extreme heat  Medications – such as beta blockers, calcium channel blockers, quinine and some antibiotics
15. COMPLICATIONS  Myasthenic crisis: A life-threatening condition, which occurs when the muscles that control breathing become too weak to do their jobs. Emergency treatment is needed to provide mechanical assistance with breathing.  Thymus tumors: About 15 percent of the people who have myasthenia gravis have a tumor in their thymus, a gland under the breastbone that is involved with the immune system. Most of these tumors are noncancerous.
16. Other disorders  Underactive or overactive thyroid. The thyroid gland, located in the neck, secretes hormones that regulate metabolism. If thyroid is underactive, body uses energy more slowly. An overactive thyroid makes body use energy too quickly.  Lupus. Disease of immune system. Common symptoms include painful or swollen joints, hair loss, extreme fatigue and a red rash on the face.  Rheumatoid arthritis. Caused by problems with immune system. It
is most conspicuous in the wrists and fingers, and can result in joint deformities that make it difficult to use hands.
17. Diagnostic tests  Blood tests  Genetic tests – diagnostic tests that evaluate for conditions that have a tendency to run in families.  Electromyogram (EMG) – a test that measures the electrical activity of a muscle or a group of muscles. An EMG can detect abnormal electrical muscle activity due to diseases and neuromuscular conditions.  Muscle biopsy – a small sample of the muscle is removed and examined to determine and confirm a diagnosis or condition.
18.  Reflexes  Muscle strength  Muscle tone  Senses of touch and sight  Coordination  Balance
19.  Edrophonium test: Injection of the chemical edrophonium (Tensilon) may result in a sudden, although temporary, improvement in muscle strength — an indication that you may have myasthenia gravis. Edrophonium acts to block an enzyme that breaks down acetylcholine, the chemical that transmits signals from nerve endings to muscle receptor sites.  Blood analysis: A blood test may reveal the presence of abnormal antibodies that disrupt the receptor sites
where nerve impulses signal muscles to move.
20.  Repetitive nerve stimulation: Is a type of nerve conduction study, in which electrodes are attached to skin over the muscles to be tested. To diagnose MG, the nerve will be tested many times to see if its ability to send signals worsens with fatigue.  Single-fiber electromyography (EMG): EMG measures the electrical activity traveling between brain and muscle. It involves inserting a very fine wire electrode through skin and into a muscle. In single-fiber EMGs, a
single muscle fiber is tested.  Imaging scans: CT scan or an MRI to confirm a tumor or other abnormality in thymus.
21. TREATMENTS & DRUGS  Specific treatment to age, overall health, and medical history and extent of the condition  No cure for MG, but the symptoms can be controlled.  MG is a life-long medical condition and the key to medically managing MG is early detection.  The goal of treatment is to prevent respiratory problems and provide adequate nutritional care to the child since the swallowing and breathing muscles are affected by this condition.
22. Medications  Cholinesterase inhibitors. Drugs like pyridostigmine (Mestinon) enhance communication between nerves and muscles. These drugs don’t cure, but improves muscle contraction and strength.  Corticosteroids. These types of drugs inhibit the immune system, limiting antibody production. Prolonged use of corticosteroids, can lead to serious side effects, like bone thinning, weight gain, diabetes, increased risk of some infections, and increase and
redistribution of body fat.  Immunosuppressants. Doctor may also prescribe other medications that alter immune system, like azathioprine (Imuran), cyclosporine (Sandimmune, Neoral) or mycophenolate (CellCept).
23. How antibodies against acetylcholine receptor block impulse conduction in synapse
24. Therapy  Plasmapheresis. This procedure uses a filtering process similar to dialysis. Blood is routed through a machine that removes the antibodies that are blocking transmission of signals from nerve endings to muscles’ receptor sites. However, the beneficial effects usually last only a few weeks.  Intravenous immune globulin. This therapy provides body with normal antibodies, which alters immune system response. It has a lower risk of side effects than do
plasmapheresis and immune- suppressing therapy, but it can take a week or two to start working and the benefits usually last less than a month or two.
25. Surgery  Thymectomy – surgical removal of the thymus gland. The role of the thymus gland in MG is not fully understood, and the thymectomy may or may not improve a child’s symptoms.  Plasmapheresis – a procedure that removes abnormal antibodies from the blood and replaces the child’s blood with normal antibodies through donated blood.  Extent of the problems is dependent on the severity of the condition and the presence of other problems that
could affect the child.
26.  In severe cases, a breathing machine may be required to help the child breathe easier.  It is important to allow the child as much independent function and self care, especially with juvenile MG, as possible and to promote age- appropriate activities to ensure a sense of normalcy.
27.  About 15 percent of the people who have MG have a tumor in their thymus  For people with MG who don’t have a tumor in the thymus, it’s unclear whether the potential benefit of removing the thymus outweighs the risks of surgery.  This is an individualized decision between patient and the doctor, but most doctors don’t recommend surgery if:  Symptoms are mild  Symptoms involve only the eyes  Patients over 60 years old
 28. Nutrition  Along with exercises & breathing practices eating habits should also be altered.  Simple, nourishing, no stimulating foods, including plenty of fresh fruits & lightly cooked vegetable, particularly greens.  Asparagus is considered excellent since it contains certain natural steroid-like nutritious elements, which help strengthen the weakened muscles caused by MG.  Whole meal grains, sprouts & pulses in places eggs and meats.  Food should
have a blend of all necessary vitamins.
1. PRESENTATION ON: PARASYMPATHOMIMETICS Presented by: Under the guidence of MOHD KHUSHTAR SIRMohd Fahad M.pharm, Pharmacology 1 st year INTEGRAL UNIVERSITY,lucknow session: 2016-2017
2. NERVOUS SYSTEM
3. BODY PARTS PARASYMPATHETIC (at rest) SYMPATHETIC (emergency situation) EYES Constrict pupil Dilates pupil HEART decrease heart rate decrease force of contraction Increase heart rate Increase force of contraction LUNGS Constrict airways Relax airways (more deep breath) GIT Increase motility Increase secretions Sphincter relaxation Decrease motility Decrease secretions Sphincter constriction BLOOD VESSELS dilatation
constriction MUSCLES Reduces blood flow to skeletal muscles Increase blood flow to skeletal muscles COMPARISON
4. PARASYMPATHETIC NERVOUS SYSTEM • It performs maintenance activities & conserves body energy • ACETYLCHOLINE is both pre-and postganglionic NEUROTRANSMITTER • Ach released at the cholinergic synapses and neuroeffector junctions, mediates its pharmacological action through cholinergic receptors
5. • PARASYMPATHOMIMETICS/ CHOLINERGIC DRUGS are agents which mimic the effects of Ach • PARASYMPATHOLYTIC/ ANTICHOLINERGIC DRUGS antagonise the effects of parasympathetic stimulation
6. NICOTINIC RECEPTORS Nm NN LOCATION Neuromuscular junction Autonomic ganglia Adrenal medulla CNS FUNCTION Depolarisation of motor end plate- contraction of skeletal muscles Depolarisation- postganglionic impulse Adrenal medulla- catecholamines release, CNS- excitation/inhibition AGONIST Nicotine Nicotine, DMPP ANTAGONIST tubocurarine Hexamethonium, trimethaphan TRANSDUCER MECHANISM Opening
of (Na+, K+) channel Opening of ( Na+, K+, Ca++) channel
7. PARASYMPATHOMIMETIC/ CHOLINERGIC DRUG CHOLINERGIC AGONIST CHOLINE ESTERS ALKALOIDS acetylcholine muscarine methacholine pilocarpine carbachol arecoline bethanechol
8. ANTICHOLINESTERASE DRUGS REVERSIBLE IRREVERSIBLE Physostigmine Echothiophate Neostigmine Malathion Edrophonium Carbamates Rivastigmine Donapezil
9. Neurotransmission at cholinergic neurons Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA = acetyl coenzyme A Neurotransmission in cholinergic neurons involves sequential six steps:
10. Acetylcholine
11. Ach is broken down in the synaptic cleft by the enzyme acetylcholinesterase (AChE)
12. Cholinergic Drugs Cholinomimetics, Parasympathomimetics • These are the drugs which produces actions similar to that of Ach, either by directly or indirectly interacting with cholinergic receptors or by increasing availability of Ach at these sites ( anticholinesterases )
13. Direct-Acting Cholinergic Agonists • Cholinergic agonists (parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors. • These agents may be broadly classified into two groups: 1. choline esters, which include acetylcholine synthetic esters of choline, such as carbachol and bethanechol. 2. Naturally occurring alkaloids, such as pilocarpine constitue the second group.
14. • All of the direct-acting cholinergic drugs have longer durations of action than acetylcholine. • Some of the more therapeutically useful drugs pilocarpine and bethanechol preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. • As a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness.
15. A. Acetylcholine: is a quaternary ammonium compound that cannot penetrate membranes. It is therapeutically of no importance because of its multiplicity of actions and its rapid inactivation by the cholinesterases. • Acetylcholine has both muscarinic and nicotinic activity.
16. 1. Decrease in heart rate and cardiac output: The actions of acetylcholine on the heart mimic the effects of vagal stimulation. For example, acetylcholine, if injected intravenously, produces a brief decrease in cardiac rate and stroke volume as a result of a reduction in the rate of firing at the sinoatrial (SA) node. ACTIONS OF ACH
17. 2. Decrease in blood pressure: Injection of acetylcholine causes vasodilation and lowering of blood pressure by an indirect mechanism of action. Acetylcholine activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels This results in the production of nitric oxide from arginine Nitric oxide then diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization
and smooth muscle relaxation
18. • Other actions: A. In the gastrointestinal tract, acetylcholine increases salivary secretion and stimulates intestinal secretions and motility. Bronchiolar secretions are also enhanced. In the urinary tract, the tone of the detrusor muscle is increased, causing expulsion of urine. • B. In the eye, acetylcholine is involved in stimulating ciliary muscle contraction for near vision and in the constriction of the pupillae sphincter muscle, causing miosis
(marked constriction of the pupil). Acetylcholine (1% solution) is instilled into the anterior chamber of the eye to produce miosis during ophthalmic surgery.
19. B. Bethanechol: is structurally related to acetylcholine, in which the acetate is replaced by carbamate and the choline is methylated. • It is not hydrolyzed by acetylcholinesterase (due to the addition of carbonic acid), although it is inactivated through hydrolysis by other esterases. • It lacks nicotinic actions (due to the addition of the methyl group) but does have strong muscarinic activity. • Its major actions are on the smooth muscle of the
bladder and gastrointestinal tract. It has a duration of action of about 1 hour.
20. • Actions: Bethanechol directly stimulates muscarinic receptors, causing increased intestinal motility and tone. It also stimulates the detrusor muscles of the bladder whereas the trigone and sphincter are relaxed, causing expulsion of urine. • Therapeutic applications: In urologic treatment, bethanechol is used to stimulate the atonic bladder, particularly in postpartum or postoperative, nonobstructive urinary retention. Bethanechol may also be
used to treat neurogenic atony ( poor muscular condition ). As well as megacolon (Hypertrophy and dilation of the colon associated with prolonged constipation). • Adverse effects: Bethanechol causes the effects of generalized cholinergic stimulation. These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm.
21. C. Carbachol (carbamylcholine): has both muscarinic as well as nicotinic actions (lacks a methyl group present in bethanechol). • Like bethanechol, carbachol is an ester of carbamic acid and a poor substrate for acetylcholinesterase. • It is biotransformed by other esterases, but at a much slower rate.
22. • Actions: Carbachol has profound effects on both the cardiovascular system and the gastrointestinal system because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems. • It can cause release of epinephrine from the adrenal medulla by its nicotinic action. • Locally instilled into the eye, it mimics the effects of acetylcholine, causing miosis and a spasm of accommodation in which the ciliary muscle of
the eye remains in a constant state of contraction.
23. • Therapeutic uses: Because of its high potency, receptor nonselectivity, and relatively long duration of action, carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma by causing pupillary contraction and a decrease in intraocular pressure. • Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration.
24. D. Pilocarpine: is alkaloid with a tertiary amine and is stable to hydrolysis by acetylcholinesterase. • Compared with acetylcholine and its derivatives, it is far less potent, but it is uncharged and penetrate the CNS at therapeutic doses. • Pilocarpine exhibits muscarinic activity and is used primarily in ophthalmology.
25. • Actions: Applied topically to the cornea, pilocarpine produces a rapid miosis and contraction of the ciliary muscle. Pilocarpine is one of the most potent stimulators of secretions such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity. The drug is beneficial in promoting salivation in patients with xerostomia (dryness of mouth)
26. Anticholinesterases: Anticholinesterases are the agents which inhibit ChE, protect Ach from hydrolysis- produce cholinergic effects and potentiates Ach. Reversible: Carbamates: Physostigmine, Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepeizil, Galantamine Acridine: Tacrine
27. Irreversible: Organophosphates: Carbamates: Dyflos ( DFP ) Carbaryl Echothiophate Propoxur Parathion Malathion Diazinon Tabun, Sarin, Soman
28. Anticholinesterases (Reversible) MOA:
29. Anticholinesterases (Irreversible) A number of synthetic organophosphate compounds have the capacity to bind covalently to acetylcholinesterase.
 30. A.Echothiophate Mechanism of action: Echothiophate is an organophosphate that covalently binds via its phosphate group to the serine-OH group at the active site of acetylcholinesterase. Once this occurs, the enzyme is permanently inactivated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules.