Applied Pharmacology Review PDF Exam 2

1 Applied Pharmacology Review Exam 2 Direct Adrenergic Agonists - Sympathomimetics Direct adrenergic agonists are known as Sympathomimetics. Direct sympathomimetics include: Epinephrine - endogenous epinephrine is the counterpart of norepinephrine which is a hormone-like substance produced by the me...

1 Applied Pharmacology Review Exam 2 Direct Adrenergic Agonists - Sympathomimetics Direct adrenergic agonists are known as Sympathomimetics. Direct sympathomimetics include: Epinephrine - endogenous epinephrine is the counterpart of norepinephrine which is a hormone-like substance produced by the medulla of the adrenal gland. ○ It is a mixed agonist which is inactivated almost immediately. ○ Its effects include conjunctival vasoconstriction and a hypotensive effect which increases uveoscleral outflow. ○ Post. ganglionic - Horner’s syndrome ○ Ocular toxic side effects with topical application include maculopathy in 20-30% of aphakic patients (reversible), madarosis (reversible), pigment deposits in the tarsal conjunctiva (mainly in elderly pts) and allergic reactions. ○ Topical side effects include burning, headaches and paradoxical conjunctival hyperemia. ○ Not indicated in patients with narrow angles. Phenylephrine - synthetic but structurally similar to epinephrine; it is virtually an alpha 1 agonist found in 0.12%, 2.5% and 10% concentrations. ○ Its effects include dilatation, Mueller’s and conjunctival arterioles with a variable hypotensive effect. ○ Clinical uses include partial dilation (2.5 and 10%) with no clinical cycloplegia and for posterior synechiae (10%), pupillary cysts (2.5%), Horner’s ptosis (0.125%), conjunctival hyperemia (0.125%) and Horner’s (1%). ○ Ocular side effects include lacrimation due to irritative effect, pain, keratitis, allergic dermatitis, iris pigment drop out, rebound miosis and decrease in conjunctival/iris PO2 (chronic use). ○ Systemic side effects include episodes of rise in blood pressure (10%), ventricular tachycardia, reflex bradycardia and subarachnoid hemorrhage. 2 ○ Drug interactions with tricyclic antidepressants and MAO inhibitors, Guanethidine, Methyldopa and Atropine. ○ Contraindicated for patients with idiopathic hypotension, Parkinson’s, history of hyper-reactions, malignant hypertension and aneurysm. ○ Indirect Adrenergic Agonists - Sympathomimetics Hydroxyamphetamine (paredrine) is found in a 1% concentration, it works to liberate norepinephrine from the presynaptic vesicle at the NMJ and it has very little effect on accommodation. Its clinical uses include: ○ Partial dilation - 1% solution is comparable with 10% phenylephrine. Also found as Paremyd (in combination with.25% tropicamide) which does induce complete dilation. ○ Differentiate between central/2nd and 3rd neuron in Horner’s syndrome. Ocular side effects include moderate irritation. Systemic side effects are rare but some cases of rise in BP have been reported (characterized by tachyphylaxis). Contraindications are similar to phenylephrine. Cocaine has anesthetic action by blocking the reuptake of norepinephrine but is not commercially available in ophthalmic solution. Its salt form (HCL) is diluted in aqueous solution (1%, 4%, and 10%) for ophthalmic use. Clinically used for forced duction tests, dacryocystorhinostomy, epithelial iodine cauterization and Horner’s syndrome. Ocular adverse side effects include grayish irregular depression of corneal epithelium and epithelial corneal erosion. Systemic side effects include restlessness, anxiety, nausea, vomiting, abdominal pain, rapid irregular pulse and even respiratory failure leading to death. Contraindicates with use of Monoaminoxidase inhibitors, tricyclic antidepressants and methyldopa. 3 Selective Adrenergic Agonists Aproclonidine (Iopidine 0.5%) is mainly an alpha 2 agonist which decreases aqueous humor production and may have some effect on the uveo-scleral outflow. 1% concentration is used pre- and post-operatively in anterior segment laser procedures. It exhibits tachyphylaxis and is primarily used as short-term therapy in patients awaiting glaucoma surgery. Has minimal side effects. Brimonidine tartrate (Alphagan P 0.2%/Allergan) is an alpha 2 agonist primarily which is used to decrease aqueous production. Mode of therapy - bid (twice a day) IOP reduction is similar to Timoptic. Side effects may include increased pressure in some patients so the blanching test is done before prescribing. Lumify is an over-the-counter brimonidine tartrate 0.025% solution for the treatment of conjunctival hyperemia. Ophthalmic Adrenergic Antagonists Dapiprazole is a mydriolytic agent which has now been discontinued. Its effects on mydriasis include: reversibly blocking a1 receptors in the dilator muscle and dilator muscle relaxation. ○ Almost complete reversal on phenylephrine and partial reversal on tropicamide. Side effects include transient hyperemia, superficial punctate keratitis and ptosis. It is contraindicated in inflammatory processes. Ophthalmic Beta Blockers Reversible blockage of the beta receptors of the ciliary non-pigmented epithelium produces an ocular hypotensive effect by decreasing active secretion in aqueous humor production. There is a 20-22% IOP reduction and 10% reduction on the fellow eye. All except for one are non-selective 4 Timolol maleate (Timoptic 0.25, 0.5; XE 0.5%; Ocudose PF; Betimol 0.5%) is a non-selective liposoluble ophthalmic beta-blocker. New mode of therapy involves 0.25% solution once a day in the AM. Maximum effect in three weeks and washout period in 1-2 months. Levobunolol (Betagan 0.25%, 0.5%) is a non-selective ophthalmic beta blocker. It has the same indications as TImoptic. May cause more side effects in some patients and may be more effective in some patients. Carteolol (Ocupress 1%) is a non-selective hydrosoluble ophthalmic beta blocker. Mode of therapy is twice a day. Equally as effective as Timoptic but less effective than Betagan in some patients. It increases the ratio of high density lipids to total cholesterol. Betaxolol is a cardio-selective ophthalmic beta-blocker with calcium channel blocker activity. Found in a Betoptic 0.25% suspension. Mode of therapy is once a day. Beta-1 blocker so it is safer in asthmatic patients. Careful with sulfa allergies. Systemic side effects of ophthalmic beta blockers include: Masking of hypoglycemic effects in patients under diabetic treatment. Bronchial asthma with non-selective blockers. Bradycardia due to hypotension. Mental depression (except Ocupress) Ocular side effects of ophthalmic beta blockers include: Allergic conjunctivitis Ocular myasthenia Transient burning and irritation Superficial punctate keratitis Corneal hypesthesia causing dry eye 5 Contraindications with ophthalmic beta-blockers include: COPD Bradycardia Bronchial asthma Hypotension Congestive heart failure Combigan is a combo alpha agonist and beta-blocker. Parasympathetic System: Cholinergic Agonists Normally, the parasympathetic system uses acetylcholine as a neurotransmitter. Cholinergic neurons are involved in Ach synthesis, storage, release, binding to receptor, degradation and recycling. Cholinergic neurons have muscarinic and nicotinic receptors. Muscarinic receptors are found primarily in the neuro-effect junction of the parasympathetic nervous system. As a group they are found in the ganglia of the PNS, autonomic effector organs, heart, smooth, muscle and brain. M1 - found in the brain, exocrine glands, autonomic ganglia and stomach (gastric parietal cells). M2 - found in the heart,brain, autonomic ganglia and smooth muscle. 6 M3 - found in exocrine glands, smooth muscle, brain and endothelial cells. M4 - found in basal ganglia, amygdala and hippocampus. M5 - found in the substantia nigra (midbrain) and its function remains unclear. Nicotinic receptors have weak muscarinic activity and are found in the CNS, adrenal medulla, autonomic ganglia and neuromuscular junction. Acetylcholine signal transduction occurs through activation of a 2nd messenger (protein G) leading to increased intracellular [Ca]. It may stimulate or inhibit a secondary enzyme. M2 in the heart stimulates protein G which inhibits adenylcyclase thus increasing K conductance with decreased HR and force of contraction. Acetylcholine is of no importance therapeutically due to its rapid inactivation and the multiplicity of its actions. It has muscarinic and nicotinic actions like decreased heart rate, decreased blood pressure, increase in salivary secretions, involuntary motility in the eye and contraction of the ciliary muscles with miosis. Bethanechol is structurally related to acetylcholine but not destroyed by acetylcholinesterase. It has no nicotinic action but strong muscarinic action. Its actions include increased intestinal motility and tone as well as stimulation of the detrusor muscle of the bladder promoting urination. Applications are important in urology. Adverse effects include generalized cholinergic stimulation sweating, decreased BP, nausea, abdominal pain, diarrhea and bronchospasms. Carbachol has muscarinic and nicotinic actions that may last up to an hour. Its actions include: promoting release of epinephrine from the adrenal medulla, systemic use causing a profound effect on the cardiovascular and GI systems as well as being available as an ophthalmic solution to reduce IOP. 7 Pilocarpine is stable to hydrolysis by acetylcholinesterase. Its actions include stimulating production of sweat, tears and saliva; ocular effects include producing miosis and enhancing accommodation. Therapeutically used for primary open angle glaucoma, acute angle closure glaucoma, pigmentary glaucoma and Sjogren’s syndrome. Adverse reactions include potent stimulation of secretion of sweat glands. Acetylcholinesterase inhibitors are indirect acting agents. By interfering with the metabolism of acetylcholine, they indirectly stimulate both nicotinic and muscarinic receptors due to the consequential increase in available acetylcholine at the synapsis site. Reversible Acetylcholinesterase Inhibitors Physostigmine stimulates muscarinic and nicotinic receptors for a duration of 2-4 hours. Therapeutically used for atony of the intestines and bladder since it promotes motility, decreases IOP and overdose of atropine, phenothiazine and tricyclic antidepressants. Adverse effects include convulsions and bradycardia. Pyridostigmine and Ambenonium are used in myasthenia gravis. Neostigmine doesn’t cross the blood-brain barrier so it has a greater effect on the skeletal muscle. Used in myasthenia gravis treatment and as an antidote for tubocurarine and neuromuscular blockers. Demecarium is similar in action as Neostigmine. It was used to treat primary open angle glaucoma. Edrophonium is like neostigmine but has a shorter duration. Used IV in the diagnosis of myasthenia gravis. 8 Tacrine, Donepezil, Rivastigmine and Galantamine are used in the treatment of Alzheimer’s disease. Irreversible Acetylcholinesterase Inhibitors Irreversible acetylcholinesterase inhibitors are synthetic organophosphate compounds and related agents which are used as insecticides. Echothiophate covalently binds to the active site of acetylcholinesterase and permanently inactivates it. It has generalized cholinergic stimulation leading to paralysis of motor function, convulsions and miosis. Therapeutically used for chronic treatment of open angle glaucoma. Pralidoxime reactivates acetylcholinesterase and is used for organo-phosphate poisoning. Muscarinic agonist side effects include diarrhea, diaphoresis, miosis, nausea, urinary urgency, transient myopia and brow pain. Cholinergic Antagonists Atropine has antimuscarinic effects with central and peripheral activity. It is derived from the belladonna alkaloid. Its actions include: mydriasis, cycloplegia, antispasmodic effects, enuresis, tachycardia, xerostomia and xerophthalmia. Therapeutically used for cycloplegic refraction, uveitis, antispasmodic, and organophosphate intoxication due to insecticides. Readily absorbed, partially metabolized in the liver and eliminated in the urine. Half-life of 4 hours. Adverse effects include dry mouth, blurred vision, tachycardia, constipation, confusion, hallucinations and delirium. Scopolamine is a belladonna alkaloid similar to atropine but with longer CNS action. It is effective for anti-motion sickness and sedation. 9 Used for cycloplegic refraction and uveitis. Ipratropium/Tiotropium is a quaternary derivative of atropine used by inhalation for asthma and COPD since it decreases smooth muscle contraction of the bronchi. Tropicamide and Cyclopentolate are ophthalmic solutions producing similar effects to atropine. Benztropine is a centrally acting antimuscarinic agent which is employed as adjuvant treatment in Parkinsons and to minimize dystonia in treatment with anti-psychotic medications. Darifenacin, Fesoterodine, Oxybutyin, Solifenacin and Tolterodine are synthetic atropine-like meds employed in treatment for overactive bladder. They increase capacity by lowering intravesical pressure. Side effects include dry mouth, constipation and blurred vision. Cholinergic antagonist side effects include blurred vision, confusion, mydriasis and constipation. Ganglionic Blockers Ganglionic blockers act specifically on nicotinic receptors. They are non-selective for para- or sympathetic ganglia. Ineffective as neuromuscular antagonists. Blocks the entire output of the ANS. Rarely used therapeutically. Nicotine depolarizes the ganglia of the ANS and striated muscle. Low doses increase BP, HR, peristalsis and secretions. High doses decrease BP and diminish muscular activity. Trimethaphan is a short-acting competitive nicotinic ganglion blocker. Used via IV in emergency lowering of blood pressure. Mecamylamine is a competitive nicotinic ganglion blocker. 10 It is active orally and one dose lasts up to 10 hours. Clinically useful to moderate to severe arterial hypertension. Neuromuscular Blocking Drugs Neuromuscular blocking drugs block cholinergic transmission between nerve-endings and nicotinic receptors at the neuromuscular end-plate. Non-depolarizing - compete with acetylcholine for receptors. Depolarizing - cause prolonged stimulation and subsequent desensitization of the receptors. Clinically useful during surgery producing complete muscle relaxation (decreasing anesthetic doses) and also used in mechanical ventilation. Non-depolarizing (Competitive) Blockers Curare (d-Tubocurarine) is a skeletal neuromuscular junction blocker. Low doses prevent binding of acetylcholine. High doses block the Na+ channels of the endplate. Its actions include muscle paralysis. Therapeutically used as an adjuvant in anesthesia. ○ Decreases concentration of general anesthetic drugs by achieving adequate muscle relaxation. Used in IV and does not readily cross the blood-brain barrier. Vecuronium rocuronium Non-depolarizing (competitive) blockers interact with: Cholinesterase inhibitors - overcome the depolarizing action at low doses. Aminoglycosides - inhibit acetylcholine release from neuromuscular junction thus potentiating the effects of blockers. Calcium channel blockers - increase the neuromuscular block of tubocurarine and other competitive blockers. 11 Depolarizing Blockers Succinylcholine attaches to nicotinic receptors acting like acetylcholine, depolarizing the NMJ, persisting in the cleft at higher concentrations for a longer time and followed by an altered repolarization. Has two phases: ○ Twitch/flaccid paralysis during depolarization. ○ Desensitization during repolarization - flaccid paralysis Its actions include a paralyzing process similar to non-depolarizing agents. Therapeutically used to rapid endotracheal intubation during induction of anesthesia to avoid gastric aspiration. Has a rapid onset of duration due to hydrolysis by plasma cholinesterase; administered by IV continuous infusion. Adverse effects include hyperthermia and may cause malignant hyperthermia in conjunction with halothane in genetically susceptible people. Miscellaneous muscle relaxants Benzodiazepines enhance or facilitate the action of GABA (an inhibitory neurotransmitter). Includes Diazepam (Valium). Used for muscle spasms. Baclofen binds to 𝐺𝐴𝐵𝐴𝐵 receptors and upon binding, causes an influx of K+ into the neuron, leading to hyperpolarization of the neuronal membrane and decreased calcium influx at presynaptic nerve terminals. Dantrolene directly inhibits Ca+ release from the sarcoplasmic reticulum. Orphenadrine (Norflex) is a methyl-derivative of diphenhydramine but its mechanism of action is causing analgesia and skeletal muscle relaxation. Ocular Cholinergic Agonists Cholinergic agonists are also known as parasympathomimetics while the antagonists are known as sympatholytics, cycloplegics and cyclomydriatics. 12 The efferent oculo-parasympathetic pathway originates in the E-W nucleus, then travels through preganglionic fibers to the ciliary ganglion. They have cholinergic innervation. Acetylcholine is the neurotransmitter for both pre and postganglionic synapses. The post ganglionic effector structures include the iris sphincter and ciliary muscle which contain M3 receptors. Ocular cholinergic agonists are divided into direct parasympathomimetics and indirect parasympathomimetics (cholinesterase inhibitors). Direct Sympathomimetics Pilocarpine is found in Ocusert, an IOP reduction mechanism. Indirect Parasympathomimetics Edrophonium chloride (Tensilon) is used in diagnosis of myasthenia gravis. Lambert-Eaton Myasthenic syndrome is a rare autoimmune disorder that affects voltage-gated calcium channels on the presynaptic membrane of the NMJ. The inhibition of the voltage-gated calcium channels prevents Ach from being released from the presynaptic terminal and the subsequent stimulation of the postsynaptic terminal which would lead to muscle contraction. Treated with steroids. Ocular Cholinergic Antagonists Atropine is a naturally occurring alkaloid from a plant called belladonna. Clinically used for cycloplegic refraction, iridocyclitis, myopia, amblyopia and provocative for narrow angle. Ocular side effects include irritation, keratitis, contact dermatitis, angle opposition/closure and increase in IOP. Systemic side effects are dosage dependent. 13 ○ Lethal dosage in adults is 100 mg. ○ Lethal dosage in children 6-12 y/o is 10mg. ○ Deaths have been reported in patients younger than 3 y/o. ○ Initial signs - decreased salivation and dryness of mouth/skin. ○ Other signs include facial flushing and fever due to inhibited sweating. ○ Blocks vagal tone in heart. ○ CNS effects include delirium, hallucinations, irritability and coma. Its specific antidote is physostigmine (antilirium). Homatropine (2%/5%) is 1/10th as potent as atropine. It has a shorter duration of mydriatic and cycloplegic action. Clinically used as adjunct treatment of iridocyclitis, as alternative in cycloplegic refraction not involving accommodative esotropia. Adverse effects similar to atropine. Scopolamine (hyoscine), on a molecular weight basis, has greater anti-cholinergic potency than atropine. Its mydriatic and cycloplegic effects are of shortion duration because of the concentration. Clinically used as an alternative treatment when an allergic reaction to atropine occurs. Adverse and side effects similar to atropine. Cyclopentolate (0.5%/1%/2%) has less mydriatic and cycloplegic effect on dark irises. There is full recovery within 24 hours. Average residual accommodation is approx. 1.25 diopters. Clinically used for cycloplegic refraction and as an alternative adjunct treatment for iridocyclitis. Ocular side effects include superficial punctate keratitis, contact dermatitis, increase in IOP in patients with POAG, angle closure and iris pigment dispersion. Central nervous system effects include drowsiness, restlessness, disorientation, incoherent speech and cerebellar dysfunctions. ○ More common in childrens. 14 Tropicamide (.5%/1%) is the cycloplegic that causes the most amount of mydriasis with the weakest cycloplegia. Clinically used for dilated fundus examination and provocative in narrow angles. Ocular side effects include angle closure and increase in IOP in patients with POAG. Systemic adverse effects are almost non-existent since it is metabolized quickly. Respiratory System Drugs The conduction zone of the respiratory system is composed of the nasal cavity, larynx, trachea and bronchus. The respiratory zone of the respiratory system is composed of the lungs. Normally, the muscles of the bronchi are relaxed, allowing easy airflow. The cells in the alveoli are: Pneumocyte type 1 cells - involved in gas exchange. Pneumocyte type 2 cells - produce surfactant. Alveolar macrophages - in charge of phagocytosis. The respiratory system functions to deliver oxygen to the cells, eliminate CO2 and regulate blood pH. The components of the respiratory function of the lungs are: Ventilation - movement of air through the airways. Distribution - air entering the lung is distributed to all parts, including the alveoli. Diffusion - oxygen from the inspired air diffuses through the walls of the alveoli to the blood capillaries surrounding the alveoli; the CO2 diffuses in the opposite direction. Perfusion - blood with high concentrations of CO2 and low in O2 is pumped to the pulmonary arteries by the right ventricle and after diffusion, the arterial blood is returned to the left atrium by the pulmonary veins. 15 Common disorders of respiratory functions include: Bronchial asthma, cough, allergic rhinitis, and COPD. Bronchial asthma is a chronic inflammatory disorder of bronchial airways that results in airway obstruction in response to external stimuli. Tends to be progressive. Clinical courses are characterized by remissions and exacerbations. Manifests as bronchoconstriction (wheezing), SOB, tachypnea, chest tightness, cough. It has an acute phase (immediate) and a chronic phase (late). Can be caused by infection, exercise, pets, seasonal changes, some drugs (Aspirin/Beta blockers). ○ Could be precipitated by stress or emotional conditions. Status asthmaticus is a prolonged asthma attack that does not respond to typical drug therapy. It may last several minutes to hours and is considered a medical emergency. The goals of bronchial asthma treatment is to relieve acute episodic attacks and to reduce frequency of attacks as well as nocturnal awakenings. Acute attacks are treated with quick-relief medications like bronchodilators: short-acting B2-agonists, antimuscarinics, xanthine preparations. Maintenance therapy is provided through anti-inflammatory agents like corticosteroids, mast cell stabilizers, leukotrienes and with bronchodilators like long acting 2 agonists. 16 Quick-relief medications include B-adrenoceptor agonists which inhibit mediators release from mast cells and increase mucus clearance (by increasing ciliary activity) Mechanism of Action: Direct B2 stimulation → Stimulates adenyl cyclase → Increases cAMP → Bronchodilation B-adrenoceptor agonists are classified into: Non-selective B-agonists - have potent bronchodilator rapid action. ○ Include Epinephrine and Isoprenaline. ○ Administered via SC or inhalation. ○ Has a short duration of action. ○ Drug of choice for acute anaphylaxis. ○ Disadvantages include: ineffectiveness orally, hyperglycemia, skeletal muscle tremors and CVS side effects like tachycardia, arrhythmia and hypertension ○ Not suitable for patients with hypertension, heart failure, CVA and diabetes. Selective B2 agonists - drug of choice for acute attack of asthma. ○ Include albuterol, terbutaline, salmeterol and formoterol. ○ Mainly given by inhalation. ○ Short-acting B2 agonists are used for symptomatic treatment of acute episodic attacks of asthma or maintenance in severe asthma. ○ Include albuterol and terbutaline. Long-acting selective B agonists have high lipid solubility and are not used to relieve acute episodes of asthma but for nocturnal asthma. Include salmeterol and formoterol. Advantages of B2 agonists include: minimal CVS side effects so they are suitable for asthmatic patients with hypertension or heart failure. Disadvantages of B2 agonists include skeletal muscle tremors, nervousness, tolerance and tachycardia. Quick relief medications also include muscarinic antagonists like Iptratropium and Tiotropium. 17 They act by blocking muscarinic receptors; acting as short-acting bronchodilators which inhibit bronchoconstriction and mucus secretion. Less effective than B2-agonists. Given by aerosol inhalation. Quaternary derivatives of atropine. Does not diffuse into the blood or enter the CNS so it has minimal side effects. Have a delayed onset of action. ○ Ipratropim has a short duration of action (3-5 hours). ○ Tiotropium has a longer duration of action (24 hours). Therapeutically used in COPD and acute severe asthma (combined with B2-agonists/steroids Methylxanthines are a purine-derived group of pharmacologic agents. Include Theophylline and Aminophylline. Mechanism of action involves phosphodiesterase inhibition causing an increase in cAMP and thus bronchodilation. They are adenosine receptor antagonists (A1). Respiratory effects include bronchial muscle relaxation. It is metabolized by Cyt P450 enzymes in the liver. Half-life of 8 hours. Used as a second-line drug in asthma (theophylline) and for status asthmaticus (aminophylline). Side effects include hypotension, arrhythmia, nausea and vomiting as well as CNS side effects like tremors, nervousness, insomnia and convulsions. Maintenance therapy drugs are anti-inflammatory agents that are used as control medications or prophylactic therapy for bronchial asthma. They reduce the number of inflammatory cells in the airways and prevent blood vessels from leaking fluid into the airway tissues. ○ By reducing inflammation they reduce the spasm of airways and bronchial hyperactivity. Types include glucocorticoids, leukotriene antagonists, mast cell stabilizers, anti-IgE monoclonal antibodies. 18 Glucocorticoids produce no bronchodilation, reduce bronchial inflammation and reduce bronchial hyper-reactivity to stimuli. They have a delayed onset of action. Given as prophylactic medications either alone or combined with beta-agonists. Effective in allergic, exercise, antigen and irritant-induced asthma. Mechanisms of action ○ Inhibition of phospholipase A2 → decreased prostaglandin and leukotrienes → decreased number of inflammatory cells in airways ○ Mast cell stabilization → Decreased histamine release ○ Decreased capillary permeability and mucosal edema. ○ Inhibition of antigen-antibody reactions. ○ Upregulate B2 receptors. Metabolic effects include hyperglycemia and increased protein catabolism with decreased protein anabolism. Mineralocorticoid effects include sodium/fluid retention, increased potassium excretion and increased blood volume. Can cause depression and bone loss (osteoporosis) due to inhibited bone formation caused by decreased calcium absorption. Routes of administration for glucocorticoids include: Inhalation - include Budesonide, Fluticasone and Beclomethasone which are given with metered-dose inhalers. ○ They are the best choice in asthma since they have less side effects (only oropharyngeal candidiasis [thrush] and dysphonia [hoarseness]).. Orally - include Prednisone and methylprednisolone which can be used to treat persistent cough associated with bronchial inflammation. IV systemic steroids - include Hydrocortisone and Dexamethasone. They are reserved for Status asthmaticus and severe asthma exacerbation. ○ Side effects include adrenal suppression, osteoporosis, fluid retention, weight gain. hypertension, hyperglycemia, susceptibility to infections, glaucoma, cataracts, fat distribution, wasting of the muscles. 19 Abrupt withdrawal from corticosteroids should be avoided. Doses should be tapered in order to avoid adrenal insufficiency syndrome/adrenal crisis. Mast Cell Stabilizers Cromolyn (cromoglycate) and Nedocromil act by stabilization of mast cell membranes. They are given by inhalation and have poor oral absorption. They are not bronchodilators so they are not effective in acute asthma attacks. It is a prophylactic anti-inflammatory drug that reduces bronchial hyper-reactivity. It is effective in exercise, antigen and irritant-induced asthma. Children respond better than adults. Mast cell stabilizers are used as prophylactic therapy in asthma (especially in children), for allergic rhinitis and for conjunctivitis. Side effects of mast cell stabilizers include bitter taste and minor upper respiratory tract irritation (burning sensation and nasal congestion). Leukotriene Antagonists Leukotrienes are produced by the action of 5-lipoxygenase on arachidonic acid. It is synthesized by inflammatory cells found in the airways like eosinophils, macrophages and mast cells). Leukotriene B4 - involved in chemotaxis of neutrophils. Cysteinyl leukotrienes - cause bronchoconstriction, increased bronchial hyper-reactivity, mucosal edema and mucus hyper-secretion. Zafirlukast, Montelukast and Pranlukast are selective, reversible antagonists of cysteinyl leukotriene receptors (CysLT1 receptors). Taken orally. They have anti-inflammatory action. They are less effective than inhaled corticosteroids and have glucocorticoid sparing effect which potentiates corticosteroid actions. 20 Leukotriene receptor antagonists are used for: prophylaxis of mild/moderate asthma, aspirin-induced asthma and antigen/exercise-induced asthma. They are not effective to relieve acute attacks of asthma. They can be combined with glucocorticoids. Side effects of leukotriene receptor antagonists include: elevation of liver enzymes, headache and dyspepsia. Omalizumab is a monoclonal antibody directed against human IgE which prevents IgE binding with its receptor on mast cells and basophils. Leads to decreased release of allergic mediators. Use for treatment of allergic therapy but they are expensive so they are not a first-line therapy. Airway innervation Afferent nerves ○ C fiber receptors - irritant receptors sensitized by endogenous inflammatory mediators after exogenous irritation. ○ A fibers ○ C-fibers upstream Efferent nerves - parasympathetic supply due to M3 receptors in smooth muscles and glands. B2-adrenergic receptors are uncoupled, leading to functional hypo-responsiveness. Respiratory System Drugs - 2 A cough is a forced expiration against a closed larynx which suddenly opens to expel air and unwanted material from the respiratory tract. It may be voluntary or involuntary. The mucosal surface lining respiratory tract sends impulses which are relayed by the vagus nerve to the cough center in the brainstem. The signals then travel to the higher cough modulating area 21 of the sensory cortex which causes efferent stimulation of the diaphragm, glottis, muscles of the chest and abdomen. The cough reflex involves both afferent stimulation mediated by the irritation of the smooth muscle of the bronchial tree followed by efferent stimulation. Irritation of the bronchial mucosa causes broncho-constriction, which stimulates cough receptors located within the tracheo-bronchial tree ○ So cough may be relieved through use of bronchodilators (B2 agonists). Afferent nerves from these receptors via the vagus, each multiple centers within the medulla that are distinct from the respiratory center. ○ Drugs acting mainly on the peripheral stimulation (afferent system) or the stimulation at the medulla oblongata may relieve cough. Most effective antitussives have been shown to elevate the threshold for coughing through centrally mediated mechanisms at the brainstem which are poorly understood. Unproductive distressing coughs can be treated with central cough depressants like dextromethorphan. Productive coughs can be treated through use of expectorants and mucolytics but no cough suppressants. Expectorants act by increasing the volume of secretions in the respiratory tract so that they may be more easily expelled by ciliary action and coughing. Dextromethorphan is the most commonly used non-opioid antitussive; it has a central action on the cough center in the medulla. Its mode of action is unclear. It is a non competitive antagonist of NMDA receptors ○ Antagonism is believed to decrease the uptake of central catecholamines, which induce cough in the cough center. Structurally related to morphine, has minimal/no analgesic properties and a minimal sedative activity. 22 Antitussive effects may last up to 5 hours. Contraindicated in patients at risk of developing respiratory failure or on MAO inhibitors. Determination of pulmonary mucus secretions and viscosity mainly depends on the concentration of mucoproteins and DNA. Mucoprotein is the main determinant of viscosity in normal mucus. Concentration of DNA in mucus increases due to increased cellular debris. Bronchial inflammation may be associated with large amounts of mucous exudate which firmly attaches to the lining of the bronchi/bronchioles, increasing its wall’s thickness. This may produce lumen narrowing and potentiate persistent coughing. Mucolytics reduce viscosity and break mucus by splitting the disulfide bonds in mucoproteins from bronchial walls. Most commonly prescribed: Acetylcysteine and Bromhexine hydrochloride. Other forms include normal saline, directly administered to the airways by effective nebulization therapy which has a powerful mucolytic and expectorant effect. (3/6% Nebusal) Opioid Antitussives Codeine phosphate is an opioid receptor agonist. It has high potency with oral administration and is commonly combined with guaifenesin (in oral solution). Short-acting since its half-life is 2-4 hours. Metabolized by the liver and excreted in the urine as inactive metabolites. Hydrocodone is an opioid receptor agonist. Combined with homatropine as both elixir and tablet formulations for cough. ○ Homatropine is a parasympatholytic designed to enhance any reduction in respiratory secretions and bronchial constriction. 23 Other Antitussives Benzonatate is a derivative of local ester anesthetics; it is a cough suppressant believed to act centrally and peripherally. In the lungs, it anesthetizes respiratory passages and pleural receptors in order to reduce the cough reflex. Dornase alfa is a recombinant human DNAse which acts as a mucolytic by hydrolyzing DNA that has accumulated in the sputum margin, decaying neutrophils. Used as a nebulizing solution. Antihistamines like Diphenhydramine are used as antitussives since they block the cholinergic activity that induces the neural activity that induces cough. They also suppress cough by sedative action. Reduce nasal secretions and therefore the post-nasal drip that causes cough. Leukotriene Receptor Antagonists Montelukast and Zafirlukast bind to cysteinyl leukotriene receptors to decrease mucous secretion and relax bronchial muscles. They also inhibit activity of other inflammatory cells. Glucocorticoids like Methylprednisolone work by reducing inflammation which reduces the irritation of C-receptors and thus the neural response that leads to coughing. Drugs Used in Treatment of Allergic Rhinitis Inflammation of mucous membranes of the nose is characterized by sneezing, nasal itching, rhinorrhea and congestion after mast cell activation from allergic responses. May be treated through use of antihistamines like diphenhydramine (Benadryl), chlorphenhydramine (Chlorthrimethron), loratadine (Claritin), among others in combination with decongestants. Phenylephrine and oxymetazoline may cause rebound nasal congestion after prolonged use. 24 May also be treated with corticosteroid nasal sprays like beclomethasone (Vancense/Beconase), fluticasone (Flonase), and triamcinolone (Nasacort). Most common side effect - nasal bleeding May also be treated with mast cell stabilizer nasal sprays like Cromolyn sodium. Drugs Used in Treatment for Chronic Obstructive Pulmonary Disease (COPD) COPD is a chronic, irreversible airflow obstruction disease in which there is lung damage and inflammation of the air sacs (alveoli). Smoking is a high-risk factor for COPD. COPD is classified based on spirometry. Mild, FEV1 < 80% - Stage 1 Moderate, FEV1 < 60% - Stage II. Severe, FEV1 < 30% - Stage III Treated with inhaled bronchodilators, inhaled glucocorticoids, xanthine derivatives, anti-leukotrienes and/or oxygen therapy. Chronic bronchitis is a continuous inflammation of the bronchi and bronchioles which often occurs as a result of prolonged exposure to bronchial irritants. Characterized by hypoxemia and productive cough. Blue bloaters - patient’s skin and lips have a bluish tint since they have difficulty expelling CO2, hypoxemia and are overweight. Emphysema is due to air spaces enlarging as a result of the destruction of alveolar walls so the surface area for gas exchange is reduced. Effective respiration is impaired. Characterized by increased paCO2 and difficulty breathing. 25 Pink puffer - normal weight, normal blood oxygen levels but the patients take short, fast breaths causing temporary redness on their cheeks/faces. Treated with B-adrenergic agents, anticholinergic agents (ipratropium), theophylline and corticosteroids (prednisone.) Treatment protocol based on severity Mild - short-acting bronchodilators. Moderate -bronchodilators and glucocorticoids. Severe - bronchodilators and systemic glucocorticoids. Long term control - antileukotrienes, cromolyn, inhaled steroids and/or long-acting B2-agonists. Acute relief - IV systemic corticosteroids and/or short-acting inhaled B2-agonists. Bronchodilators: B2 Agonists Short acting, main choice in Salbutamol, terbutaline administered via inhalation. Salmeterol, formoterol Antimuscarinics Ipratropium (short) Tiotropium (long) Xanthine derivatives acute attack of asthma and Long acting, used as prophylaxis Increase adenylyl cyclase. Increase cAMP. for nocturnal asthma. Main drugs for COPD Block M receptors. Administered via inhalation. Administered orally and Theophylline Aminophylline Anti-Inflammatory drugs (prophylactic) parenterally. Inhibit phosphodiesterase which increases cAMP. 26 Corticosteroids Inhibit phospholipase A2 Inhalation Dexamethasone, Fluticasone, Budesonide Prednisolone Orally Hydrocortisone Parenterally Mast stabilizers Inhalation, prophylaxis in children. Cromoglycate (Cromolyn), Nedocromil Cysteinyl antagonists CyLT1 antagonists Orally Zafirlukast Omalizumab Anti-IgE antibody SC injection