storage.googleapis.com · web viewdescribe the pharmacology of anti-asthma drugs with particular...

1

Describe the pharmacology of anti-asthma drugs with particular reference to beta2 agonists corticosteroids anticholinergics leukotriene antagonists andTheophylline

Beta 2 receptor agonists Mechanism of action

With few exceptions they are delivered directly to the airways via inhalation

Stimulation of β2 receptors activates the Gs adenylyl cyclase-cyclic AMP pathway with a consequent reduction of in smooth muscle tonebronchodilation

β2 Adrenergic receptor agonists also increase the conductance of large Ca2+-sensitive K+ channels in airway smooth muscle leading to membrane hyperpolarization and relaxation

Stimulation of β2 adrenergic receptors inhibits the function of numerous inflammatory cells including mast cells basophils eosinophils neutrophils and lymphocytes

long-term exposure to β2-agonists may desensitize some of these receptor-response pathways

Short acting beta agonists (acute relief symptoms) Salbutamol Levosalbutamol Metaproterenol Terbutaline pirbuterol

Long acting beta agonists (for prophylaxis) Salmeterol Formoterol

Salbutamol Physicochemical

Structure

Class β2 selective agonistPresentation Inhalant 90 mcgpuff aerosol 0083 05 063 solution for nebulization

2

Oral 2 4 mg tablets 2 mg5 mL syrup

Pharmacodynamics MOA Read above for mechanism of action

Use Asthma CORD

Adjunct in hyperkalaemia managementDose Metered dose inhaler - children 1- 2 puffs qid adults 2 puffs qid

Nebulizer - children 25 mg qid adults 5 mg qid

Also oral syrup and tablet

IV 250 - 500 mcg stat then approximately 5 mcg per minute

CVS Tachycardia CNS Poor penetrationRespiratory Peak effect oral 2-3 hours

nebulizer inhalation 05 - 2 hours

Duration oral = 4-6 hours

nebulizer inhalation = 3-4 hours

Other Increased lactate and lactic acidosis

Side effectsadverse effects

Tachycardia palpitations

GI upset nausea

Nervousness CNS stimulation diziness

Special precaution in

Hyperthyroidism diabetes

Coronoary insufficiency or hypertension

Excessive use may result in tolerance

Toxicity Hypertension tachycardia angina hypokalaemia and tachyarrythmias

Interactions Decreased effects beta adrenergic blockers

3

Increased therapeutic effect with ipratropium

Increased toxicity with MAOIs tricyclics sympathomimeticsPharmacokinetics

Absorption Aerosol deposition depends on particle size pattern of breathing and geometry of airways

80 deposited in mouth or pharynx

Absorption can be increased by held inspirationDistribution Half life inhalation = 38 hours

oral = 27 - 5 hoursMetabolism By liver to an inactive sulphate

28 appears in urine unchangedExcretion 28 in urine unchanged

Evidence

SalmeterolPhysicochemical

Structure ClassPresentation 25 microg MDI

Pharmacodynamics MOA

Use Dose 50 - 100 microg BD

CVSCNSRespiratory Other

Side effectsadverse effectsInteractions

Pharmacokinetics Absorption

4

DistributionMetabolism

Excretion

Evidence

Glucocorticoids

Mechanism of Glucocorticoid Action in Asthma effective in inhibiting airway inflammationmodulation of cytokine and chemokine production inhibition of eicosanoid synthesis marked inhibition of accumulation of basophils eosinophils and other leukocytes in lung tissue and decreased vascular permeability

Inhaled Glucocorticoids greatly enhance the therapeutic index of the drugs substantially diminishing the number and degree of side effects without sacrificing clinical utility

Beclomethasone triamcinolone flunisolide budesonide fluticasone ciclesonide

Systemic Glucocorticoids Systemic glucocorticoids are used for acute asthma exacerbations and chronic severe asthma

Hydrocortisone Prednisolone Methyl prednisolone

BudesonidePhysicochemical

Structure Class Inhaled glucocorticoidsPresentation Aerosol powder (Turbuhaler) 160 mcgactivation

Inhalation suspension (Respules) 025 05 mg2 mL

Pharmacodynamics MOA Penetrate cells and bind to a high affinity cytoplasmic receptor protein a

5

structural change occurs in the steroid receptor complex that allows its migration into nucleus and binding to specific sites on chromatictranscription of specific mRNA regulation of protein synthesis In many tissues the effect is catabolic because of synthesis of inhibitory protein Anti-inflamatory actions are due to

Induction of lipocortins in macrophages endothelium and fibroblasts Negative regulation of genes for cytokines in macrophages

endothelial cells and lymphocytes darr production of acute phase reactants from macrophages and

endothelial cells darrproduction of ELAM 1 and ICAM 1 in endothelial cells Inhibit IgE mediated histamine and LT C4 release from basophils

darr production of collagenase and stromolysinUse Asthma

COPDAllergic rhinitis

Dose 200-400microg BD-QID

CVS No effectsCNS No effectsRespiratory Decreased inflammation decreased mucus production decreased edema

smooth muscle relaxation Other


Hypothalamic-pituitary-adrenal axis suppression

No significant risk until dosages of budesonide or beclomethasone increased to gt1500 ugday in adults or gt400 ugday in children

Bone resorption Modest but significant effects at doses possibly as low as 500 ugday

Carbohydrate and lipid metabolism

Minor clinically insignificant changes occur with dosages of beclomethasone gt1000 ugday

Cataracts Anecdotal reports risk unprovenSkin thinning Dosage-related effect with beclomethasone

dipropionate over a range of 400 to 2000 ugdayPurpura Dosage-related increase in occurrence with

beclomethasone over a range of 400 to 2000 ugdayDysphonia Usually of little consequenceCandidiasis Incidence lt5 reduced by use of spacer deviceGrowth retardation

Difficult to separate effect of disease from effect of treatment but no discernible effects on growth when all studies are considered

Interactions Nil

Pharmacokinetics

6

Absorption Minute systemic absorptionDistribution -Metabolism Systemically absorped drug is rapidly metabolized Metabolized in liver by

red-ox reactions followed by conjugation with glucoronic acid or sulfate Excretion Metabolites excreted in urine

Evidence

HydrocortisonePhysicochemical

Structure ClassPresentation 100mg Inj





endothelial cells darrproduction of ELAM 1 and ICAM 1 in endothelial cells Inhibit IgE mediated histamine and LT C4 release from basophils darr production of collagenase and stromolysin

Use 1 Endocrine disorders - adrenocortical insufficiency Congenital adrenal hyperplasia etc2 Rheumatic disorders ndash Acute gout Psoriatic arthritis Rheumatoid arthritis Ankylosing spondylitis etc3 Collagen diseases - Systemic lupus erythematosus Acute rheumatic carditis Systemic dermatomyositis (polymyositis)4 Dermatologic diseases eg Pemphigus5 Allergic states eg bronchial asthma allergic rhinitis 6 Ophthalmic diseases Allergic conjunctivitis

7

Dose Initial dosage of prednisolone tablets may vary from 5 mg to 60 mg per day

CVS Restrict capillary permeability maintain time of arterioles permissive effect on pressor action of Adr and angiotensin

CNS Euphoria increased motor activity insomnia anxiety High dose lower seizure threshold

Respiratory Decreased inflammation decreased mucus production decreased edema Other


Increased susceptibility to infection

Fluid and Electrolyte Disturbances - Sodium retention Fluid retention Potassium loss Hypokalemic alkalosis Hypertension

Musculoskeletal- Muscle weakness Steroid myopathy Loss of muscle mass Osteoporosis Vertebral compression fractures Aseptic necrosis of femoral and humeral heads Pathologic fracture of long bones

Gastrointestinal-Peptic ulcer with possible perforation and hemorrhage Pancreatitis Abdominal distention Ulcerative esophagitis

Dermatologic - Impaired wound healing Thin fragile skin Petechiae and ecchymoses Facial erythema Increased sweating May suppress reactions to skin tests

Neurological- Convulsions Increased intracranial pressure with papilledema (pseudotumor cerebri) usually after treatment Vertigo Headache

Endocrine - Menstrual irregularities Development of Cushingoid state Suppression of growth in children Decreased carbohydrate tolerance Manifestations of latent diabetes mellitus Increased requirements for insulin or oral hypoglycemic agents in diabetics

Ophthalmic - Posterior subcapsular cataracts Increased intraocular pressure Glaucoma Exophthalmos

Metabolic - Negative nitrogen balance due to protein catabolism

Interactions Phenobarbitone and phenytoin induce metabolism

Pharmacokinetics

8

Absorption High first pass metabolism Distribution 90 protein boundMetabolism Metabolized in liver by red-ox reactions followed by conjugation with

glucoronic acid or sulfate t12~ 12-36hrs Excretion Metabolites excreted in urine

Evidence

PrednisonePhysicochemical

Structure

Class Glucocorticoids Presentation 5mg tabs






Use 1 Endocrine disorders - adrenocortical insufficiency Congenital adrenal

9

hyperplasia etc2 Rheumatic disorders ndash Acute gout Psoriatic arthritis Rheumatoid arthritis Ankylosing spondylitis etc3 Collagen diseases - Systemic lupus erythematosus Acute rheumatic carditis Systemic dermatomyositis (polymyositis)4 Dermatologic diseases eg Pemphigus5 Allergic states eg bronchial asthma allergic rhinitis 6 Ophthalmic diseases Allergic conjunctivitis













10




Pharmacokinetics Absorption Orally absorbed readily DistributionMetabolism Metabolized in liver by red-ox reactions followed by conjugation with


Evidence

IpratropiumPhysicochemical

Structure Quaternary isopropyl derivative of atropineClass Anti-cholinergicPresentation Aerosol 17 (freon-free) 18 mcgpuff in 200 metered-dose inhaler 002 (500 mcgvial) for

nebulization

Nasal spray 21 42 mcgspray

Pharmacodynamics MOA Blocks the action of acetylcholine at parasympathetic sites in bronchial smooth

muscle causing bronchial dilation

Onset of bronchial dillation 1-3 minutes after administration

Peak effect in 15 to 2 hours

Duration 4-6 hours

Use Broncho spasm associated with COPD bronchitis and emphysemaDose Nebuliser solution 0025 solution use 1 - 2 mls 2 - 4 hourly

11

Metered dose inhaler Adults 2 puffs qid Children 1-2 puffs tidCVSCNSRespiratory Other


Poorly absorbed from lung so systemic effects are rare

CNS nervousness dizziness fatigue headache

Special precaution

Not indicated for initial treatment of bronchospasm as a sole agent

Caution with narrow angle glaucoma

Prostatic hypertrophy

Bladder neck obstruction

Toxicology Dry mouth drying of secretions coughnausea GI distress blurred vision If life threatening treat with physostigmine 1-2mg SC or IV

Interactions Salbutamol - increased effect of both drugs

Increased toxicity with anticholinergicsPharmacokinetics

Absorption Not readily absorbed into the systemic circulation from the surface of the lung or GI tract

lt1 absorbedDistribution Inhalation 10-15 of dose reaches lower airways

Approximately 90 of the dose is swallowed

Half life = 3 hoursMetabolism

Excretion Approximately 90 excreted unchanged in faeces

Evidence

Montelukast

12

Physicochemical Structure Class leukotriene-receptor antagonistsPresentation Oral 10 mg tablets 4 5 mg chewable tablets

Pharmacodynamics MOA Blocks leukotriene receptors The effects of cys-LTs that are potentially

relevant to bronchial asthma are not limited to bronchial smooth muscle contraction Cys-LTs can increase microvascular leakage increase mucous production and enhance eosinophil and basophil influx into the airways The extent to which inhibiting these non-smooth muscle effects of leukotrienes contributes to the therapeutic effects of the drugs is not known

Use AsthmaAllergic rhinitis

Dose

CVSCNSRespiratory Bronchodilatation reduced sputum eosinophil count suppression of

bronchial inflammation and hyper reactivity Other


Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions

Pharmacokinetics Absorption Montelukast is absorbed rapidly with about 60 to 70 bioavailability Distribution At therapeutic concentrations it is highly protein-bound (99) Metabolism It is metabolized extensively by CYP3A4 and CYP2C9 The half-life of

montelukast is between 3 and 6 hoursExcretion Biliary

Evidence

13

TheophyllinePhysicochemical

Structure methylated xanthenes

ClassPresentation Oral 100 125 200 250 300 mg tablets

Pharmacodynamics MOA Non selective inhibition of cyclic nucleotide PDEs thereby

preventing breakdown of cyclic AMP and cyclic GMP accumulation of cyclic AMP and cyclic GMP increasing signal transduction through these pathways

Competitive antagonist at adenosine receptors adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from human lung mast cells

Activates histone deacetylases in the nucleus In theory the deacetylation of histones could decrease the transcription of several proinflammatory genes and potentiate the effect of corticosteroids

Use AsthmaApnea of pre-term infants

Dose 12 to 16 mgkg per day of theophylline (calculated as the free base) up to a maximum of 400 mgday

CVS Positive chronotropic inotropic CNS Irritability increased alertness anxiety Respiratory Relaxes airway smooth muscle bronchodilation

inhibits synthesis and secretion of inflammatory mediators from numerous cell types including mast cells and basophils At therapeutic concentrations the antiinflammatory effect of theophylline may be more relevant to the drugs therapeutic actions than direct bronchodilation

Other


Rapid intravenous administration of therapeutic doses sometimes results in sudden death that is probably due to cardiac arrhythmias

headache palpitation dizziness nausea hypotension and precordial pain

tachycardia severe restlessness agitation and emesis

Focal and generalized seizures also can occur

14

InteractionsHepatic cirrhosis congestive heart failure and acute pulmonary edema all increase the half-life as does concurrent therapy with cimetidine or erythromycin In contrast clearance is increased twofold by phenytoin or barbiturates whereas cigarette smoking rifampin and oral contraceptives induce smaller changes

Pharmacokinetics Absorption Absorbed readily after oral or parenteral administration

In the absence of food solutions or uncoated tablets of theophylline produce maximal concentrations in plasma within 2 hours

There is marked interpatient variability with regard to the rate and extent of absorption and especially the effect of food and time of administration on these parameters

Food ordinarily slows the rate of absorption of theophylline but does not limit its extent

Distribution Distributed into all body compartmentsCross the placenta and pass into breast milkVd ~ 06 Lkg the protein binding of theophylline averages about 60

Metabolism primarily by metabolism in the liverlt 15 of theophylline is recovered in the urine unchanged T12~8 or 9 hours drug obeys first-order elimination kinetics At higher concentrations zero-order kinetics become evident because of saturation of metabolic enzymes

Excretion Biliary lt 15 in urine unchanged

Evidence

Outline the pharmacology of drugs used to treat pulmonary hypertension

15

Describe the pharmacology of oxygen

OxygenDiscovered by Priestley in 1772

Lavoisier elucidated its role in respiration

Oxygen therapy introduced by Beddoes in 1794

Physicochemical Structure Colourless odourless tasteless gas

99 VV of O2 residue = argon with trace of hydrogen or nitrogen

Physicochemical Properties Colourless odourless gas Molecular formula O2

MW = 32 Supports combustion Oxidant Critical temp -119degC

Class Medical gasPresentation

Manufactured by the fractional distillation of liquid air Based on different boiling points of O2 and N2

Used for commercial production

- O2 concentrator N2 adsorber (zeolite mesh) Useful for home useremote locations

Oxygen is supplied as a compressed gas in steel cylinders and a purity of 99 is referred to as medical grade Most hospitals have oxygen piped from insulated liquid oxygen containers to areas of frequent use For safety oxygen cylinders and piping are color-coded and some form of mechanical indexing of valve connections is used to prevent the connection of other gases to oxygen systems Oxygen concentrators which employ molecular sieve membrane or electrochemical technologies are available for low-flow home use Such systems produce 30 to 95 oxygen depending on the flow rate

16

Oxygen is delivered by inhalation except during extracorporeal circulation when it is dissolved directly into the circulating blood


Use Optimise O2 delivery if patients have deficits in O2 transport chain or increased O2 consumption increased haemoglobin saturation in dyspnoea or respiratory failure decompression sickness in divers to titrate O2 dose in chronic CO2 retention relying on hypoxia for respiratory drive

Dose Administered by inhalation by nasal catheter face mask endotracheal tube or oxygen tent

Usually to give inspired concentration of 30 but can be up to 100 Via mask 6L minLow-Flow Systems Low-flow systems in which the oxygen flow is lower than the inspiratory flow rate have a limited ability to raise the FIO2 because they depend on entrained room air to make up the balance of the inspired gas The FIO2 of these systems is extremely sensitive to small changes in the ventilatory pattern Nasal cannulaesmall flexible prongs that sit just inside each narisdeliver oxygen at 1 to 6 Lmin The nasopharynx acts as a reservoir for storing the oxygen and patients may breathe through either the mouth or nose as long as the nasal passages remain patent These devices typically deliver 24 to 28 FIO2 at 2 to 3 Lmin Up to 40 FIO2 is possible at higher flow rates although this is poorly tolerated for more than brief periods because of mucosal drying The simple facemask a clear plastic mask with side holes for clearance of expiratory gas and inspiratory air entrainment is used when higher concentrations of oxygen delivered without tight control are desired The maximum FIO2 of a facemask can be increased from around 60 at 6 to 15 Lmin to greater than 85 by adding a 600- to 1000-ml reservoir bag With this partial rebreathing mask most of the inspired volume is drawn from the reservoir avoiding dilution by entrainment of room air

High-Flow Systems The most commonly used high-flow oxygen delivery device is the Venturi mask which uses a specially designed mask insert to entrain room air reliably in a fixed ratio and thus provides a relatively constant FIO2 at relatively high flow rates Typically each insert is designed to operate at a specific oxygen flow rate and different inserts are required to change the FIO2 Lower delivered FIO2 values use greater entrainment ratios resulting in higher total (oxygen plus entrained air) flows to the patient ranging from 80 Lmin for 24 FIO2 to 40 Lmin at 50 FIO2 While these flow rates are much higher than those obtained with low-flow devices they still may be lower than the peak inspiratory flows for patients in respiratory distress and thus the actual delivered oxygen concentration may be lower than the nominal value Oxygen nebulizers another type of Venturi device provide patients with humidified oxygen at 35 to 100 FIO2 at high flow rates Finally oxygen blenders provide high inspired oxygen concentrations

17

at very high flow rates These devices mix high-pressure compressed air and oxygen to achieve any concentration of oxygen from 21 to 100 at flow rates of up to 100 Lmin These same blenders are used to provide control of FIO2 for ventilators CPAPBiPAP machines oxygenators and other devices with similar requirements Again despite the high flows the delivery of high FIO2 to an individual patient also depends on maintaining a tight-fitting seal to the airway andor the use of reservoirs to minimize entrainment of diluting room air

CVS Aside from reversing the effects of hypoxia the physiological consequences of oxygen inhalation on the cardiovascular system are of little significance Heart rate and cardiac output are slightly reduced when 100 oxygen is breathed blood pressure changes little While pulmonary arterial pressure changes little in normal subjects with oxygen inhalation elevated pulmonary artery pressures in patients living at high altitude who have chronic hypoxic pulmonary hypertension may reverse with oxygen therapy or return to sea level In particular in neonates with congenital heart disease and left-to-right shunting of cardiac output oxygen supplementation must be regulated carefully because of the risk of further reducing pulmonary vascular resistance and increasing pulmonary blood flow

CNSRespiratory Inhalation of oxygen at 1 atm or above causes a small degree of respiratory

depression in normal subjects presumably as a result of loss of tonic chemoreceptor activity However ventilation typically increases within a few minutes of oxygen inhalation because of a paradoxical increase in the tension of carbon dioxide in tissues This increase results from the increased concentration of oxyhemoglobin in venous blood which causes less efficient removal of carbon dioxide from the tissues In a small number of patients whose respiratory center is depressed by long-term retention of carbon dioxide injury or drugs ventilation is maintained largely by stimulation of carotid and aortic chemoreceptors commonly referred to as the hypoxic drive The provision of too much oxygen can depress this drive resulting in respiratory acidosis In these cases supplemental oxygen should be titrated carefully to ensure adequate arterial saturation If hypoventilation results then mechanical ventilatory support with or without tracheal intubation should be provided

Expansion of poorly ventilated alveoli is maintained in part by the nitrogen content of alveolar gas nitrogen is poorly soluble and thus remains in the airspaces while oxygen is absorbed High oxygen concentrations delivered to poorly ventilated lung regions dilute the nitrogen content and can promote absorption atelectasis occasionally resulting in an increase in shunt and a paradoxical worsening of hypoxemia after a period of oxygen administration

Other


- Free radical toxicity (pP gt 200kPa) Occurs more rapidly with hyperbaric O2

CNS effects anxiety nausea seizures

18

Pulmonary effects lipid peroxidation of alveolar capillary membrane rarr regional lung collapse

- Absorption atelectasis (high FiO2) Areas of darrVQ remove more gas from alveoli than is replaced with

ventilation No N2 to act as alveolar splint

- darrHypoxic drive

o Evident in Pts with COAD who are CO2 retainers

10487071048707Blunts hypercarbic response to uarrventilation

104870710487071deg control is via hypoxic drive

o uarrFiO2 rarr darrhypoxic drive rarr darrstimulation of medullary vent centre rarr darrRR

- Neonatal

o Susceptible to retrolental fibroplasia 2deg vasoconstriction of retinal vessels during development

10487071048707More reflection of PaO2 rather than PAO2 Avoided with PaO2 lt 140mmHg

Special precautions

High concentration - depress hypoxic drive

Danger of flame or spark especially if O2 under pressure

Toxicology

Toxic in high doses Function of partial pressure and duration of exposure

Symptoms and signs are more rapid with greater PiO2

Toxicity primarily affects the respiratory tract CNS and eye

Three mechanism postulated 1) formation of free radicals 2) inhibition of enzymes 3) direct toxic effects on cerebral metabolism

Interactions

Pharmacokinetics Absorption Diffuses from alveoli into pulminary capillaries thence to every body cell Moves

down a stepwise series of pressure gradients from inspired air to the bodyrsquos cells and their mitochondria

19

Air normally contains 209 O2 equivalent at normal barometric pressure to a partial pressure of 149mm Hg (21kPa)

Distribution Total body

Metabolism O2 is essential to respiration of all animal cells

Permits the process of oxidative phosphorylation in mitochondria converting food fuels into energy for cell processes

Excretion

Evidence

Describe the pharmacology of nitric oxide with particular reference to its inhaleduse

NOPhysicochemical

Structure Class Medical gasPresentation 100 ppm [nitric oxide 001 and nitrogen 9999] (353 L) [delivers

344 L] (1963 L) [delivers 1918 L]800 ppm [nitric oxide 008 and nitrogen 9992] (353 L) [delivers 344 L] (1963 L) [delivers 1918 L]

Pharmacodynamics MOA NO is both an intracellular and a cell-cell messenger implicated in a wide range of

physiological and pathophysiological events in numerous cell types including the cardiovascular immune and nervous systems NO activates the soluble guanyl cyclase increasing cellular cyclic GMP

In the vasculature basal release of NO produced by endothelial cells is a primary determinant of resting vascular tone NO causes vasodilation when synthesized in response to shear stress or a variety of vasodilating agents

It also inhibits platelet aggregation and adhesion

In the immune system NO serves as an effector of macrophage-induced cytotoxicity and overproduction of NO is a mediator of inflammation

In neurons NO acts as a mediator of long-term potentiation cytotoxicity resulting from N-methyl-D-aspartate (NMDA) and non-adrenergic noncholinergic

20

neurotransmission NO has been implicated in mediating central nociceptive pathways

The lack of systemic effects of inhaled NO is due to its strong binding to and inactivation by oxyhemoglobin on exposure to the pulmonary circulation

Use Therapeutic Use of NO Inhalation of NO gas dilates selectively the pulmonary vasculature with minimal systemic cardiovascular effects Ventilation-perfusion matching is preserved or improved by NO because inhaled NO is distributed only to ventilated areas of the lung and dilates only those vessels directly adjacent to the ventilated alveoli Thus inhaled NO will decrease elevated pulmonary artery pressure and pulmonary vascular resistance and often improve oxygenation

Inhaled NO has been approved by the FDA only for use in newborns with persistent pulmonary hypertension and has become the first-line therapy for this disease In this disease state NO inhalation has been shown to reduce significantly the necessity for extracorporeal membrane oxygenation

Several small studies and case reports have suggested potential benefits of inhaled NO in a variety of conditions including weaning from cardiopulmonary bypass in adult and congenital heart disease patients primary pulmonary hypertension pulmonary embolism acute chest syndrome in sickle-cell patients congenital diaphragmatic hernia high-altitude pulmonary edema and lung transplantation

Diagnostic Uses of NO Inhaled NO can be used during cardiac catheterization to evaluate safely and selectively the pulmonary vasodilating capacity of patients with heart failure and infants with congenital heart disease

Inhaled NO also is used to determine the diffusion capacity (DL) across the alveolar-capillary unit

Dose amp administration

Courses of treatment of patients with inhaled NO are highly varied extending from 01 to 40 ppm in dose and for periods of a few hours to several weeks in duration A constant inspired concentration of NO is obtained by administering NO in nitrogen to the inspiratory limb of the ventilator circuit in either a pulse or continuous mode While inhaled NO may be administered to spontaneously breathing patients via a closely fitting mask it usually is delivered during mechanical ventilation

Acute discontinuation of NO inhalation can lead to a rebound pulmonary artery hypertension with an increase in right-to-left intrapulmonary shunting and a decrease in oxygenation To avoid this phenomenon a graded decrease of inhaled

21

NO concentration is important in the process of weaning a patient from inhaled NO



Administered at low concentrations (01 to 50 ppm) inhaled NO appears to be safe and without significant side effects

Pulmonary toxicity can occur with levels higher than 50 to 100 ppm Part of the toxicity of NO may be related to its further oxidation to nitrogen dioxide (NO2) in the presence of high concentrations of oxygen Even low concentrations of NO2 (2 ppm) have been shown to be highly toxic in animal models with observed changes in lung histopathology including loss of cilia hypertrophy and focal hyperplasia in the epithelium of terminal bronchioles Laboratory studies have suggested potential additional toxic effects of chronic low doses of inhaled NO including surfactant inactivation and the formation of peroxynitrite by interaction with superoxide The ability of NO to inhibit or alter the function of a number of iron- and heme-containing proteinsincluding cyclooxygenase lipoxygenases and oxidative cytochromesas well as its interactions with ADP-ribosylation

The development of methemoglobinemia is a significant complication of inhaled NO at higher concentrations and rare deaths have been reported with overdoses of NO Methemoglobin concentrations should be monitored intermittently during NO inhalation

Inhaled NO can inhibit platelet function and has been shown to increase bleeding time in some clinical studies although bleeding complications have not been reported

In patients with impaired function of the left ventricle NO has a potential to further impair left ventricular performance by dilating the pulmonary circulation and increasing the blood flow to the left ventricle thereby increasing left atrial pressure and promoting pulmonary edema formation

gt10Cardiovascular Hypotension (13)Miscellaneous Withdrawal syndrome (12)

1 to 10Dermatologic Cellulitis (5)Endocrine amp metabolic Hyperglycemia (8)Genitourinary Hematuria (8)

22

Respiratory Atelectasis (9 - same as placebo) stridor (5)Miscellaneous Sepsis (7) infection (6)

Postmarketing andor case reports Headache (environmental exposure eg hospital staff) hypoxemia pulmonary edema (in CREST syndrome patients)

Interactions No known

Pharmacokinetics Absorption Systemic after inhalation Rapidly inactivated by oxyhaemoglobin DistributionMetabolism Nitric oxide combines with hemoglobin that is 60 to 100 oxygenated Nitric oxide combines

with oxyhemoglobin to produce methemoglobin and nitrate Within the pulmonary system nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite respectively which interact with oxyhemoglobin to then produce methemoglobin and nitrate At 80 ppm the methemoglobin percent is ~5 after 8 hours of administration Methemoglobin levels gt7 were attained only in patients receiving 80 ppm

Excretion Urine (as nitrate)Clearance Nitrate At a rate approaching the glomerular filtration rate

Evidence

No change in mortality has been demonstrated yet

Describe the pharmacology of prostacycline with particular reference to its inhaled use

Prostacycline Physicochemical

Structure Class prostaglandinPresentation 500microg vial

Pharmacodynamics MOA Prostacyclin causes selective pulmonary vasodilation increases cardiac output

and improves venous and arterial oxygenation

23

Use Used in patients with severe pulmonary hypertension severe ARDS and severe hypoxia due to respiratory failure used intravenously or subcutaneously as a vasodilator in severe Raynauds phenomenon or ischemia of a limb

Dose amp administration 500 microg Prostacyclin reconstituted in the accompanying sterile glycine buffer

solution and made up to 50mls in a 50ml syringe 5ml of the prostacycline solution loaded into the nebuliser chamber Administered at a rate of 5-15mlhr Nebulizer works on wall oxygen The T-piece and rubber connector is then inserted into the ventilator circuit on the Inspiratory limb While nebulising Prostacyclin the oxygen outlet is dialed to deliver 4 Lminute and kept at a constant rate The dose is adjusted by the mlshour set on the syringe driver



Hypotension Platelet dysfunction

Interactions

Pharmacokinetics Absorption DistributionMetabolism Prostacyclin which has a half-life of seconds is broken down into 6-keto-

PGF1 which is a much weaker vasodilatorExcretion

Evidence

24

Describe the pharmacology of surfactant with particular reference to its inhaledUse

Surfactant Physicochemical

Structure ClassPresentation Exogenous products can be divided into two groups

Natural - derivatives of human bovine and porcine surfactants - faster onset of action

Synthetic Advantages of natural surfactants

Faster onset of action

Advantages of synthetic surfactants

More resistant to inactivation by the meconium componentsdecreased risk of transmission of infectious disease and immunologic sensitization

Pharmacodynamics MOA Reduces surface tension increasing lung compliance and alveolar stability

Use RDS of new born - Infants whose birth weight is lt1250 g with signs of surfactant deficiency as a prophylaxis or as a rescue in Infants who have RDS confirmed by radiographic findings and who require mechanical ventilation

Adult ARDSDose amp administration

Dose amp administration Prophylaxis is initiated preferably within 15 minutes of birth

on the basis of risk factors and before a confirmed diagnosis of RDS Theoretically the optimal time to

deliver surfactant into the lung fluid is before the infant takes a breath to allow for uniform mixing with fetal lung fluid which serves as a vehicle for optimal distribution to distal sites

Rescue therapy which usually occurs within eight hours of birth in infants requiring mechanical ventilation because of

25

radiographically confirmed RDS The doses and administration techniques vary by product

Good bioavailability in the distal airways can usually be attained by using one to four bolus doses ranging from 1 to 5 mLkg of exogenous surfactants



Apnea of prematurity increases among infants receiving surfactant presumably because of the shorter time to extubation

Transient episodes of bradycardia (119) and decreased oxygen saturation (98) during the administration

Tachycardia

Plugging of the endotracheal tube by secretions

pulmonary hemorrhage

Interactions

Pharmacokinetics Absorption Only small amounts reach the systemic circulation

Bioavailability to the distal airways and alveoli depends on the method of delivery the stage and severity of pulmonary disease and the properties of the particular surfactant

DistributionMetabolism Clearance is a local phenomenon that primarily involves type II

alveolar cells Half life for bovine surfactant extract - 43 11 hours for phosphatidylglycerol from synthetic surfactant is 105 23 hours

Excretion

Evidence

2

Oral 2 4 mg tablets 2 mg5 mL syrup

Pharmacodynamics MOA Read above for mechanism of action

Use Asthma CORD

Adjunct in hyperkalaemia managementDose Metered dose inhaler - children 1- 2 puffs qid adults 2 puffs qid

Nebulizer - children 25 mg qid adults 5 mg qid

Also oral syrup and tablet

IV 250 - 500 mcg stat then approximately 5 mcg per minute

CVS Tachycardia CNS Poor penetrationRespiratory Peak effect oral 2-3 hours

nebulizer inhalation 05 - 2 hours

Duration oral = 4-6 hours

nebulizer inhalation = 3-4 hours

Other Increased lactate and lactic acidosis


Tachycardia palpitations

GI upset nausea

Nervousness CNS stimulation diziness

Special precaution in

Hyperthyroidism diabetes

Coronoary insufficiency or hypertension

Excessive use may result in tolerance

Toxicity Hypertension tachycardia angina hypokalaemia and tachyarrythmias

Interactions Decreased effects beta adrenergic blockers

3








Evidence








4


Excretion

Evidence

Glucocorticoids










5




















Interactions Nil

Pharmacokinetics

6



Evidence









7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

3








Evidence








4


Excretion

Evidence

Glucocorticoids










5




















Interactions Nil

Pharmacokinetics

6



Evidence









7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

4


Excretion

Evidence

Glucocorticoids










5




















Interactions Nil

Pharmacokinetics

6



Evidence









7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

5




















Interactions Nil

Pharmacokinetics

6



Evidence









7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

6



Evidence









7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

7
















Pharmacokinetics

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

8



Evidence


Structure








9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

9














10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

10






Evidence



nebulization






Duration 4-6 hours


11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

11





Special precaution













Evidence

Montelukast

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

12





Dose




Headache

Rashes

Eosinophilia

Neuropathy

Churg strauss

Interactions



Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

13












Other






14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

14









Evidence


15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

15














16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

16







17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

17






Other




18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

18




- darrHypoxic drive





- Neonatal



Special precautions



Toxicology





Interactions



19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

19





Excretion

Evidence


NOPhysicochemical









20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

20











21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

21











22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

22







Evidence







23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

23







Interactions



Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

24
















25







Tachycardia



Interactions





Excretion

Evidence

25







Tachycardia



Interactions





Excretion

Evidence

storage.googleapis.com · web viewdescribe the pharmacology of anti-asthma drugs with particular...

Documents