18B Flashcards
dyspepsia
combination of symptoms that indicates an Upper GIT problem Sx- Epigastric pain or burning Early satiation Post prandial fullness Belching, bloating, nausea, discomfort
Heartburn
a burning sensation in the chest, just behind the sternum or in the epigastrium
The pain often rises in the chest and may radiate to the neck, back, shoulder, throat, or angle of the jaw
~50% of patients with GORD will present with chest pain
It may also be a symptom of ischemic heart disease
Heartburn cont
Cardiac and oesophageal causes may share similar symptoms as these two structures have the same nerve supply.
GORD is the most common cause of heartburn
recognized as a symptom of an acute myocardial infarction and angina
chest pain caused by GORD
has a distinct ‘burning’ sensation
occurs after eating or at night
worsens when a person lies down or bends over
It also is common in pregnant women
may be triggered by consuming food in large quantities, or specific foods containing certain spices, high fat content, or high acid content.
Heartburn and indigestion – Danger signs
Dysphagia
Dyspepsia at any age combined with one or more of the following ‘alarm’ symptoms: Weight loss,Proven anaemia, Vomiting (or haematemesis
Dyspepsia in a patient aged 55 years or more with at least one of the following ‘high-risk’ features: Onset of dyspepsia <1 year previously, Continuous symptoms since onset
Dyspepsia combined with at least one of the following known ‘risk factors’: Family history of upper GI cancer in more than two firstdegree relatives, Pernicious anaemia, Palpable Virchow’s node
Regulation of gastric acid secretion
Gastric acid secretion by parietal cells in gastric mucosa stimulated by:
Acetylcholine (induces increase in intracellular calcium)
Histamine (activation of adenylyl cyclase)
Gastrin (induces increase in intracellular calcium)
Gastric acid secretion diminished by Prostaglandin E2 (inhibits adenylyl cyclase) Somatostatin (inhibits adenylyl cyclase)
factors that can affect gastric acid secretion
dicyclomine blocks cholinergic receptor
cimetidine blocks histamine receptor
omeprazole blocks proton pump
misoprostol stimulates prostaglandin receptor
peptic ulcer disease causes
NSAIDS (espAspirin)
Infection with Helicobacter pylori- (90% duodenal ulcers)- (70% gastric ulcers)
Increased hydrochloric acid and pepsin secretion
Inadequate mucosal defence against gastric acid
peptic ulcer disease Non-Pharmacological Rx
Stop smoking
Avoid ulcerogenic drugs (alcohol, NSAIDS, glucocorticosteroids)
Reduce caffeine intake
peptic ulcer disease Pharmacological Rx
Eradicating H.pylori infection- Antimicrobial therapy (amoxicillin, clarithromycin and metronidazole) + PPI (Esomeprazole, Lanzoprazole, Pantoprazole)
Reducing secretion of gastric acid- PPI, H2 receptor antagonists
Providing agents that protect the gastric mucosa from damage- Misoprostol, Sucralfate, alginates, bismuth
Antacids- Aluminum hydroxide, Calcium carbonate, Sodium bicarbonate
Proton Pump Inhibitors facts
Inhibit irreversibly H+/K+ – ATPase enzyme (proton pump) thereby suppressing secretion of hydrogen ions into the gastric lumen
Omeprazole inhibits CYP450 : thus inhibits metabolism of warfarin, phenitoin, diazepam, cyclosporine, digoxin
Most potent suppressors of gastric acid secretion
Acid suppression begins on average 1-2 hours after 1st dose
Effect for 2-3 days because of accumulation in gastric canaliculi
Preferred to H2 antagonists
Proton Pump Inhibitors indications
short term mx of peptic ulcer disease and GORD
Long term prevention of relapse of GORD
Treatment of Zollinger-Ellison syndrome
Treatment and prevention of NSAID-associated erosions and ulcers
IV PPI useful for high risk bleeding peptic ulcer
Proton Pump Inhibitors adverse effects
Hypomagnesemia (in prolonged use) Increased risk of fracture Headaches Skin rashes Diarrhoea
H2-receptor antagonists facts
Reduces gastric acid secretion by reversibly blocking the action of histamine at the H2 receptors in the parietal cells of the stomach
Very efficient in nocturnal acid secretion
H2-receptor antagonists indications
Peptic ulcers, oesophagitis
Acute stress ulcers
GORD
Hypersecretory states (Zollinger-Ellison syndrome)
H2-receptor antagonists adverse effects
Headache, dizziness, diarrhoea, muscular pain
CNS – confusion, hallucinations, slurred speech
Anti-androgenic effect (esp. cimetidine)- Impotence, Gynaecomastia, Galactorrhoea
Cimetidine (H2-receptor antagonists)
high potential for drug interactions (inhibits P450)- theophylline, phenytoin, fluorouracil, metformin, diazepam, imipramine (increased effects)
Ketoconazole (increased absorption)
Ranitidine
Doesn’t cross BBB as easily, therefore less CNS symptoms
Less potential for drug-drug interactions (no effect on P450)
Little or no anti-androgenic effect compared to cimetidine
Prostaglandins facts
inhibits secretion of HCl, stimulates secretion of mucus and bicarbonate and causes vasodilation in the submucosa
Less effective than H2 antagonists or PPI’s
Routine use only in NSAID induced ulcers
Adverse effects-Uterine contractions (Contra indicated with pregnancy), Nausea and diarrhoea
adverse effects of GORD drugs
sucralfate- interferes with absorption of Tetracycline & Phenytoin
Bismuth subcitrate- Blackening of the tongue, teeth, stools
Aluminum hydroxide- constipation and faecal impaction
Magnesium (hydroxide and trisilicate)- diarrhoea and N+V
Calcium antacids- Milk-alkali syndrome
Sodium bicarbonate- Liberates CO2, causing belching and flatulence
H.pylori eradication
Triple therapy (7-(14) day regimen for eradication therapy)
PPI) PLUS TWO of the following antibiotics
Clarithromycin 500mg bd
Amoxicillin 1g bd
Metronidazole 400mg bd
(Tetracycline)
Quadruple therapy- Ranitidine 300mg dly for 7 days (if PPI contraindicated) PLUS Bismuth subcitrate 120mg 6hrly for 7 days PLUS 2 above antibiotics
PPI may be continued for 1 month or until the ulcer has healed
cause secondary hypertension
kidney disease
adrenal disease
thyroid problems
obstructive sleep apnea
Thiazide diuretics
inhibit Na+ and Cl- transporter in distal convoluted tubules
increased Na+, Cl- & K+/Mg2+ excretion
decrease Ca2+ excretion
weak inhibitors of carbonic anhydrase, increased HCO3- excretion
side effects Thiazide diuretics
hypokalemia hypovolemia hyperuricemia metabolic ADRs (impaired glucose tolerance and dyslipidemia - mostly after high doses) erectile dysfunction
Potassium-sparing Diuretics
Works in the collecting duct
Binds and blocks aldactone receptors resulting in blocked Na water reabsorption; decreased SVR and BP
Considered a weak diuretic & thus often used in conjunction with more potent K depleting diuretics
side effects Potassium-sparing Diuretics
Monitor K levels closely for hyperkalemia especially with renal impairment, use of potassium supplements, or ACE drugs gynecomastia amenorrhea post-menopausal bleeding dizziness, cramps, nausea, diarrhea
ACE Inhibitor Side Effects
Cough (15% of patients. Is reversible) Taste disturbance (reversible) Angiodema First-dose hypotension Hyperkalaemia (esp. in patients with type II diabetes and renal dysfunction
Angiotensin II receptor blockers
Block the binding of Angiotensin II to AT1 receptors on vessels & adrenal gland thereby: -promoting vasodilation / lower aldosterone -decreased SVR and decreased BP
side effects Angiotensin II receptor blockers
Minimal side effect profile
Metabolically neutral
No impact on lipids, insulin or K+
Lowers uric acid levels
angiotensin II type 1 receptor effects
vessels- vasoconstriction, atherosclerosis, inflammation
heart- hypertrophhy, fibrosis
kidneys- incr aldosterone, salt retention
Calcium Channel Blockers
They act by reducing Ca2+ influx through voltage dependant L-type Ca2+ channels – resulting in smooth muscle relaxation and vasodilatation.
Effectively treat systolic hypertension
May be superior to other antihypertensives for stroke prevention
Effective in patients with: Comorbid conditions (Raynauds, migraine)
Particularly effective in- Elderly and African American’s
Calcium Channel Blockers side effects
Dihydropyridines- Peripheral edema, reflex tachycardia, flushing/headache, Hypotension
Non dihydropyridines- constipation, conduction abnormalities
Calcium Channel Blockers caategories
benzothiazepines, phenylalkylamines & dihydropyridines (1st, 2nd and 3rd gen)
Alpha-Beta Blockers
Work by binding to both alpha-1 and beta-1 and/or beta-2
Carvedilol & Labetalol both block: alpha-1 + beta-1+ beta-2
Beta Blockers: CV Pharmacodynamics
Reduced: heart rate, force of heart contraction, cardiac output, blood pressure
Decreased renin
Reduction in LVH, arrhythmias
Hypertension in Pregnancy
Pre-existing HPT
Drugs with best safety record are: Methyldopa, Nifedipine, Labetalol (also given IV in severe pre-eclampsia)
In the second trimester, although the risk of malformations is lower, diuretics and beta blockers are still contraindicated because they may retard foetal growth and cause electrolyte imbalance in the newborn
Hypertension in Pregnancy
Pre-eclampsia
Presents with HPT, oedema, proteinuria or hyperuricaemia in those whose BP had been norma
Complications: convulsions, cerebral haemorrhage, abruptio placentae, pulmonary oedema and renal failure
HT therapy in Special Populations
Africans- Responsd best to diuretics & CCB
Angioedema 2 – 4-fold higher
LVH- Aggressive BP control regresses LVH but hydralazine & minoxidil (vasodilators) DO NOT!
Elderly- Thiazide or CCB may be better tolerated
Pregnancy- Avoid ACEI & ARBs
Children/adolescents- Avoid ACEI & ARBs in pregnant or sexually active girls
Alpha Blockers
Results in vasodilatation
Fair tolerability; May cause postural effects
Additive agent for older men to decrease BPH symptomatology
Add-on agent only, should never be used as monotherapy due to increased risk of stroke and CHF
Direct Vasodilators
Hydralazine – dilates arterioles but not veins
Minoxidil – opens K+ channels in smooth muscles by its active metabolite
Sodium Nitroprusside – powerful vasodilator for treatment of hypertensive emergencies, Works by increasing intracellular GMP and dilates both arteries and veins
Diazoxide – stimulates opening of K+ channels, Can be used for treating hypertensive emergencies
Direct Vasodilators Precautions include
tachycardia, significant peripheral oedema and hair growth
centrally acting drugs
stimulates central alpha2 receptors which results in: Inhibiting efferent sympathetic activity
Additive agents
Should be used 3rd or 4th line
Caution: sedation, orthostatic hypotension
Clonidine (Centrally Acting drugs)
α-2 agonists
Reduces norepinephrine production
Blood vessel dilation results in decreased BP
Adverse effects: Sedation, dry mouth, Na and water retention
α-methyldopa (Centrally Acting drugs)
does not alter most of the cardiovascular reflexes
It is a pro-drug that exerts its antihypertensive action via an active metabolite (α-methylnorepinephrine)
Adverse effects- Sedation, lassitude (lack of energy), nightmares and lactation
Pharyngitis Causative organisms
Viral- Rhinovirus, corona virus, adenovirus, parainfluenza, influenza, EBV, CMV
Bacterial- Streptococcus pyogenes (GABHS)– 15-30% of cases in children and 5-10% adults, Mycoplasma Pneumoniae
Pharyngitis presentation
Sore throat Odynophagia Fever Anterior Cervical lymphadenopathy Pharyngotonsillar exudate Absence of cough
Pharyngitis treatment
Penicillin VK orally -10 days
IM penicillin (ie, benzathine penicillin G) for persons who may not be compliant with a 10-day course of oral therapy
Cephalosporins- Only considered first line if patient has a history of recent antibiotic use, recurrent pharyngitis infection or high penicillin failure rate is documented in the community
Macrolides- Only when penicillin or cephalosporins cannot be used
Tonsilitis Causative organisms
Viral- EBV, CMV, HSV, adenovirus
Bacterial- Streptococcus pyogenes
Tonsilitis: clinical presentation
Fever Sore throat Foul smelling breath Difficulty swallowing (dysphagia) Painful swallowing (Odynophagia) Tender cervical lymph nodes Tonsillar exudate
Tonsillitis -Complications
Peritonsillar abscess (Quinsy)
Peritonsillar cellulitis
Complications due to GABHS: Scarlet fever (bright red tongue,rash), Acute poststreptococcal glomerulonephritis, Rheumatic fever
Tonsilitis- treatment
Oral penicillin
Recurrent tonsillitis- Amoxicillin/ clavulanate
Other antibiotics- Cephalosporin, Clindamycin, Macrolides
Bacterial Rhinosinusitis Causative organisms
Strep Pneumonia Heamophillus Influenzae Moraxella catarrhalis Staph aureus Strep pyogenes
Acute Viral Rhinosinusitis causes
Rhinovirus, Influenza virus, Parainfluenza virus
Sinusitis –Clinical presentation
Maxillary sinuses often affected Pain and pressure over cheek, radiating to frontal region or teeth Post nasal discharge Blocked nose (Nasal congestion) Cough Discolored nasal discharge Poor response to decongestants
Sinusitis -complications
Orbital cellulitis
Osteomyelitis
Intracranial extension
Carvenous sinus thrombosis - ophthalmoplegia
Sinusitis -Treatment
Amoxicillin with or without clavulanate (1st line) or clarithromycin or azithromycin
2nd line – 2nd or 3rd generation cephalosporins, macrolides, fluoroquinolones, clindamycin
Patients with an allergy to penicillin- doxycycline or a respiratory quinolone as first-line therapy
Treatment – Viral Rhinosinusitis
Analgesics and antipyretics (NSAIDS , paracetamol) Intranasal steroids (relieve facial pain and nasal congestion) Saline irrigation (thin mucous and improve mucociliary clearance)
Community acquired pneumonia Causative organisms
Streptococcus Pneumoniae
Haemophillus Influenzae
Moraxella Catarrhalis
Staph aureus (post-influenza) Klebsiella Pneumoniae (chronic alcoholism) Pseudomonas Aeruginosa (bronchiectasis or cystic fibrosis
Community acquired pneumonia atypical Causative
Chlamydia Pneumoniae
Mycoplasma Pneumoniae
Legionella species
Community acquired pneumonia clinical presentation
Fever, Productive cough, Pleuritic chest pain (sudden and intense sharp, stabbing, or burning pain in the chest when inhaling and exhaling)
Community acquired pneumonia home Rx
<65 years old, without antibiotic exposure in the past 90 days or comorbidities- oral high dose amoxicillin ≥65 years old, have received antibiotics within the previous 90 days or who have comorbidities- oral amoxicillin-clavulanate or an oral second generation cephalosporin.
In both groups the alternative- oral respiratory fluoroquinolone when there is severe beta-lactam allergy
if beta-lactam allergy is presesnt oral macrolide/azalide
Community acquired pneumonia hospital Rx
<65 years with no comorbidities- IV ampicillin or penicillin
≥65 years, have recent antibiotic exposure or comorbidities- amoxicillin-clavulanate, cefuroxime or a third generation cephalosporin
An alternative is a respiratory fluoroquinolone which is equally effective given orally or intravenously
severe Community acquired pneumonia Rx
combo of amoxicillin-clavulanate, cefuroxime or a third generation cephalosporin plus a macrolide/azalide antibiotic
An alternative regimen- respiratory fluoroquinolone, combined with a betalactam
therapy should be initiated within 4–8 hours of hospital arrival
acute uncomplicated cystitis cause
Escherichia coli Klebsiella Proteus Enterobacter Staphylococcus sacrophyticus Pseudomonas
Lower urinary tract symptoms
Dysuria, Frequency of micturition, Urinary urgency
Haematuria (sometimes)
Suprapubic dyscomfort (less common
acute cystitis Rx
First-line- Nitrofurantoin 100mg BD x 5 days
Trimethoprim / sulfamethoxazole 960mg (DS) BD
Fosfomycin Tromeatamol
Second line- Fluoroquinolones
Beta-lactam antibiotics
Cystitis in pregnancy- Penicillins, cephalosporins
acute cystitis alternative Rx
Augmentin 500 mg/125 mg PO BID for 3-7d OR Augmentin 250 mg/125 mg PO TID for 3-7d
Second & third generation cephalosporins
Cefaclor 500 mg PO TID for 7d or
Cefpodoxime 100 mg PO BID for 7d or
Cefuroxime 250 mg PO BID for 7-10d
Pyelonephritis sx and causes
sx- fever, flank pain
causes- E coli, Klebsiella, Staph saprophyticus
Empiric Outpatient therapy of pyelonephritis
If local rates of E. coli fluoroquinolone resistance are low (< 10%):- Ciprofloxacin 500 mg PO twice daily x 7 d
Ciprofloxacin extended release 1000 mg PO x 7 d
Levofloxacin 750 mg orally x 5-7 d
Consider an initial dose of a parenteral agent, particularly if fluoroquinolone resistance is >10%.
Ceftriaxone 1 gm IM or IV x 1
Gentamicin 5 mg/kg IM or IV x 1
Ciprofloxacin 400 mg IV x 1
Empiric in-hospital therapy of pyelonephritis
If local fluoroquinolone resistance rates < 10% -Ciprofloxacin 400 mg IV q12h OR Levofloxacin 500 mg IV once daily
Ceftriaxone 1 g IV once daily (with or without an aminoglycoside, e.g., gentamicin 5 mg/kg IV daily)
Gentamicin/tobramycin 5 mg/kg IV once daily (with or without ampicillin 2 grams IV q4h)
Piperacillin/tazobactam 3.375 g IV q6h (with or without an aminoglycoside, e.g., gentamicin
Meropenem 2 grams IV q8h
Duration: typically 48h parenteral therapy or until afebrile, then switch to oral therapy based upon susceptibility data to complete 7d (fluoroquinolone) or 14d (TMP-SMX) course
Quinolones
Inhibits bacterial DNA gyrase
Bioavailability decreased by antacids
Large volume of distribution: including eye, lungs, prostatic fluid, CSF, bone and cartilage
Entero-hepatic cycle: AB in urine 5 days after stopping Rx
t½=4 hours
Less active in acidic urine
Quinolones side effects
GIT- nausea, dyspepsia, vomiting CNS- dizziness, insomnia and headache Hypersensitivity QT prolongation/ torsades de pointes Liver and renal damage
Sulfamethoxazole + Trimethoprim
Inhibits production of folic acid
Hypersensitivity reaction- Steven Johnson’s Syndrome
Aplastic/ hemolytic anaemia
CI: newborn, porphyria, G6PD deficiency
asthma
triad of wheeze, cough and breathlessness
symptoms are due to a combination of
constriction of bronchial smooth muscle
oedema of the mucosa lining the small bronchi
plugging of the bronchial lumen with viscous mucus and inflammatory cells
Inflammatory mediators implicated in asthma include
Histamine Several leukotrienes (LTC4/D4 and E4) 5-hydroxytryptamine (serotonin) Prostaglandin D2 Platelet-activating factor (PAF Neuropeptides Tachykinins
asthma vs COPD
Asthma- Young age onset < 20
Symptoms worse at night, during resp. infections, weather changes, when upset
Marked improvement with beta2 agonist
COPD- Older age onset > 40
Symptoms worsen over long period of time (not rather at night)
Little improvement with beta2 agonist (not fully reversible obstruction)
Asthma Classification (4 types)
Mild intermittent asthma- Patients have mild symptoms up to two days per week or two nights per month
Mild persistent asthma- Symptoms are still mild but occur more than twice per week
Moderate persistent asthma- Patients have symptoms at least once per day, also at least one night per week
Severe persistent asthma – Patients have symptoms most days and nights & sdesn’t respond well to medications even when taken regularly
High probability of asthma
1/+ of sx: wheeze, breathlessness, cough, chest tightness – Especially if symptoms are worse at night and early morning
Symptoms in response to exercise, allergen exposure, cold air
Symptoms after taking aspirin or beta-blockers
Low FEV1/PEF
Otherwise unexplained peripheral blood eosinophilia
Low probability of asthma
Dizziness, light-headed, peripheral tingling
Chronic productive cough, in absence of wheeze or breathlessness
Voice disturbance
Symptoms with cold only
Normal PEF or spirometry when symptomatic
Global initiative for Asthma goals (GINA)
Achieve and maintain control of symptoms
Maintain normal activity levels, including exercise
Maintain pulmonary function as close to normal as possible
Prevent asthma exacerbations
Avoid adverse effects from asthma medications
Prevent asthma mortality
drugs that aggravate asthma
beta-blockers (even eyedrops)
aspirin
NSAID”s
asthma Treatment classification
Preventers- Drugs with anti-inflammatory action to prevent asthma attacks eg Inhaled/ Oral corticosteroids
Controllers-sustained bronchodilator action but weak or unproven anti-inflammatory effect eg Long acting β2 agonists, Methylxanthines, Leukotriene receptor antagonists
Relievers- short acting β2 agonists, Anticholinergic agents, Short acting theophylline
Mast cell stabiliser: Sodium chromoglycate, Ketotifen
β2Agonists (Sympathomimetics)
used to treat the symptoms of bronchospasm in asthma and COPD
Drugs of choice in the management of acute bronchoconstriction
given via inhalation where possible
cAMP phosphorylates a cascade of enzymes which results
Relaxation of smooth muscle including bronchial, uterine and vascular
Inhibition of release of inflammatory mediators
Increased mucociliary clearance
Increase in heart rate, force of myocardial contraction
Vasodilatation in muscle
Short acting β2 agonists
Salbutamol, Fenoterol, Terbutaline
Work within 15-30 minutes Peak= 30 -60 minutes Relief for 4-6 hours Metered dose inhaler via spacer Dry powder/Nebulizer Symptomatic relief
Long acting β2 agonists
Salmeterol, Formoterol
Onset of action= 1-2 hours
Duration = 12 hours
Reduces need for additional bronchodilators
Improves lung functions
Reduces exacerbation rate
Combination with long acting anticholinergic agents very effective in COPD as well but very expensive
β2 agonists Drug interactions
D/I- Corticosteroids (increased risk of hypokalaemia and hyperglycaemia)
Digoxin and diuretics (increased risk of cardiac arrhythmias)
Side effects – Uncommon with inhalation preparations – Fine tremor, nervousness, headache, dizziness, cardiac stimulation (tachycardia and palpitations)
Anticholinergic agents
Ipratropium and Tiotropium
Are potent inhibitor of vagus-mediated bronchoconstriction and has significant bronchodilator activity
But do not have a significant inhibitory effect on mucociliary clearance
They are not the preferred relievers in asthma
They are more useful in COPD
They may be used in patients (especially the elderly) who cannot tolerate β2 agonist side-effects.
Anticholinergic agents
Clinical use and Indications
Equal (or better) than β2 agonists in COPD
Relief of bronchospasm in asthma – Less effective than β2 agonists in acute bronchoconstriction – Used as additional bronchodilator in asthmatic patients not controlled on a Long-Acting BetaAgonists (LABA)
Cystic fibrosis
Anticholinergic agents
Pharmacokinetics
Slow onset of action (>30min) and duration of action 4 hours. (Ipratropium)
Tiotropium – longer acting and only 1x dly inhalation
NOT for use in acute bronchospasm
Short acting anticholinergics
Ipratropium
Onset of action= 30-60 minutes
Duration= 3-6 hours thus take 3-4 times a day
Longer duration of action than β2 agonists
Metered dose
nebulizer
Long acting anticholinergics
Tiotropium
Onset of action= 30-60 minutes
Duration= 24-72 hours thus Once daily dosing
Elimination half life=5-6 days
anticholinergics side effects
Dry mouth and unpleasant bitter taste
Urinary retention in patients with prostate hypertrophy tachycardia
Inhaled ipratropium may precipitate glaucoma in elderly patients
Constipation possible but seldom occurs
Phosphodiesterase inhibitors
Methylxanthines: theophylline, aminophylline
Second line treatment for acute, severe and chronic persistent asthma
Advantages include: – Oral administration (theophylline), sustained bronchodilator action, mild antiinflammatory actions and a complementary mode of action to other bronchodilators
Once-a-day administration at lower doses
IV administration: aminophylline @ 1ml/min
Methylxanthines
Inhibit phosphodiesterase and thus ↑cAMP- relaxes smooth muscle and inhibit mediator release from mast cells
Antagonists of Adenosine at A2 receptors
Anti inflammatory activity on T-lymphocytes by ↓ release of PAF
Pharmacokinetics of Methylxanthines
Variable t½ (3-12hrs)
Good oral absorption
Metabolized by liver (Substrate for CYP1A2 and CYP3A4)
NB – Very narrow therapeutic index (10-20mcg/ml)
The enzyme inducing interaction achieved its maximal effect 6 days after starting
Methylxanthines Adverse effects
GIT- nausea, vomiting, anorexia
Cardiovascular: – dilatation of vascular smooth muscle – headache, flushing and hypotension; tachycardia and cardiac dysrhythmias (atrial and ventricular)
CNS insomnia, anxiety, agitation, hyperventilation, headache and fits
Glucocorticosteroids
Used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect
Most effective controller therapy available for asthma. Inhaled corticosteroids (ICS) - Beclometasone, Budesonide
Systemic preparations – Prednisone, Betamethasone, Dexamethasone
MOA- Induce the formation of lipocortin-1: inhibits phospholipase A2 – reduce free arachidonic acid and thus leukotriene synthesis
Corticosteroids
Decrease formation of cytokines (esp Th2), eosinophils, macrophages and T lymphocytes
Reversing mucosal oedema
Inhibit the generation of PGE2 and PGI2 by inhibiting induction of COX2
Decrease permeability of capillaries
Decrease release of leukotrienes and histamine which cause bronchoconstriction
Decrease hyperresponsiveness of airway smooth muscle to sensitive stimuli such as cold, irritants, allergens etc
Corticosteroids – Inhaled adverse effects
Oral Candidiasis
Irritation and hoarseness of voice
Dryness of mouth
headache, skin reactions skin bruises, psychiatric symptoms
paradoxical bronchoconstriction, hypersensitivity reactions
minimal systemic adverse effects if taken by inhalation, but higher doses can cause adrenal suppression
Corticosteroids – Systemic adverse effects
Suppression of Hypothalamic-pituitaryadrenal (HPA) axis depends on dose – Oral: prednisone >7.5-10 mg/day, after few months – Inhalational: beclomethasone >2000ug/day after few months
HT Increased appetite hirsutism glaucoms peptic ulcer hypookalaemia
what mediator antagonists can be used as adjunctive therapy
Antihistamines
Anti-leukotrienes
Mast cell stabilizers
Histamine acts on 4 types of receptors
H1 = anti-allergic and anti-emetic action H2 = inhibits acid secretion (GI) H3 = afferent pain and itch perception H4 = Inflammatory and immune suppression
1st Gen H1 antihistamine (Sedative)
Indications
Allergic conditions urticaria angioedema acute anaphylaxis motion sickness common cold and rhinorrhea
1st Gen H1 antihistamine (Sedative)
Adverse effect
Sedation
hallucinations
precipitation of seizures in epileptics
Anticholinergic effects (sinus tachycardia, dry skin, dry mucous membranes)
1st Gen antihistamine (Sedative) facts
t½ between 4-8 hours
Crosses BBB, good absorption, metabolized by liver
CNS depressants (effect potentiated) Anticholinergic agents, antidepressants (anticholinergic effect potentiated)
2nd Gen H1 antihistamine (NON sedative) facts
t½ 10h (thus daily dosing )
Minimal BBB penetration
Minimal metabolized – excreted by kidney unchanged
Drug interactions- CNS depressants
Drugs with arrhythmogenic potential (ketoconazole, erythromycin, protease inhibitors
2nd Gen H1 antihistamine (NON sedative)
Indications
Symptomatic treatment for allergic conditions (allergic rhinitis, atopic dermatitis, chronic urticaria)
Not very effective in common colds
2nd Gen H1 antihistamine (NON sedative)
Adverse effects
Sedation (uncommon
Headache, dizziness, GI disturbances, hypersensitivity reactions
Potential for cardiac arrhythmias (QT prolongation)
Leukotrienes facts
Leukotrienes are more powerful bronchoconstrictors and longer acting than histamine
Leukotrienes increase bronchial mucus secretion and vascular permeabilit
LTB4, C4 & D4 induce bronchoconstriction and increased bronchial reactivity.
Pathophysiology of cysteinyl leukotrienes in asthma
Constriction of bronchiolar smooth muscle Airway hyperresponsiveness Plasma exudation Eosinophilic inflammation Increased endothelial permeability Promotion of mucous secretion
Anti-Leukotrienes
Prophylaxis and prevention of asthma
Inhibits variety of bronchoconstriction causes: allergen induced, Exercise, cold air, aspirin
Reduction in amount of B2 and corticosteroids needed
Improved respiratory function in mild to moderate asthma
Increased compliance in children
No benefit in severe cases of asthma or COPD)
Anti-Leukotrienes Pharmacokinetics
Good oral absorption
90% plasma protein bound
Undergo biliary excretion
Pharmacological response within 24h
Anti-Leukotrienes Adverse effects
Abdominal pain, headache, rash, anaphylaxis Eosinophilia, vasculitis (Churg Strauss Syndrome) Liver dysfunction (very rare)
anti leukotrienes Drug interactions
Zafirlukast extensively metabolized by liver (inhibitor of CYP3A4 and CYP2C9)
Warfarin – anticoagulant effect enhanced
Erythromycin, Theophylline and terfenadine – zafirlukast levels are reduced
Mast cell stabilizers Ketotifen
MOA- Histamine antagonist, Functional leukotriene antagonist, Phosphodiesterase inhibitor
Indications- Useful adjunct to bronchodilator therapy in highly allergic children <3 years who have atopic eczema or hay-fever in addition to asthma
Mast cell stabilizers Adverse reactions
somnolence, xerostomia, mild dizziness, and fatigue (reversible with withdrawal)
Weigh gain, increased appetite
Hypersensitivity in immunocompromized patients
Mast cell stabilizers Drug interactions
oral antidiabetic preparations enhances the risk of reversible thrombocytopenia
potentiates the effect of sedatives, hypnotics, antihistamines and alcohol
Mast cell stabilizers: Chromones
Drugs – Cromolyn, Nedocromil
cromone molecules used to prevent or control allergic disorder
Have no effect if bronchoconstriction has already occurred
MOA- Block calcium channels essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators
Mast cell stabilizers
indications, kinetics and adverse effects
Indications- Effective prophylactic anti-inflammatory agents (Not for use in acute asthmatic attacks
Useful in allergic rhinitis (nasal sprays)
Allergic conjunctivitis (eye drops)
Kinetics- Efficacy only determined after 4-6 weeks
Short duration of action – TDS, QID dosing
Adverse effects- Minimal adverse effects
mainly transient irritant effects such as pharyngeal irritation, chest tightness, coughing and nasal congestion, mouth dryness
Immunomodulatory therapies in asthma
Immunosupressive therapy could be considered when ALL other treatments are unsuccessful- Methotrexate, Cyclosporine, IV immunoglobulins
Less effective and more side effects than oral corticosteroids therefor NOT recommended for routine therapy
Anti-IgE receptor therapy (Monoclonal antibodies) – Only omalizumab to be considered
Specific immunotherapy – May have anaphylactic and local reactions
Omalizumab
Leads to decreased binding of IgE to receptors on mast cells and basophils
Reduces the requirement for oral and inhaled corticosteroids and reduces asthma exacerbations
Not used in acute bronchoconstriction
Other Adrenergics acting on the respiratory system
Indirect Acting: Causes release of NE from storage vesicles- amphetamine, cocaine
Direct acting agonists on α1 receptors- Pseudoephedrine, Phenylephrine
Direct acting agonists
Indications- Systemic and topical nasal decongestants
Usually in combination with antihistamines
MOA- Constrict dilated arterioles in nasal mucosa and reduce airway resistance
Direct acting agonists C/I and precautions
Contraindications- Severe hypertension, Monoamine oxidase inhibitors (MAOI)
Precautions- Cardiovascular disease, hyperthyroidism, diabetes, prostatic hypertrophy, renal and hepatic impairment
Do not use longer than 7 days (rhinitis medicamentosa
Direct acting agonists Adverse effects
CNS stimulation, anxiety, restlessness, tremors, headache
Reduced appetite, nausea and vomiting
Hypertension, cerebral haemorrhage, pulmonary oedema
Antitussives Cough suppressants (Opium Alkaloids)
MOA- Suppress medullary cough centre in brain by acting on mu opioid receptors in lower doses needed for pain relief
Drug interactions- CNS depressants, Amiodarone, fluoxetine, MAOI (may be fatal)
Antitussives Cough suppressants (Opium Alkaloids) Side effects
Decreases bronchial secretions (thickens sputum) Inhibits ciliary activity Constipation, GI disturbances, dizziness Respiratory depression Confusion and sedation
Mucolytics
Acetylcysteine (ACC), Carbocisteine (Mucospect)
Agents used to reduce disulphide bonds in mucous plugs in order to decrease the viscosity and enhance the mucus expulsion by coughing
Side effects- GIT ulceration
Expectorants
Guaifenesin (Benylin) • Tinct Ipecacuanha
Agents used to increase the volume of mucus in order to decrease the viscosity and enhance the mucus expulsion by coughing
Enhances the ciliary movements in the respiratory tract
Side effects- Irritation of GI mucous membrane (Can be used as emetic)
Inhalants and antiseptics
Inhalations: Camphor, menthol, eucalyptus oil, benzoin Antiseptics and anaesthetics in gargles and lozenges and sprays
Allergic rhinitis
A symptomatic disorder of the nose, induced after allergen exposure, by IgE-mediated inflammation of the nasal mucous membranes
Symptoms – Nasal- sneezing, nasal obstruction/congestion, rhinorrhoea/post nasal drip and pruritis.
– Non-nasal- itchy palate or ears, conjunctivitis
Symptoms of Allergic rhinitis are severe when…
One or more of the following: abnormal sleep, ↓of daily activities such as sport, leisure problems caused at work or school, symptoms troublesome-patient seeks treatment
Allergic rhinitis sx
Rhinorrhea
Secretions ↑( mucous glands stimulated)
Vascular permeability increased – plasma exudate
Vasodilatation – congestion and pressure
Sensory nerves stimulated – sneezing and itching
Systemic effects – fatigue, sleepiness, malaise
physical s/s of Allergic rhinitis
Allergic shiners
allergic salute
Pale boggy blue gray mucosa of nasal turbinates
Dennie Morgan lines, swelling of palpebral conjunctivae
“Cobblestoning”: lymphoid tissue on posterior pharynx
Prophylactic treatment of Allergic rhinitis
Intranasal corticosteroids –first line treatment
Oral antihistamines (preferably second generation)
Decongestants oral and topical
Ocular antihistamines and cromolyns especially in seasonal allergic rhinitis
Leukotriene receptor antagonists
Pharmacological Rx of Allergic rhinitis
Intermittent symptoms- Oral antihistamine & Decongestants
Chronic symptoms- Intranasal steroid spray
Other- Ocular / Intranasal antihistamine
Intranasal cromolyn
Short course of oral steroids in severe, acute episode
Leukotriene receptor antagonists if both rhinitis and asthma
dont use 1st generation antihistamines
2nd generation antihistamines on Allergic rhinitis
Compete with histamine at H1 receptor in blood vessels, GI tract, respiratory tract
Improve rhinorrhea, sneezing, itching
No effect on nasal congestion
Use for seasonal/episodic rhinitis
Oral decongestants (pseudoephedrine)
α-adrenergic agonists that act by constricting blood vessels in the nasal mucosa
Pseudoephedrine produces weak bronchial relaxation, has no effect on asthma
It can also cause side effects such as tremor, insomnia and nervousness
They should be avoided in males with benign prostatic hyperplasia (BPH) as they can cause urinary retention
Are contraindicated in patients with hypertension and glaucoma
Topical decongestants: oxymetazoline and xylometazolin
These agents can be used for the symptomatic relief of nasal congestion
Their use should be limited to < 5 days as often secondary vasodilatation follows the initial vasoconstriction giving rise to rebound congestion “rhinitis medicamentosa”
Are long acting α-receptor stimulants which have a vasoconstrictor and decongestive effect on the nasal mucosa
Phenylephrine –has a shorter duration of action, with maximal effects lasting up to 4 hours
Side effects: transient burning or dryness of the mucosa may occur
Intranasal corticosteroids e.g. beclomethasone, budesonide, fluticasone, mometasone and triamcinolone
They are the most effective maintenance therapy for allergic rhinitis both intermittent and persistent
They are poorly absorbed from the nasal mucosa and have little systemic effect
Side effects: – Transient burning or stinging, headache
Dry nose, sneezing, nasal bleeding, stuffy nose, and Irritation of the throat
Excessive use may lead to adrenal suppression
Corticosteroids in allergic rhinitis
Relief of all symptoms
More effective than monotherapy with antihistamine/cromolyn
Greater benefit if combined with other agents
Does not Rx eye symptom
Intranasal antihistamines eg Azelastine, Levocabastine
Intermittent allergic rhinitis
Some effect on nasal congestion
Vasomotor rhinitis
11% of pt- systemic absorption - sedation
Immunotherapy allergic rhinitis
Success rate 80-90% for certain allergens esp pollen, dust mites, cat
Long term treatment: 3-5 years
Severe systemic allergy can occur
Indications: – Severe disease
– Poor response to treatment
– Presence of co-morbid conditions/Complications
