Pharmacology ๐ Flashcards
What are the goals of therapy of bronchial asthma?
- Drug therapy for long-term control of asthma is designed to reverse and prevent airway inflammation.
- The goals of asthma therapy are to decrease the intensity and frequency of asthma symptoms, prevent future exacerbations, and minimize limitations in activity related to asthma symptoms
What are the drugs used in treatment of bronchial asthma?
1- ฮฒ2-Adrenergic agonists
2- Corticosteroids
3- Alternative Drugs Used to Treat Asthma
-Leukotriene modifiers
-Cholinergic antagonists ((ipratropium/ tiotropium)
-Theophylline (bronchodilator/ anti-inflammatory)
-Ketotifen
-Monoclonal antibodies
What is the classification of beta 2 adrenergic agonist?
1) Short-acting ฮฒ2 agonists (SABAs): Salbutamol, terbutaline albuterol
2) long-acting ฮฒ2 agonists (LABAs): salmeterol, formaterol
What is the mechanism of action of beta 2 adrenergic agonists? โRelaxation of bronchial smooth musclesโ
1) ฮฒ2-Agonists stimulate ฮฒ2-receptors (Gs) stimulate adenyl cyclase and increase formation of cAMP in the airway tissues & relaxation of bronchial smooth muscles.
2) They inhibit release of inflammatory mediator or bronchoconstricting substances from mast cells.
3) Improve Ciliary Function
Compare between short acting and long-acting beta 2 adrenergic agonists Acc to:-
Duration of action
Designation
Indication
Duration of action: (4-6 h) - (โฅ 12 h)
Designation: Quick reliever drugs - Long-term Controller
Indication:
โ Monotherapy for mild, intermittent asthma and Exercise-induced bronchospasm.
โ Part of poly therapy for persistent asthma
โ used only in combination with an asthma controller medication
โ Some LABAs are available as a combination product with an ICS โfor increased complianceโ
What is the route of administration of beta 2 adrenergic agonist?
โข In general, ฮฒ-adrenoceptor agonists are best delivered by inhalation.
โข This results in the greatest local effect on airway smooth muscle with the least systemic
toxicity
What are the adverse effects of beta 2 adrenergic agonists?
โข Tachycardia โdue to lost selectivityโ
โข Tremors โB2 found on SK MSโ
โข Tolerance
โข Hypokalemia โinc K+ entryโ
โ3T + Hโ
What is the importance of corticosteroids?
Steroids are corner stone for treatment of BA
What is the classification of corticosteroids?
1) Systemic: hydrocortisone and prednisolone
2) Inhalation: beclomethasone, fluticasone, Ciclesonide,โฆโฆ. etc.
What is the mechanism of action of corticosteroids?
โCorticosteroids and beta two agonists act in a complementary way as corticosteroids have anti-inflammatory effect and up-regulate the B2 receptors (which was down-regulated by the B2 agonists) while beta two agonists have direct relaxation effect and a little anti-inflammatory effectโ
- Inhibition of PLA2 & the production of inflammatory mediators (PGs, LTs) โwhich are bronchoconstricting agentsโ
- decreasing the inflammatory cascade (eosinophils, macrophages, and T lymphocytes)
- reversing mucosal edema
- decreasing the permeability of capillaries
- They also up-regulate ฮฒ2- receptor โprevent toleranceโ
What is the route of administration of corticosteroids?
a) Inhalation
To be effective in controlling inflammation, they must be used regularly to decrease responsiveness of air way to triggers.
b) Oral/systemic
Patients with a severe exacerbation of asthma (status asthmaticus) may require intravenous or oral steroids to reduce airway inflammation.
What are the clinical uses of corticosteroids in bronchial asthma?
1) ICS is 1st choice in newly diagnosed BA
2) Urgent treatment of acute severe asthma not improved with BD (IV, inhalation).
3) Chronic asthma (aerosol, oral).
What are the adverse effects of corticosteroids in treatment of bronchial asthma?
Inhaled steroids
โข Oropharyngeal candidiasis
- Patients should be instructed to rinse the mouth in a โswish-and-spitโ method with water following use of the inhaler to decrease the chance of these adverse events.
- If Candida infection occurs, it must be treated by antifungal e.g, nystatin mouthwash.
โข Hoarseness of voice
What are in the alternative drugs used in treatment of asthma?
- Leukotriene modifiers
- Cholinergic antagonists ((ipratropium/ tiotropium)
- Theophylline
- Ketotifen
- Monoclonal antibodies
When are alternative drugs to treat asthma used?
- These drugs are useful for treatment of asthma in patients who are poorly controlled by conventional therapy or experience adverse effects secondary to corticosteroid treatment.
- These drugs should be used in conjunction with ICS therapy for most patients. โIn 1st caseโ
what is the metabolism cascade of arachidonic acid and what are the functions of the products?
- Leukotrienes (LT) B4 and the cysteinyl leukotrienes are products of the 5-lipoxygenase pathway of arachidonic acid metabolism and part of the inflammatory cascade.
- LTB4 is a potent chemoattractant for neutrophils and eosinophils
- whereas the cysteinyl leukotrienes constrict bronchiolar smooth muscle, increase endothelial permeability, and promote mucus secretion.
What are the types of leukotriene modifiers?
a) Zileuton โblock the cascade from the middle while corticosteroids block the cascade from the originโ โbut has side effectsโ
b) Zafirlukast and montelukast
What is the mechanism of action of the zileuton?
Selective inhibitor of 5-lipoxygenase enzyme; preventing the formation of LTB4 and the cysteinyl leukotrienes.
What is the mechanism of action of the zafirlukast and montelukast?
Selective antagonists of the cysteinyl leukotriene-1 receptor, and they block the effects of cysteinyl leukotrienes.
What are the uses of leukotriene modifiers?
1) Prevention of asthma symptoms.
2) Should not be used in acute BA
3) Leukotriene receptor antagonists used for prevention of aspirin & exercise-induced asthma.
What is the mechanism of action of cholinergic antagonists what are examples for cholinergic antagonists?
(ipratropium/ tiotropium) โThe first is short acting and the second is long-actingโ
Mechanism of action: block M3 R inhibit contraction of airway smooth muscle and mucus secretion
What are the uses of cholinergic antagonists in the treatment of bronchial asthma?
โข Patients who are unable to tolerate a SABA โWants to avoid Tremors for exampleโ
โข Bronchospasm precipitated by B antagonist
preparation of theophylline
aminophylline & theophylline
What is the mechanism of action of theophylline?
- Inhibit PDE3 increase in cAMP level โlike beta agonistsโ lead to
a. relaxation of airway muscles
b. inhibition of release of the bronchoconstrictor substances from the mast cells
c. reduction in the immune and inflammatory activity of specific cells.. - Block adenosine R (Adenosine causes contraction of airway smooth muscle, enhances histamine release from cells present in the lung). These effects are antagonized by thoephylline.
- Enhancement of histone deacetylation anti-inflammatory and immunomodulating effect
What is theophylline replaced by nowadays and why is it replaced by these drugs?
- beta agonists and corticosteroids due to its narrow therapeutic window, adverse effect profile, and potential for drug interactions.
- Overdose may cause seizures or potentially fatal arrhythmias.
What metabolizes theophylline and how should it be monitored if given chronically?
- Theophylline is metabolized in the liver and is a CYP1A2 and 3A4 substrate. It is subject to numerous drug interactions.
- Serum concentration monitoring should be performed when theophylline is used chronically.
What type of drug is ketotifen and what are its uses?
- It is a 2nd generation antihistamine and a mast cell stabilizer.
- Used orally as a prophylactic treatment in bronchial asthma and other seasonal allergies.
What are the monoclonal antibodies used in treating bronchial asthma?
โข Omalizumab is a monoclonal antibody that selectively binds to human immunoglobulin E(IgE).
โข Mepolizumab is interleukin-5 (IL-5) antagonists.
What are the uses of monoclonal antibodies in treatment of bronchial asthma?
1) Treatment of severe persistent asthma in patients who are poorly controlled with conventional therapy.
2) Their use is limited by the high cost, route of administration (SC) , and adverse effect profile
What are the guidelines followed in treatment of acute severe asthma?
โ O2 - SABA - Anticholenergic - SCS - Fluids - Magnesium sulfate and antibiotics in specific casesโ
1) Hospitalization, Administration of oxygen
2) Frequent or continuous administration of aerosolized SABA like salbutamol by nebulizer
3) Add ipratropium to the inhaler
4) Systemic corticosteroid like methyl-prednisolone or hydrocortisone IV
5) IV magnesium sulfate infusion in case of failure to inhaled bronchodilators
6) Iv fluid to avoid dehydration & correction of electrolyte disturbances
7) Antibiotics in the presence of infection
What are the drugs used in treatment of cough?
โ Antitussives: are used to stop dry cough.
โ Mucolytics and expectorants: are used in productive cough to liquefy bronchial secretions and facilitate their removal.
What are types of antitussives?
Peripheral & Central
What is the mechanism of action of peripheral antitussives?
- Decrease the input of stimuli from the cough receptor in the respiratory passages.
What are Examples of peripheral antitussives?
1) Steam inhalation with menthol or tincture benzoin
2) Benzonatate
3) Demulcents e.g. liquorices, lozenges, honey
What are examples of central antitussives?
1)Opioid non selective e.g. codeine, hydrocodeine, etc
2) Opioid selective antitussives e.g. dextromethorphan
What is the mechanism of action of central antitussives?
- Suppress the medullary cough center
What are the uses of antitusseves?
Uses: to relieve a nonproductive cough caused by
1) Pharyngitis
2) Viral infections
3) Allergy
4) Smoking
5) Acid reflux
6) Drugs: ACEI
What are mucolytics?
- they are agents that reduce viscosity of respiratory secretions without increasing their amount.
What are examples of mucolytics?
โ Bromhexine
โ Ambroxol
โ N-Acetylcysteine and carbocyseine
โ IODIDES [Sodium & Potassium Iodide]
What are expectorants?
- drugs that increase water content and amount of the respiratory secretions. This action facilitates the removal of respiratory secretions.
What is an example of expectorants?
Guaifenesin
What is a very important measure to encourage expectoration?
- Adequate hydration โwith expectorantsโ is the single most important measure to encourage expectoration. Using an expectorant in addition may produce the desired result.
What is the mechanism of action of expectorants?
- Stimulate the bronchial glands to secrete low-viscosity mucous
What are the therapeutic uses of mucolytics and expectorants?
โช Chronic respiratory diseases: chronic bronchitis, emphysema, bronchiectasis and cystic fibrosis.
โช Post-operative and post-traumatic pulmonary complications.
โช Chronic sinusitis and chronic otitis media.
โช Intravenous N-acetylcysteine is used as an antidote for acetaminophen (paracetamol) toxicity (quite apart from its mucolytic activity).
What is the difference between mucolytics and expectorants?
Expectorants increase airway water to help with mucus clearing. Mucoregulators increase the movement of mucus via cough.
What is the definition of antimicrobial drugs?
Antimicrobial drugs โ chemical substances (natural or synthetic) that suppress the growth of, or kill, microorganisms (bacteria, fungi, helminths, protozoa and viruses)
What are antimicrobial drugs classified according to?
- According to their chemical structure โinto familiesโ
- According to their mechanism of action โimpโ
- According to the effect done by their safe plasma concentration
- According to the spectrum of activity โthe most impโ
What are anti-microbial drugs classified into according to their mechanism of action?
- Inhibition of bacterial cell wall synthesis โ ฮฒ-lactams
- Increased permeability of the bacterial cell phospholipid membrane
- Impaired bacterial ribosome function โ reversible inhibition of protein synthesis โ macrolides
- Selective block of bacterial metabolic pathways
- Interference with bacterial DNA or RNA synthesis
โDrugs which attack structures that are found exclusively in the bacterial cell are the best due to their low side effectsโ
What are antimicrobial drugs classified into according to the effect done by their safe plasma concentration?
Bacteriostatic
Bactericidal
What are bacterostatic antibiotics?
Bacteriostatic antibiotics: remember of โMs. Coltโ
- Macrolides
- Sulfonamides
- Chloramphenicol
- oxazolidinones
- Lincosamides (clindamvcin)
- Tetracyclines
What are bactericidal antibiotics?
Bactericidal antibiotics: remember of โBANG Q R.I.P.โ
- Beta-lactams
- Aminoglicosides
- Nitroimidazoles (metronidazole)
- Glycopeptides (vancomycin)
- Quinolones
- Rifampicin
- Polymyxins (colistin)
What are bacteriostatic antibiotics?
- inhibit bacterial growth but do not kill the bacteria at plasma concentrations that are safe for humans โ natural immune mechanisms are required to eliminate the bacteria.
What are bacteriostatic drugs less affective against?
- less effective in immunocompromised individuals or when the bacteria are dormant and not dividing.
What are bactericidal antibiotics?
- kill bacteria at plasma concentrations safe for humans
โHowever, they are not better in immunocompetent individualsโ
What is the definition of antimicrobial resistance?
โHappens due to administration of incomplete courses and takes place mainly due to the plasmidโ
- the ability of bacteria to grow in the presence of a drug that would normally kill them or inhibit their growth.
What are the types of antimicrobial resistance?
โ Intrinsic (innate)
โ Acquired resistance โ due to modification of its genetic structure (acquired resistance).
What is the mechanisms of antimicrobial resistance?
โ Mask - Attack - Defend - Quit โฆ then Expellโ
- Structural change in the target molecule for the antibacterial drug
- Production of enzymes that inactivate the antibacterial drug โrareโ
- Decreased penetration of the antibacterial drug into the bacterial cell โBy changing the transporters that allow entryโ
- Acquisition of efflux pumps that remove the antibacterial drug from the bacterial cell
What are the antimicrobial drugs that affect the cell wall?
โ ฮฒ-Lactam Antibacterials
โ Vancomycin
What are the types of beta-lactam antibacterials?
โ Penicillins โgram +โ
โ Cephalosporins
โ Monobactams
โ Carbapenems โthe most resistant to beta lactamasesโ
What is a characteristic thing in the structure of beta lactam antibacterials?
- All drugs in this class โ have a ฮฒ-lactam ring โ must be intact for them to be active
- ฮฒ-Lactam โ susceptible to inactivation by bacterial ฮฒ-lactamases โ split the ฮฒ-lactam ring
What is the difference between Cephalosporins, Monobactams, Carbapenems and penicillins?
- They have structural modifications โ show some resistance to ฮฒ-lactamases.
What is the mechanism of action of beta-lactams?
- ฮฒ-lactam antibiotics โ bind to penicillin-binding proteins PBPs (transpeptidases) in bacteria, which is required for the last step of the bacterial cell wall synthesis (cross-linking of the peptidoglycan layer) โ inhibit transpeptidation reaction โ inhibits cell wall synthesis when bacterium divides โ exposure of the osmotically unstable cell membrane โ bacterial cell swelling, rupture and death of the bacterium.
- In Gram positive bacteria โ binding of ฮฒ-lactam antibiotics to other PBPs โ โ activity of autolytic enzymes โ promotes lysis of the bacterial cell wall.
what are the forms of bacterial resistance to beta-lactams?
- Production of ฮฒ-lactamases โ hydrolyse the ฮฒ-lactam ring โattackโ
- There are hundreds of ฮฒ-lactamases โ produced by various organisms
โ Methicillin โtype of penicillinโ sensitive Staph. aureus (MSSA) โ release extracellular ฮฒ-lactamases. โAffect some penecilinsโ
โ Gram-negative bacteria โ secrete ฮฒ-lactamases between the inner and outer cell membranes in the periplasmic space.
โ Enterobacteria โ release extended-spectrum ฮฒ- lactamases (ESBLs) โ hydrolyse 3rd-generation cephalosporins, monobactams & carbapenemase.
โVery strongโ
- Mutation in PBP โ PBP2A โ do not bind ฮฒ-lactam antibacterials โ gonococci and in meticillin-resistant S. aureus (MRSA). โmaskโ
What is the arrangement of penicillins according to the spectrum of activity?
Anti-staph penicillins (Narrow spectrum)
Natural penicillins (Intermediate spectrum)
Animo-penicillins (Broad spectrum)
Antipseudomonal penicillins (Extended spectrum)
What are examples of anti-Staph penicillins?
Dicloxacillin
Nafcillin
Flucloxacillin
Methicillin
What are examples of natural penicillins?
Penicillin G
Penicillin V
What are examples of aminopenicillins?
Amoxicillin +/- clavulanate โbeta - lactamase inhibitorsโ
โโุดุฑุงุจโ
Ampicillin +/- sulbactam
โโุญููโ
What are the examples of antipseudomonal penicillins?
Piperacillin + tazobactam
Ticarcillin + clavulanate
What are cephalosporins classified into?
Classified into 5 generations
โโ The fifth generation is very valuableโ
What is the effect of cephalosporins? โGram -โ
โ Successive generations โ have โ activity against Gram-negative bacilli.
โ Moving from the 1st to 3rd generations โ โ Gram-positive activity & moving from 3rd to 5th generations โ progressively โ Gram-positive activity again
What is the spectrum of activity of monobactams (aztreonam)? โSpecific especially for pseudomonasโ
- Spectrum of activity โ limited to Gram-negative bacteria, including Pseudomonas, Neisseria meningitidis , N. gonorrhoeae and H. influenzae.
What is the special thing about monobactams?
- No cross-allergenicity with the penicillins โ given to people with penicillin allergy
What are examples of carpapenems?
Ertapenem, imipenem, meropenem
What is the spectrum of activity of carpapenems? โValuable drugs and they are not oralโ
- Extremely broad spectrum of activity โ Gram-positive cocci + Gram-negative bacilli + P. aeruginosa + many anaerobic bacteria.
Mention a note about each of:-
Etrapenem
Imipenem
Meropenem
โ Only ertapenem is inactive against Pseudomonas.
โ Imipenem is rapidly hydrolysed by dehydropeptidase in the kidneys โ is always given in combination with the dihydropeptidase inhibitor cilastatin โ Imipenem-Cilastin.
โ Meropenem is available in combination with ฮฒ-lactamase inhibitor vaborbactam
โbeta-lactase inhibitorโ
What are the antimicrobial drugs that are eliminated by the biliary way?
Nafcillin
Ampicillin
Ampicillin
What are the side effects of penicillins? โPrescribed to pregnant womenโ
โ GIT
- Nausea, vomiting โ most common with oral preparations
- Diarrhoea (Clostridium difficile -related colitis) โHarmful bacteria normally killed by floraโ โ a result of disturbance of normal colonic flora โ especially with broad-spectrum penicillins.
โ Allergic reactions โ common (5% of exposed individuals). โAll types of hypersensitivity reactionsโ
โโุดุฎุต ููุน ุจุนุฏ ุญูู ู
ุถุงุฏ ุญูููโ
Manifestations:-
- Urticaria, wheeze and anaphylaxis (IgE-mediated reactions);
- Vasculitis and serum sickness (immune complex-mediated reactions).
- Nonspecific maculopapular rash, and the rare serious Stevensโ Johnson syndrome โPeeling of skinโ(T-cell-mediated allergy)
- Cross-allergenicity โ with cephalosporins is < 2%;
with carbapenems is < 1%, no cross-allergenicity with monobactams.
โ Aminopenicillins โ frequently produce a nonallergic maculopapular rash in people with glandular fever (infectious mononucleosis with Epstein-Barr virus) โindicates false treatmentโ
- Not associated with other types of penicillin..
โ Encephalopathy โrareโโ excessively high concentrations in the CSF โ occurs in severe renal failure or after mistaken intrathecal injection
โ Cholestatic jaundice โ flucloxacillin โanti-staphโor clavulanic acid
What are the side effects of cephalosporins?
- GIT โ same as penicillins โ more common with cephalosporins โmore broad spectrumโ
- Allergic reactions โ A history of IgE-mediated reaction to penicillin (e.g. anaphylaxis, wheeze, urticaria) โ contraindicates use of cephalosporins.
โUsed in patients with penicillin Hypersensitivity but with cautionโ
What are the side effects of carpapenems?
โ Allergic reactions
โ Neurotoxicity with seizures โโุชุดูุฌุงุชโ โ more common with imipenem
What is the mechanism of action of vancomycin?
โStrong acid, low pKa, bad oral Absorbtionโ
- it binds to the terminal D-Ala-D-Ala portion of pentapeptide side chain โ block transpeptidation and inhibit cross-linking of peptidoglycan โ interfere with cell wall synthesis
What is the spectrum of action of vancomycin?
โSpecific for serious gram-positive infectionsโ
- narrow spectrum โ only against Gram-positive bacteria, particularly MRSA. โLike penicillinsโ
What are the uses of vancomycin?
usually reserved for
โ Ttt of serious Gram-positive bacterial infection
โ Ttt of bacterial endocarditis not responding to other treatments. โNot commonโ
โ Ttt of C. difficile colitis โ given orally โacts locallyโ
What are the side effects of vancomycin? โFaulty infusion and toxicityโ
โLike aminoglycosidesโ
โNot absorbed orally โ given by i.v infusionโ
โ Nephrotoxicity โ โ if used in combination with other nephrotoxic drugs (aminoglycosides).
โ Ototoxicity โ uncommon โ usually starts with tinnitus. โSound of buzzingโ
โ Thrombophlebitis at the site of i.v infusion. โNeeds good techniqueโ
โ Rapid i.v injection or infusion of vancomycin โ histamine release โ โ BP, wheezing, urticaria, upper body flushing โ the โred manโ syndrome.
โHowever, is this drug is used due to increasing infections with MRSAโ
Therapeutic monitoring of the trough plasma concentrations of vancomycin and dose adjustment โ โ risk of toxic effects.
What are the drugs that affect bacterial protein synthesis?
โ Macrolides
โ Tetracyclines
โ Aminoglycosides
What is the mechanism of action of Macrolides?
- bind reversibly to the 50S subunit of the bacterial ribosome โ inhibit peptidyl transferase & block translocation of the aminoacyl-tRNA from the A site to the P site โ preventing elongation of the polypeptide chain โ interfere with bacterial protein synthesis
What is the spectrum of activity of macrolides?
โKinda Like aminopenicillinsโ
โ Erythromycin โ has a similar spectrum of activity to amoxicillin + Legionella + atypicals โunlike penicillinsโ. (Mycoplasma, Chlamydia, Campylobacter and Bordetella pertussis).
Used to treat infections in people who are allergic to ฮฒ-lactams.
โ Clarithromycin & Azithromycin โmost commonly usedโ > erythromycin โ โ activity against H. influenzae & mycobacterium avium
โ Clarithromycin โ part of the multidrug treatment of H. pylori โwhich causes peptic ulcerโ
What are the side effects of macrolides?
โNear to penicillins since they have the same spectrum of activityโ
โLess allergy but more bad effectsโ
โ GIT โ common โ Epigastric discomfort, nausea, vomiting and diarrhoea โ erythromycin.
โ Rashes.
โ Cholestatic jaundice โ with erythromycin estolate โ if treatment is continued > 2 week.
โ Prolongation of the Q โT interval โ predispose to ventricular arrhythmias.
โ Drug interactions โ erythromycin and clarithromycin inhibit P450 drug- metabolising enzymes (CYP3A4, CYP2D6) โ โ plasma concentration of other drugs metabolised by these enzymes, including carbamazepine, cyclosporine and simvastatin.
What are the contraindications of macrolides?
a. Patients with hepatic dysfunction โ these drugs accumulate in the liver livery esp. Erythromycin & azithromycin
b. Patients with proarrhythmic conditions or concomitant use of proarrhythmic agents.
What is the selection of a suitable antibiotic based on?
Host factors
Drug factors
What are the host factors that affect antibiotic selection?
- pregnancy, drug allergies, age and immune status, and the presence of renal impairment, hepatic insufficiency, abscesses, or indwelling catheters and similar devices.
What are the drug factors that affect antibiotic selection?
โ Antimicrobial spectrum of activity โ
โ Based on laboratory tests (microbial culture and sensitivity)
โ Based on knowledge of the most common organisms causing various types of infections and the preferred drugs for these organisms (empiric selection) โ may be used to treat serious infections until lab test results are available or to treat minor upper respiratory and urinary tract infections
โ Pharmacokinetic Properties โ oral bioavailability, peak serum concentration, distribution to particular sites of infection, routes of elimination, and t1/2.
โ Adverse Effect Profile
What is PCT responsible for?
Reabsorption of:
- 60-70% of the filtered Na
- > 90% of HCO3
What is key for NaHCO3 reabsorption and distal tubular urine acidification?
Carbonic anhydrase
What is the loop of henle responsible for?
20โ30% of the filter the NaCl is actively reabsorbed in the thick ascending limb of henleโs loop by Na/K/2CL co transporter
What is DCT responsible for?
5-10% of filtered Na is reabsorbed in the early portion of DCT by Na/CL co-transporter
What is CD responsible for?
- 1-2% of Na is reabsorbed in Distal portion of DCT, CT, and CD
- K and H are secreted in exchange with Na (Under the effect of aldosterone)
What are the diuretics classified according to?
- Efficacy
- Potassium level
- Site of action
What are diuretics classified into according to efficacy?
High: Loop diuretics
Moderate : Thiazides
Low : CAEIs, K Sparring
What are diuretics classified into according to their effect on potassium level in blood?
โข K_ losing: Loop - Thiazides - CAEI
โข K _ sparring: spironolactone- Amiloride -Triameterine
What are examples of loop diuretics?
- sulphonamides derivatives: Furosemide, bumetanide โbetter bioavailabilityโ (the most potent) and torsemide. (Cross allergy)
โThatโs why they cause allergyโ - Non-sulphonamides derivatives: Ethacrynic acid
(No allergy)
What are the kinetics of loop diuretics?
โRapid onsetโ
โ Can be taken orally 30-60 min (for chronic use) or I.V 5min (for emergency use)
โ Rapid onset and short duration (2h I.V) & (6-8 orally) ,so can be used in emergencies
โ Secreted by organic acid secretory system (acidic carrier) of Kidney (competition with uric acid)
What is the MOA of loop diuretics?
โผ Loop diuretics inhibit Na+ /K+ /2CI- co-transporter in thick ascending limb of loop of Henle , so increase Na+/H2O excretion .. 25%
โผ Increase PGE2 and PGI2 causing VD of all blood vessels โlow BPโ
โผ Also:
โ inhibition Ca2+ and Mg2+ transport โ> Ca and Mg excretion โhelps in treatment of hypercalcemiaโ
What are the uses of loop diuretics?
- Acute Pulmonary Edema
- Acute Renal Failure
- Hypertensive encephalopathy (Crisis ) โemergencyโ
- Refractory edoema (not respond to less powerful diuretic) in liver Cirrhosis, severe HF, severe RF .
- Metabolic ( Non diuretic uses )
How do Diuretics treat pulmonary edema?
- Because it increase PG and cause VD even before diuresis occur .
How do diuretics treat renal failure?
- As they maintain GFR
- Even Only 20% residual nephrons can respond normally to the loop diuretic .
- Blocking Na . K . 2Cl pump
Are loop diuretics used in localized edema or generalized edema?
- Loop diuretics are not used in localized edema as edema due to lymphatic obstruction or inflammation.
What are the metabolic uses of loop diuretics?
A. Treatment of hypercalcemia : decrease Ca reabsorbtion from ascending limb ( IV saline can be used . if not add Loop )
B. Treatment of hyperkalemia :
C. Treatment Of dilutional hyponatremia :- Because Loop diuretics Loss of H2o»_space; Na in urine โโ blood level of Na+ in Dilutional hyponatiemia .
D. Treatment of acidosis :
Because they โ Na exchange with H+ in DCT
โLike compensatory mechanismโ
What are the side effects of loop diuretics?
- Hypovolemia (Powerful)
- Metabolic adverse effects
- Organ adverse effects โinterfere with antibioticsโ
- Refractoriness
what is the order of administration of diuretics?
- Resistance to loop diuretics can be reversed by addition of thiazides and resistance to latter can be decreased by adding potassium sparing diuretics
What are the results of hypovolemia caused by loop diuretics?
Hypotensionโ->Collapse
Hameoconcentrationโ>Thrombosis
What are the metabolic adverse effects caused by loop diuretics?
- Hypokalemia (Hypomagnesmia and alkalosis)
- Hypocalcemia
- Hyperglycemia (hypokalemia โ โinsulin release) so CI in DM .
- Hyperuricemia (Loop diuretics interfere with uric acid secretion by acidic Carrier ) CI in Gout.
What are the organ adverse effects caused by loop diuretics?
- Ototoxicity with ethacrynic acid (aminoglycosides )
- Interstitial nephritis ( with Cephalosporins )
- Hypersenstivity ( Related to sulfa )
- Gastric upset ( with ethacrynic acid )
- Blood dyscariasis
- Myalgia ( Bumetanide )
What are examples of thiazide diuretics?
Chlorothiazide โข : the prototype (rarely used now)
Hydrochlorothiazide โข is now used more commonly , it is more potent than chlorothiazide & inhibits carbonic anhydrase enzyme (CAE).
What are the kinetics of thiazide diuretics?
โ Effective orally (used for chronic cases only), onset 1-2h.
โ Secreted by organic acid secretory system (acidic carrier) of Kidney (competition with uric acid)
What is the mechanism of action of thiazide diuretics?
โผ they inhibit Na+ /Cl co-transporter (symporter) in early portion of distal tubule โโ Na/H2O excretion โฆ 5-10% (moderate, Low ceiling)
โผIncrease PGE2 and PGI2 causing VD of all blood vessels (but Less than loop diuretics)
โThe difference from diureticsโ
โผ Also:
โ cause Ca reabsorption โtreat hypercalcuriaโ
- Inhibit Carbonic anhydrase enzyme ( in supra-pharmacological dose).
What are the uses of thiazide diuretics?
โHeart - vessels - kidney - edema - metabolicโ
- Congestive heart failure and other cause of mild edema (Not effective in edema of renal failure: because it do not act if GFR < 20 ml/min) and it has low ceiling effect (10% loss of Na).
- Hypertension ( with other drugs )
- Nephrogenic diabetes Insipidus (paradoxical effect).
- Treatment of idiopathic hypercalcuria and prevention of Ca stones (Nephrolithiasis)
How do thiazide diuretics treat hypertension?
โInitial then persistentโ
- Initial hypotensive: decrease blood volume due to diuretic effect
- Persistant hypotensive effect Due to opining of K channel of BV โ out flux โ membrane hyperpolarizationโโ BP.
How do thiazide diuretics treat nephrogenic diabetes insipidus?
โD.I โ-> Increase in the amount of urineโ
โข Chronic use of thiazide โ โblood volume โ โGFR โ โreabsorption from PCT โ โurine volume
โข Increase sensitivity of receptor to ADH
How do thiazide diuretics treat idiopathic hypercalciuria and prevent calcium stones?
โCa is reabsorbedโ
- chronic use of thiazide โ GFR โโ Ca reabsorption from PCT โโ Ca in urine โโ Ca oxalate stones.
What are the side effects of thiazide diuretics?
โMAINLY METABOLICโ
- Hyperglycemia (hypokalemia โกopen Kchannels in B.cells DM โกโฌk outflux โกmemb hyperp โกโฌ insulin R)
- Hypercalcemia (โฌblood volume โกโฌ GFR โก increase Ca reab from Pct)
- Hyperuricemia (compete with uric acid on itโs Carrier) CI in Gout
- Hyperlipidemia (increase LDL, decrease HDL ) โก May cause a throsclerosis
- Hypokalemia
- Natremia
- Hepatic encephalopathy
- Sensitivity reactions ( related to sulfa)
- High lithium level (Lithium reabsorption with Na+ from PCT in reaponse To low GFR)
- Pancreatitis
- Impotence
โ Loop diuretics โโ> ototoxicity while Thiazides โโโ> lithium toxicityโ
How does hepatic encephalopathy occur as with use of thiazide diuretics?
it cause metabolic alkalosis which increase lipid soluble NH3 which affect brain.
What is the most commonly used diuretic in essential hypertension?
Thiazide
When is thiazide contraindicated and why?
โข Lithium toxicity can occur if used with thiazides (due to increased absorption of lithium in the PT) .. not used in lithium nephrogenic diabetes insipidus
What is the definition of K retaining diuretics?
Weak diuretic excrete 5 % of Na filterate
What are the types of K retaining diuretics?
- Aldosterone receptor antagonists ( Spironolactone and Eplerenone ) โintracellularโ
โข Synthetic steroid - Non-Aldosterone antagonists (Amiloride and triamterene )
โข Synthetic non steroid
โข Amiloride is more potent and longer acting than triamterene.
What is the mechanism of action of K retaining diuretics?
Aldosterone receptor antagonists: antagonize aldosterone on its receptor โ โ formation of mediator protein โ โ opening of Na Channel โ Loss of 5% of Na . (Delayed onset of action)
Non-Aldosterone antagonists: Block Na channels directly (Aldosterone independent ). (Rapid onset)
โข Inhibit Na+/K+/H+ pump in late part of distal tubules, collecting tubules and collecting duct.
What are the general uses of k retaining diuretics?
- Used in combination with thiazide or loop diuretics to correct Hypokalemia and hypomagnesemia
What are the uses of spirolactone?
โEdema due to aldosterone & CHFโ
1- Edema of hyper-aldosteronism:
primary Connโs syndrome or secondary
2- in CHF:
spironolactone decreases mortality in patients with CHF by preventing cardiac remodeling, Spironolactone is safer in liver Cirrhosis than other diuretics
What are the uses of amiloride?
- in lithium nephrogenic diabetes insipidus
(Lithium is absorbed through epithelial Na channels in the CD cells and at toxic doses can cause diabetes insipidus. Amiloride acts by blocking the entry of lithium through these channels.)
What are the general side effects of K retaining diuretics?
- Hyperkalemia and metabolic acidosis: especially in DM or renal dysfunction.
What are the side effects of spironolactone?
โCompetes with aldosteroneโ
- Gynecomastia and impotence:- due to anti androgenic effect. ( Eplerenone has no antiandrogenic effect)
- So, play a role in ttt of hirsutism, androgenic alopecia in female
What are the side effects of trimatrene?
โCompetes with folic acidโ
- megaloblastic anemia especially in cirrhotic person
( Triamterene is a weak folic acid antagonist) - Have no endocrinal side effects .
What is used to treat diabetic insipidus?
โข DOC for central DI- ( ADH (Desmopressin) )
โข DOC for nephrogenic DI- (Thiazides)
โข DOC for Li+ induced DI- (Amiloride)
What are examples of osmotic diuretics?
Mannitol (I.V), urea (I.V), glucose (I.V), Isosorbitol (orally), Glycerol(orally)
What is the mechanism of action of osmotic diuretics?
โโูุจุณุญุจ ุงูู ูุงู ูู ุทุฑููุฉ ููุฎุฑุฌูุง ุจุฑุง ุงูุฌุณู โ
- They increase osmotic pressure in blood vessel leading to drawing of water from interstial space to blood .Then they are filtered in nephron to increase osmotic pressure inside nephron leading to prevention of water reabsorption.
Where do osmotic diuretics act?
- Act on sites that freely permeable to water, PCT, thin descending limb of loop of Henle
What are the uses of osmotic diuretics?
โข Raised intracranial pressure (cerebral edema).
โข Raised intraocular pressure (glaucoma).
โข prophylactic against Acute renal failure (stimulate urination to prevent anuria) prevent kidney shutdown
What are the side effects of osmotic diuretics?
โข if used in acute renal failure :
canโt reach nephron, so remain in blood leading to increased volume of blood , heart failure. And dilutional hyponatremia.
When are osmotic diuretics contraindicated?
1-Acute Renal Failure
2- Congestive Heart Failure. โ> โopposite to loop and k sparring diureticsโ
Give an example for carbonic anhydrase inhibitor
- (Acetazolamide 250 mg oral)
- methazolamide
What is the mechanism of action of carbonic anhydrase inhibitors?
- They are sulfonamide derivative that inhibit carbonic anhydrase in PCT reabsorption of Na+ and HC03- and also inhibit Na+/H+ exchange pump in proximal tubule , so inhibit H+ secretion in urine causing metabolic acidosis in blood and alkalininzation of urine
- Metabolic acidosis due to โ Na Hco3 reabsorption
What are the uses of carbonic anhydrase inhibitors?
1- Used with loop diuretic treat refractory edema .
2- Used to treat Glaucoma because it decrease aquous
humor formation. (methazolamide is prefered because it has less renal and systemic effect). โAway from its diuretic effectโ
3- Treatment of urate stones and toxicity of acidic drugs by Urinary alkalinization
4- Treatment of alkalosis in emphysema and high altitude sickness
5- Treatment of petit mal epilepsy(suppress irritable focus directly and induce acidosis)
What are the side effects of carbonic anhydrase inhibitors?
- Drowsines and confusion : due to metabale acidosis .
- Ca and Po4 stones formation due to alkaline urine .
- Hypersensitivity โ reaches : due to similarity to sufonamides .
- Refractorniess to its diuretic effect due to absorption of Na lost by the drug in more distal parts of nephrons .
5.Hypokalemia (k /Na exchange increases to compensate decreased H/Na exchange)
Why are carbonic anhydrase inhibitors contraindicated with hepatic encephalopathy with liver impairment?
- As a cause hypokalemia and patients with liver encephalopathy are already hypokalemic
What are the advantages of diuretics in CHF?
- Correction of fluid retention. โThe mainโ
- โโโ of blood pressure. โโโ lung congestion
- โโโ preload (venodilatation and โโโ venous return) and
- โโโ afterload (due to arterial VD) leads to improvement of cardiac contraction.
- Spironolactone โโโ morbidity and mortality rates in patients with advanced heart failure.
What are the disadvantages of diuretics in CHF?
- Excessive hypovolemia โโ โโ COP.
โโูู ุฒูุฏุช ุงูุฌุฑุนุฉ ุงูู ู ู ูู ุชุนู ู ุงูุนูุณโ - Diuretic-induced acid-base and electrolyte imbalance โ impair cardiac function.
- Diuretic-induced hypokalemia; can predispose to digitalis toxicity and cardiac arrhythmia.
What are the advantages of diuretics in CKD?
- Correction of fluid retention.
- Reduction of hyperkalemia.
- Reduction of hypertension.
What are the disadvantages of diuretics in CKD?
- Thiazides are ineffective when GFR is <30 ml/min,
- K+ sparing diuretics can exacerbate hyperkalemia and acidosis.
- Carbonic anhydrase inhibitors (acetazolamide) can exacerbate acidosis.
What are the advantages of diuretics in liver cirrhosis?
- Correction of fluid retention.
- Spironolactone antagonizes aldosterone.
What are the disadvantages of diuretics in liver cirrhosis?
Aggressive use of diuretics can precipitate:
- Hepato-renal syndrome,
- Hyper-ammonemia and
- Hepatic encephalopathy
How do diuretics cause hepatic encephalopathy?
- Diuretics cause hypokalemia and metabolic alkalosis which increases the entry of NH3 to the brain
How is ammonia trapped?
- Normally, the urine pH is acidic (5.6). In acidic urine, most of the absorbable ammonia (NH3) is converted into the non-absorbable ammonium ions (NH4+) and so it is removed out by the kidney (this is known ammonia trapping).
What causes lower limb edema during late pregnancy?
โโุญุงุฌุฉ ุทุจูุนูุฉโ
hormonal imbalance, and compression of pelvic veins by the enlarged uterus.
How can lower limb edema during pregnancy be reduced?
Melevating the lower extremities and Wear elastic stockings.
Why should diuretics be avoided during pregnancy?
โNo diuretics During Pregnancyโ
- because they effectively reduce maternal plasma volume and consequently may reduce amniotic fluid and/or placental blood flow.
What are the symptoms of pathologic edema?
deep venous thrombosis (DVT).
๏ต Unilateral leg edema, redness,
๏ต warmth, and tenderness
๏ต Require evaluation for deep venous thrombosis (DVT).
What is the drug of use in each case of the following?
Edema
- Due to CHF
- Due to renal disease or nephrotic syndrome
- Pulmonary edema
- Cerebral edema
- Edema due to cirrhosis
Furosemide
Furosemide
Furosemide
Mannitol
Spirolactone
What is the drug of use in each of the following cases?
Diabetes insipidus
- Central
- Nephrogenic
- Lithium-induced
desmopressin
Thiazides
Amiloride
What is a drug of use in recurrent calcium stones in kidney due to hypercalciuria?
Thiazides
What is the drug of use in acute congestive gluccoma?
Acetazolamaide
What is the drug of use in acute mountain sickness?
Acetazolamide
What is the drug of use in nocturnal enuresis?
Desmopressin
What is the drug of use in SIADH?
Fluid restriction + hypertonic saline + furosemide
What should happen for diuretics to act?
- Reach their sites
โโุฃุญูุงูุง ุจููู ูู ู ุดุงูู ูู ุงูููู ุชุชุณุจุจ ูู ุนุฏู ุงููุตููโ - Sufficient Na reaches the site of action
How do each of these drugs reach its site of action?
Osmotic diuretics
Loop and thiazides
Spirolactone
- With GF
- Through acidic carrier into the lumen
- Through peritubular circulation into the cells
What causes decrease in reaching each of the following drugs to its site?
Osmotic diuretics
Loop and thiazides
- Acute renal failure โโู ุด ูุชูุตู ุฃุตูุงโ
- Renal dysfunction
What happens in edematous states concerning NA concentration at the site of action of the diuretics?
- In edematous state ( HF) R.hypoperfusion โ โ GFR โโ Na reabsorption from PCT โ โ Na at the rest of nephrone โ โ effect of more distally acting diuretic e.g thiazide more than loop diuretic .
What should be avoided during the complete NA restriction in diet?
Diuretics
โโูู ุง ุชููู ู ููู ุงูู ูุญ ุจูุงุด ุชุฃุฎุฐ ู ุฏุฑ ููุจูู ูุงู ูููููู ุงูุชุฑโ
How do diuretics cause hypokalemia and alkalosis?
- Diureticsโ Na reabsorption โโ Na exchange with K or H at DCTโ โIn DCT as compensatory mechanismโ alkalosis .
How do diuretics interfere with the absorption of electrolytes related to sodium?
- Loop diuretics โ โ Ca reabsorption from Loop of henle
- K-sparing โ โ excretion of Mg+
When are diuretics more effective?
- They are more effective in Cases of โ intra vascular volume e.g CHF than in cases of โ intra vascular volume e.g Liver Cirrhosis or nephrotic Syndrome (โ plasma protein โ โ osmolarity of blood ) .
What happens if diuretics acting at different sites are introduced?
- They have synergistic effect
Why is thiazide given with loop diuretics?
- Add thiazide in case of hyperplasia in the cells of DCT due to chronic use of loop diuretics.
When are carbonic anhydrase inhibitors given with loop diuretics?
- Add CAEIs acting at PcT to โ Na delivery to Loop of henle in case of severe HF to improve the effect of Loop diuretic .
What do thiazides and loop diuretics enhance?
- digitalis toxicity by causing hypokalemia and hypomagnesemia.
When is thiazide contraindicated?
- In renal impairment
When are thiazides and loop diuretics used concerning renal failure?
โข Thiazides : use till stage 3 renal failure
โข Loop : preferred in sever caseโโ GFR
โข Mannitol : is vey dangerous in acute RF
What are proteins synthesis inhibitors?
โข Macrolides
โข Clindamycin
โข Linezolid
โข Aminoglycosides
โข Tetracycline
What is the mechanism of action of clindamycin and what is its the spectrum of activity?
- Clindamycin is similar, in the mechanism and kinetics, to erythromycin but has activity against anaerobic bacteria.
What are the side effects of clindamycin?
- It is associated with high incidence of diarrhea and pseudomembranous colitis as side effect due to superinfection.
โAs it is kinda broad-spectrumโ
What is the mechanism of action of linezolid and what is its spectrum of action?
- Linezolid is similar, in the mechanism and kinetics, to erythromycin but has activity against anaerobic bacteria.
What are the side effects of Linezolid?
โข Gastrointestinal disturbance
โข Thrombocytopenia
What are examples of aminoglycosides?
- Streptomycin (prototype), Gentamicin, Neomycin, Amikacin, Tobramycin
What is the pharmacokinetics of aminoglycosides?
โข All aminoglycosides are not absorbed orally (must be given parentally) and cannot penetrate to CSF because they are highly polar compounds.
โข They can cross the placental barrier and may cause congenital deafness.
โข They are excreted unchanged in urine by glomerular filtration (dose adjustment is
necessary in renal dysfunction).
What are the pharmacodynamics of aminoglycosides?
โข Bind to 30S ribosomal subunit and inhibit bacterial protein synthesis
โข Synergistic with penicillin. Because penicillin inhibits cell wall synthesis and facilitate the entry of aminoglycosides to inside the bacterial cell.
โข Spectrum: Gram-negative bacilli and Mycobacteria TB.
What are the therapeutic uses of aminoglycosides?
โ2S & 2 Tโ
โข They are used in gram-negative septicemia, usually combined with penicillin. โCritical caseโ
โข Used orally for sterilization of intestine before surgery.
โAs they arenโt absorbedโ
โข Used topically for skin and eye infections.
โข Treatment of tuberculosis (never alone) streptomycin
What are the side effects of aminoglycosides?
โข Neurotoxicity
โข Allergic reactions
โข Nephrotoxicity. โExcreted unchangedโ
โข Ototoxicity
What is the spectrum of activity of tetracycline?
Chlamydia infections
What is the mechanism of action of tetracycline?
- Bind to 30S ribosomal subunit and inhibit bacterial protein synthesis
What are the adverse effects of tetracycline?
โข Decrease mineralization of bone and teeth (chelation of Ca) โinterfere with the Absorbtionโ
โข Contraindicated with pregnancy & lactation & children
What are inhibitors of nucleic acid synthesis?
Quinolones
What are examples of quinolones?
โข First generation: Nalidixic acid.
โข Second generation: Pipemidic acid
โข Third generation: Most are fluorinated. They include ciprofloxacin, ofloxacin, levofloxacin etcโฆ
โข Fourth generation: e.g. moxifloxacin
What is the pharmacokinetics of quinolones?
โข The absorption of fluoroquinolones is โ by stomach contents e.g. milk, iron and antacids. โNeed acidityโ
โข Newer fluoroquinolones (e.g. levofloxacin and moxifloxacin) have long t1/2 (given once daily).
โข They are excreted primarily unchanged in urine, so they are useful in UTIs.
What is the pharmacodynamics of quinolones?
โข They inhibit type II DNA topoisomerase (DNA gyrase) that is necessary for bacterial replication.
โข Quinolones are bactericidal. โKills DNA, The most important partโ
โข 3rd generation e.g. have greater activity against gram-negative bacteria and moderate activity against gram-positive organisms and anaerobes. Newer compounds (moxifloxacin) have activities against all.
โNewer are killersโ
What are the therapeutic uses of quinolones?
โข Fluoroquinolones are especially indicated in resistant infections.
โข Empiric use of these agents in minor infections should be discouraged.
What are the adverse effects of quinolones?
โAffects CTโ
โข GIT: nausea, vomiting (the most common).
โข Arthropathy (in experimental animals): not recommended in children <18 years.
โข Tendinitis and tendon rupture
โข CNS: cautiously in patients with epilepsy.
What is the first line therapy of tuberculosis?
Essential: โlong durationโ
- Isoniazid
- Rifampicin
- Ethambutol
- Pyrazinamide
Supplementary :
- Rifabutin/ Rifapentine
What is the second line therapy for tuberculosis and what are their characters?
- Less effective, More toxic
โSAAM FECCโ
- Streptomycin
- Amakicin
- Aminosalicylic acid
- Capreomycin
- Cycloserine
- Ethionamide
- Fluoroquinolones
- Macrolids
Why are standard antibacterial agents not as effective as specific anti tuberculous drugs?
a) Mycolic acid-rich cell wall.
b) Efflux pumps in the cell membrane.
c) Some of the bacilli are hiding inside the patientโs cells
What is the antibacterial activity of isoniazid?
- Bactericidal to actively dividing and non-dividing intracellular and extracellular organisms.๏ฟผ
What is the mechanism of action of isoniazid?
- Inhibits mycolic acid synthesis (essential component of cell wall).
what is the pharmacokinetics of isoniazid?
โข Prodrug โactivated by TB, Mutation of TB may cause resistanceโ
โข Absorbed orally
โข Widely distributed (intracellular, CSF, Necrotic material).
โข Metabolism: mainly acetylation in liver by N-acetyl transferase enzyme. (Fast and slow acetylators)
โข Excreted by kidney (dose adjustment in RF)
What are the adverse effects of isoniazid?
- Hepatotoxicity: This risk increases with age, presence of liver disease, alcoholism, pregnancy. โLAAPโ
- Neurotoxicity:
โข Increase risk with alcoholism, DM, uremia, malnutrition & slow acetylators โADUMSโ
โข peripheral neuropathy (numbness, tingling of lower limbs)
โข It can be prevented and treated by administration of pyridoxine (vit B6) - Hypersensitivity reactions: Skin rashes, fever and arthralgia.
- GIT upset. โOrallyโ
- Haemolytic anaemia โBreakdown of RBCsโ
- Drug interactions: inhibits metabolism of phenytoin.
โAnti-convulsantโ
What is the antibacterial activity of rifampicin?
โข bactericidal against dividing & non dividing mycobacteria (intra & extracellular) and H.influenza caused meningitis
โข can kill organisms that are poorly accessible to many other drugs
What is the mechanism of action of rifampicin?
- Inhibits DNA dependent RNA polymerase leads to inhibition of RNA synthesis.
What are the adverse effects of rifampicin?
- Drug interaction:
โข Hepatic microsomal induction, Shortens half-life of many drugs (warfarin, oral contraceptive pills).
โข Major problem with RMP is drug interactions๏ฟผ - Hepatotoxicity (avoided in old age and chronic liver ds)
- Hypersensitivity reaction
- GIT upset
- Red urine & tears
โNo neurotoxicityโ
When is rifabutin used?
โข Preferred for TB patients coinfected with the human immunodeficiency virus (HIV) who are receiving protease inhibitors or several of the nonnucleoside reverse transcriptase inhibitors.
What characterizes rifabutin?
Less drug interactions.
What is the antibacterial activity of Ethambutol?
Bacteriostatic
What is the pharmacokinetics of Ethambutol?
โข Absorbed orally/ wide distributed
โข Excreted mainly by kidney (dose adjustment in RF)
What is the mechanism of action of ethambutol?
โข Inhibits synthesis of arabinogalactan (component of cell wall)
โข Increase penetration of other drugs into the organisms. Cannot be used alone/ Used in combination of INH of rifampin to prevent resistance.
โIt only perforates cell wallโ
What are the adverse effects of ethambutol?
โEthambutol โ-> eye affection
- Visual disturbance due to optic neuritis.
โข Increase with higher doses & renal disease
โข Decrease visual acuity and red/ green blindness
โข Visual acuity and color discrimination have to tested prior to its administration
โข Contraindicates in children โas testing is hardโ - Hyperuracemia โCI in goutโ
- Mild GIT upset, malaise fever, rash, headache and peripheral neuritis.
What is the antibacterial activity of pyrazinamide?
โข Bactericidal more against slow dividing organisms
โข Effective only against intracellular organism (acidic pH)
What is the pharmacokinetics of pyrazinamide?
โข Activated by mycobacterium โprodrugโ
โข Well absorbed orally and wide distribution
โข Excreted mainly by kidney (dose adjustment)
What is the mechanism of action of pyrazinamide?
- disrupt cell membrane โnot cell wallโ metabolism and transport function.
What are the adverse effects of pyrazinamide?
- Hepatotoxicity (liver function assessed before ttt)
- Hyperuricemia
- GIT upset.
What is the anti-bacterial activity of streptomycin?
โข It is bactericidal for extracellular bacilli but it is ineffective against intracellular bacilli.
What are the therapeutic uses of streptomycin in treatment of tuberculosis?
Therapeutic uses: in combination with INH & rifampin โlike ethambutolโ to treat extensive pulmonary TB and renal TB
What is the method of administration of streptomycin?
I.M injection
What is the standard regimen for treatment of tuberculosis?
- Use drug combinations to enhance efficacy and to delay the emergence of resistance (MDR, XDR).
โข ALWAYS USE AT LEAST 2 DRUGS:
โข Begin with 4 drugs
โข If bacilli resistant to 1, will be killed by others
โข Prolonged Length to therapy: 6-9 months DEPENDING UPON the condition
โข Directly Observed Therapy (DOT)
Why is the standard regimen for treatment of tuberculosis followed?
a) To avoid the development of acquired resistance
b) To reach the intracellular location of mycobacteria
c) To cure latent or dominant disease.
How long does the initial phase for treatment of tuberculosis last and what are the drugs administrated in this phase?
- Normally two months
- HRZ +/- E
- Daily and observed
How long does the continuation phase for treatment of tuberculosis last and what are the drugs administrated in this phase?
- Normally 4 months
- HR
- Daily and observed
What are anti-TB drugs administrated in cases of pregnancy?
- HREZ can be used during pregnancy.
- Streptomycin is not given as it can cause ototoxicity to the fetus.
What are the precautions that must be taken in case of treatment of tuberculosis in case of liver disease?
- Frequent monitoring of liver function tests is required. Only use 2drugs (HR) or one of them but avoid them in very advanced disease
What are the precautions that must be taken in case of treatment of tuberculosis in case of renal failure?
- Dosages may have to be adjusted according to the creatinine clearance especially for streptomycin, ethambutol and isoniazid
