Advanced Clinical Pharmacology

For Nursing MSc. Students

Drugs that affect the respiratory system
• Pneumonia: Lower respiratory disease
• Signs and symptoms: cough, dyspnea, or
sputum production, fever or abnormal breath
sounds
• Causes: Bacteria are common causes; viruses,
fungi, rickettsiae, inhalation of toxic
substances may be involved
 contd
• Bacterial pneumonia is caused most commonly by
gram positive streptococci and staphylococci and
by gram negative organisms that normally reside
the GI tract
• Strep. pneumoniae is the most common in
community-acquired pneumonia(pneumonia in
previously healthy people)
• Staph. aureus and enteric gram negative bacilli are
most common in hospital acquired
pneumonia(after at least 2 days in hospital)
 contd
• Goal of treatment: resumption of respiratory
status to the state before the illness
• Benzylpenicillin i.v. or amoxacillin p.o. are the
treatment of choice for community acquired
pneumonia ,;if Streptococcus pneumoniae
(pneumococcus) is very likely
• Erythromycin/clarithromycin used in penicillin-
allergic patients
• Seriously ill patients should receive
 contd
benzylpenicillin(to cover pneumococcus) plus
ciprofloxacillin to cover Haemophillus influenzae and
atypical pathogens (e.g.Mycoplasma pneumonia)
• Cefotaxime i.v. is a reasonable choice where
penicillin-resistant pneumococci are prevalent
• Amoxicillin dose: 875 mg q12h or 500 mg q8h for
7-14 days
• Erythromycin estolate: 250-500 mg q6h for 7-14
days
 contd
• Hospital-acquired pneumonia: common
pathogens are Staphylococcus aureus,
Enterobacteriaceae, S. pneumoniae, P. aeruginosa
and H. influenzae
• It is reasonable to initiate therapy with
ciprofloxacin, meropenem, ceftriaxone or
ceftazidime(plus vancomycin if the local
prevalence of MRSA is high) pending the results of
sputum culture and antimicrobial susceptibility
tests
 contd
• Benzylpenicillin(Penicillin G), amoxicillin are
penicillins(beta lactam antibiotics)
• Penicillins are bactericidal drugs
• Inhibit cell wall synthesis by preventing the
formation of peptidoglycan cross-bridges in
actively multiplying bacteria
• Benzylpenicillin(penicillinG) is gastric acid
labile and has narrow spectrum of activity
 contd
• Amoxicillin is gastric acid stable and has broad
spectrum of activity
• Both penicillins can be destroyed by beta
lactamase enzyme(some bacteria produce it)
• Combination of beta lactamase inhibitors such
as clavulanic acid, sulbactam increases the
spectrum of activity of beta lactamase labile
penicillins(amoxicillin plus clavulanic acid)
 contd
• Penicillins are eliminated via active secretion
in the renal tubules
• Dose modification is necessary in severe renal
failure to avoid drug accumulation and toxicity
• Immediate hypersensitivity reaction
(anaphylaxis) is a rare but life-threatening
adverse effect
• Adrenaline i.v is drug of choice for treatment
 contd
• Cephalosporins e.g. ceftazidime, ceftriaxone,
cefotaxime are bactericidal and have similar
mechanism of action as penicillins
• Are bactericidal drugs more resistant to
enzymatic degradation than penicillins
• Distributed widely, and eliminated renally
• Hypersensitivity is the main adverse effect with
10% cross reactivity with penicillin-sensitive
patients; more expensive
 contd
• Pneumonia in immunocompromised patients:
Common bacteria such as S. aureus and
S.pneumoniae as well as viruses, fungi and
Enterobacteriaceae can be causal
• Aminoglycosides(e.g. gentamicin) plus
ceftazidime started until the pathogen is
known
• Pnemocystis carinii(fungus) is an important
pathogen in patients with deficient
 contd
cell-mediated immunity.
• Co-trimoxazole 120 mg/kg daily by mouth or i.v in
two to four divided doses for 14 days is effective
• Co-trimoxazole is a fixed-dose combination of
trimethoprim plus sulfamethoxazole
• Pneumonia due to anaerobic microorganisms that
accompany other pathogens can be treated by
adding metronidazole to the antimicrobial
regimen
 contd
• Ciprofloxacin, gatifloxacin, etc. are quinolones
• Bactericidal in action, broad-spectrum activity
• Inhibit DNA gyrase activity by binding to
chromosomal DNA strands
• This interferes with DNA replication and
prevents supercoiling within the chromosome
• Well absorbed and widely distributed
. Well tolerated drugs with mild GI and CNS effects
 contd
• Co-administration of aluminum and
magnesium antacids reduces their absorption
• Have broad spectrum of activity
• Adult dose of ciprofloxacin: 500 mg q12 h
• Usually well tolerated; may cause cartilage
damage in growing children if used routinely
• Contraindicated during pregnancy
 contd
• Atypical pneumonia caused by Legionella
pneumophilia and Mycoplasma pneumonia
can be treated with fluoroquinolones /
doxycycline or azithromycin
• Atypical pneumonia due to Avian influenza
can be treated with oseltamivir
 Anti-tubercular(TB) drugs
• TB is an infectious disease caused by M.
tuberculosis
• The organism is inhaled into the aveolus
where it is ingested by the pulmonary
macrophages
• The bacilli multiply and spread to local
pulmonary area and to extra-thoracic organs
• M. tuberculosis grows quite slowly
 contd
• This makes laboratory culture investigation,
drug susceptibility tests and skin test reactivity
to be delayed
• Prolonged treatment duration is also the
consequence of slow growth
• Pulmonary TB symptoms: cough with
productive, purulent secretions, often with
blood streaks; wide temperature variations,
 contd
malaise, fatigue, wasting, chest pain, dyspnea,
night sweating
• Anti-TB drugs are administered in combination
in order to slow the emergence of resistance
• Shortest duration of therapy is six months
• First-line anti-TB drugs: isoniazid, rifampin,
pyrazinamide, ethambutol
• Second-line drugs: streptomycin,
capreomycin,cycloserine, ethiomamide,
 contd
para-aminosalycylic acid, quinolones, linezolid
• Isoniazid and rifampin are the two most active
drugs
• Isoniazid(isonicotinic acid hydrazide, INH)
prevents the synthesis of mycolic acids which
is an essential component of mycobacterial
cell wall
• It is bactericidal(intracellular and extracellular)
 contd
• INH is well absorbed from alimentary tract and
widely distributed including CSF
• Standard oral dose: 300 mg /day
• Although generally well tolerated, It may
cause INH-induced hepatitis, peripheral
neuropathy, especially in slow acetylators,
malnourished, elderly, alcoholics, liver disease
• Pyridoxine(10 mg/d) can prevent neuropathy
 contd
• Other adverse effects include mental
disturbances, incoordination, optic neuritis
and convulsions
• Isoniazid inhibits the metabolism of
phenytoin, carbamazepine and ethosuximide,
increasing their effect
 contd
• Rifampicin: has bactericidal activity against
tubercule bacillus, comparable to that of INH
• It inhibits the DNA dependent RNA
polymerase of Mycobacterium species
• Thus inhibits RNA synthesis in sensitive
bacteria at much lower concentration than
mammalian cells
• It is particularly effective against mycobacteria
 contd
that lie semi-dormant with-in cells
• Rifampicin has a wide range of antimicrobial
activity
• Other uses include leprosy, chemoprophylaxis
of meningococcal meningitis, severe
legionaire’s disease(with erythromycin or
ciprofloxacin), severe Staphylocccal infection
(with flucloxacillin and vancomycin)
 contd
• Rifampicin is well absorbed from the GIT
• It penetrates most tissues including CSF
especially when meninges are inflamed
• Enterohepatic recycling takes place and
eventually 60% of a single dose is excreted in
faeces; deacetylated in the liver
• Urinary excretion of unchanged drug also
occurs( orange-red discoloration of urine); a
clue for patient compliance
 contd
• Rifampicin is hepatic enzyme inducer and
increases its own metabolism and the
metabolism of other co-administered drugs
(e.g oral contraceptives, warfarin,
sulfonylureas, barbiturates)
• Decreases the efficacy of others and its own
• Adverse effects include flushing, itching,
thrombocytopenia, fatal hepatitis(but rare),
influenza-like syndrome , acute renal failure
 contd
• Rifampicin is given at a dose of 10 mg/kg daily
before breakfast
• Rifabutin is a congener of rifampicin that can
also be used for treatment of TB
• It has similar activity and adverse reactions
• It is also used for non-tuberculous
mycobacterial infection in combination with
other drugs
 contd
• Pyrazinamide: is a derivative of nicotinamide
• Included in first-choice combination regimen b/c of
its particular ability to kill intracellular persisters,
i.e. mycobacteria that are dividing or semi-
dormant, often within cells
• It is converted into its active form ,(pyrazinoic acid)
by intrabacterial pyrazinamidase(most effective in
acidic environment)
• It is well absorbed from the GIT, widely distributed
and metabolized in the liver and
 contd
renal excretion eliminate the drug from body
• Its has bactericidal action
• Its exact mechanism of action unknown
• Adding pyrazinamide to the first two months
of treatment with INH and rifampicin shortens
the duration of therapy to 6 months for most
patients
• INH and rifampicin should be given for at least
 contd
9 months(without pyrazinamide)
• Adverse effects include hyperuricemia and
arthralgia at therapeutic doses and
hepatotoxicity(high dose)
• Affects both large and small joints
• Usual adult dose: 1500 mg/day(20-30 mg/kg)
• It can be given up to a maximum of 3 g
 contd
• Ethambutol: Is bacteriostatic drug
• Mechanism not fully understood, but it is found
to inhibit synthesis of arabinoglycan essential
for mycobacterial cell wall synthesis
• It is well absorbed from the GIT
• Used as a fourth drug for TB while awaiting
susceptibility data.
• If the organism is susceptible to INH, RIF and
PYR, it can be stopped
 contd
• It causes optic neuritis with loss of visual
acuity and red-green color discrimination
problem(dose and duration dependent
toxicity)
• Because young children may be unable to
report early visual impairment, should not be
used below 6 yeas of age
• Usual adult dose: 1600 mg/daily
 contd
• The standard TB treatment regimen is INH,
rifampicin, pyrazinamide, and ethambutol for
two months, followed by INH and rifampicin
for 4 months, a total of 6 months of treatment
• Ethambutol can be stopped at any time if
susceptibility to the other three is shown
• When intermittent therapy is used directly
observed therapy(DOT is essential)
 contd
• Isoniazid is the preferred drug for treatment of
latent TB infection
• It is given for 9 months
• It reduces a person’s lifetime risk of active TB
from 10% to 1%, which in turn decreases the
wave of transmission
• When intermittent dosing is used, DOT is
essential; rifampicin can be considered if
organism is resistant to INH
 contd
• Initial resistance occurs in some patients
• Patients with multiply drug-resistant
tuberculosis(MDR-TB),i.e. resistant to rifampicin
and isoniazid at least should be treated with
three or four to which organisms are sensitive
• Second-line drugs can be considered also
• Treatment should extend for 12-24 months
• Expert management is required to monitor
toxicities
 contd
• Meningeal tuberculosis: An effective regimen is
isoniazid, rifamipicn, pyrazinamide and
streptomycin
• Treatment need to continue for longer period
than modern short-course chemotherapy
• Tuberculosis in immuno-compromised patients
may involve large numbers of tubercule bacilli
• Usually at least four drugs are started for
conventional 6 months duration
 contd
• TB treatment during pregnancy should not be
interrupted
• At least three drugs(INH, RIF, PYR or ETH) can
be used for at least 6 months
• Aminoglycosides should be contraindicated b/c
of danger of fetal eighth cranial nerve damage
• Breast feeding is not contraindicated during
treatment
 contd
• Drugs with early bactericidal action rapidly
reduce bacillary load in the patient
• Achieve quick sputum negativity so that the
patient is non-contagious to the community
• This also affords quick symptom relief
• To effect cure and prevent relapse killing
persisting bacilli is essential(sterilizing effect of
pyrazinamide)
 contd
• INH and rifampicin are the most potent drugs
• Use of a single drug results in emergence of
resistance and relapse of the disease
• Drug combinations prevents the emergence of
resistance and synergizes effect
• Symptomatic relief can be achieved within 2-4
weeks
• Slow multiplying organisms respond gradually
and bacteriological cure may take longer
 Drugs used for Asthma
• Asthma is chronic inflammatory disorder of
the airways
• Inflammation causes an associated increase in
existing bronchial hyper-responsiveness to a
variety of stimuli(specific and nonspecific)
• Airway hyper-responsiveness is the hallmark
of asthma leading to clinical symptoms of
wheezing, chest tightness, dyspnea, cough
 contd
after exposure to allergens, environmental
irritants, viral infections, exercise and cold air
• Airflow obstruction is caused by acute
bronchoconstriction, mucosal edema, and
mucus plug formation
• Bronchoconstriction is easily reversible as
compared to the other pathologic features
 contd
Approaches to treatment:
• Prevention of exposure to allergens(applicable
for extrinsic asthma but not for intrinsic);
identification of an allergen is not easy
• Reduction of bronchial inflammation and
hyperreactivity
• Dilatation of narrowed bronchi
• Asthma severity determines treatment choice
 contd
Mild intermittent asthma: Treatment consists of
short-acting inhaled beta2 agonists
• Inhaled beta2 agonists(albuterol, terbutaline)
are used on as needed basis
• Produce effects within minutes and duration
of action is 4-6 hours
• Cause relaxation of bronchial smooth muscle
by increasing intracellular cyclic AMP
 contd
• Typical recommended dosage of
albuterol(salbutamol) by aerosol inhalation:
0.1-0.2 mg
• Terbutaline: 0.25- 0.5 mg
• They should not be taken on regular basis
• Administration by inhalation minimizes their
systemic adverse effects
 contd
• Mild persistent asthma: Preferred treatment is
low-dose inhaled corticosteroids
• Inhaled corticosteroids include
beclomethasone, budesonide, fluticasone,
triamcinolone, flunisolide
• Beginning dose of beclomethasone: 200-500
microgram/day
• Fluticasone: 100-300 mg/day
 contd
• As persistent inflammation is central to
bronchial hyperreactivity, use of
antiinflammatory drugs is logical
• Corticosteroids/glucocorticoids have
antiinflammatory effect, probably by
decreasing the production of proinflammatory
cytokines
• Most of the effects of corticosteroids are due
 contd
to an intracellular effect that involves
transcription of messenger RNA which is one
reason for their slow onset of action
• They do not cause bronchodilatation, but
reduce mucosal edema
• Do not act acutely
• Adverse effects of inhaled steroids can be
divided into local and systemic effects
 contd
• Local effects include candidiasis of the
pharynx and larynx
• Systemic effects(at high doses) include adrenal
suppression, bone disorder, increased risk of
infection, hypertension, ulcer, delayed wound
healing, worsening glaucoma
• Alternative treatments include
cromolyn,nedocromil, leukotriene modifiers
 contd
• Inhaled short-acting beta2 agonists are used to
relieve symptoms
• If symptoms persist , inhaled corticosteroids
should be increased to 750 to 800
microgram/day for beclomethasone
• Similar measures with other corticosteroids
• Cromolyn and nedocromil are mast cell
stablisers
 contd
• Act by inhibiting the release of mediators from
mast cells
• Reduce bronchial inflammation and
hyperreactivity
• Do not reverse bronchospasm and not
effective in terminating an existing attack
• Prevent bronchoconstriction than inducing
bronchodilation
 contd
• Leukotriene receptor antagonists,e.g.
montelukast and zafirlukast competitively
prevent the bronchoconstrictor effects
cysteinyl-leukotrienes(C4 , D4 ) by blocking
cysLT1 receptors
• Have similar efficacy to low-dose
corticosteroids
• Theophylline, a methylxanthine, relaxes
bronchial smooth muscle
 contd
• Acts by inhibiting phosphodiesterase(type-4
isoform) ,thereby inhibits inactivation of
intracellular cyclic AMP
• Results in bronchodilation
• It also exhibits modest antiinflammatory effect
• Aminophylline, the soluble form of
theophylline permits i.v use in acute severe
asthma(status asthmaticus)
 contd
• Theophylline has narrow margin of safety
• Adverse effects include tachycardia,
palpitations, nausea, vomiting, arrhythmia,
and convulsions
• It is advisable to monitor serum theophylline
concentration to minimize the risk of
dangerous toxic effects
 contd
• Moderate persistent asthma: preferred treatment low
to medium dose inhaled corticosteroids and long-acting
beta2 agonists such as salmeterol and formoterol
• Patients need to have a short-acting bronchodilator for
short-term relief
• Salmeterol and formoterol are given on regular basis,
twice daily
• Salmeterol: 2 puffs bid(25 microgram/puff)
• Not to be used for short-term relief
 contd
• Severe persistent asthma: preferred treatment
is daily high dose inhaled corticosteroids and
long-acting2 –agonists
• Inhaled beclomethasone dose: 800-
2000micrograms
• Short-acting inhaled beta2 –agonists may be
required as a rescue treatment at times of
exacerbations
 contd
• Additional treatment with one or more of the
following may be considered to improve
response:
- Leukotriene antagonist/ theophylline po /
inhaled ipratropium bromide
• In patients not adequately controlled, institute
oral corticosteroid attempting withdrawing
oral steroid periodically
 contd

• Maximum dose of inhaled corticosteroids

should be tried before adding oral ones
• Severe persistent asthma associated with
allergies may benefit from omalizumab
• Omalizumab is humanized monoclonal
antibody against IgE
• It neutralizes free IgE in the circulation
 contd
• On antigen challenge, little IgE is available
bound to the mast cell surface receptors to
trigger mediator release
• Used to reduce exacerbations in severe
extrinsic asthma and it also reduces steroid
requirement
• It is very expensive reserved for resistant
extrinsic asthma
 contd
• Status asthmaticus/Refractory asthma: any
patient of asthma has the potential to develop
acute severe asthma which may be life-
threatening
• Upper respiratory infection is the most
common precipitant
• Management approaches include:
a) Hydrocortisone i.v stat, takes 6 hours to act
and shift to oral therapy
 contd
b) Nebulized salbutamol plus ipratropium
bromide
c) High flow humidified oxygen
d) Salbutamol/terbutaline im, or sc
e) Intubation and mechanical ventilation
f) Treat chest infection, if any
g) Correct dehydration and acidosis with saline+
sodium bicarbonate/lactate infusion
 Chronic obstructive pulmonary
disease(COPD)
• COPD is characterized by incompletely reversible
airways obstruction
• It is predominantly a disease of smaller airways;
cigarette smoking is the primary risk factor(85%)
• Distinguishing COPD and asthma can be difficult in
some patients/ both may be present
• It is important to maximize the reversible
component
 contd
• COPD is a heterogeneous disorder that
includes primarily chronic bronchitis and
emphysema
• Pathology is characterized by both acute and
chronic inflammation
• Symptoms: cough(B), dyspnea(E), increased
sputum usually purulent in bronchitis, noisy
chest(B)
 contd
• Goal of therapy is to slow disease process and
maintain quality of life
• Drugs used to treat COPD are exactly the same
as for asthma
• However, antimuscarinics such as ipratropium
or longer-acting tiotropium are often more
effective bronchodilators than beta2 agonists
• Antimuscarinics reduce the volume of sputum
in addition to their bronchodilator effects
 contd
• Theophylline is also effective but less safer
than other bronchodilators
• For immediate relief, combination of albuterol
and ipratropium is recommended
• Corticosteroids are useful in the short-term
treatment of acute COPD exacerbation b/c of
their anti-inflammatory effects
• Benefit of prolonged inhaled corticosteroids
 contd
for COPD is not clearly established
• Infection is considered present when the
patient is producing a purulent sputum
• Antibiotics should be prescribed based on the
involved pathogen and its susceptibility
characteristics
• Most common organism is S. pneumoniae
• Until sensitivity data are available, start
 contd
therapy with amoxicilln/clavulanic acid or
erythromycin or co-trimoxaxole
• Continue treatment for 7 to 14 days with the
chosen antibiotic
• Smoking cessation is essential to halt disease
progression in COPD
• Nicotine replacement therapy in different
forms(gum, transdermal patch, nasal spray),
 contd
and antidepressants such as bupropion are used
for smoking cessation
 Drugs that affect the renal system
• Diuretic drugs: substances that increase urine
and solute excretion
• To be therapeutically useful, a diuretic should
increase the output of sodium as well as of
water
• Each day the body produces 180 L of
glomerular filtrate, modified in its passage
down the renal tubule forming 1.5 L urine
 contd
• Normal sodium reabsorption from tubular
sites:
- Proximal convoluted tubule: 65%
- Loop of Henle: 25%
- Distal convoluted tubule: 5-10 %
- Collecting duct: 2-3%
• Various transporters are involved on different
sites
 contd
• Diuretic drugs increase sodium excretion by
inhibiting these transporters
• Maximum efficacy in removing salt and water
depends on its site of action
• According to natriuretic capacity, diuretics
categorized into:
- High efficacy
- Moderate efficacy, and low efficacy diuretics
 contd
• High efficacy diuretics are loop diuretics
• Furosemide, bumetanide, piretanide and
ethacrynic acid belong to this group
• Cause up to 25% of filtered sodium to be
excreted
• Site of action is on thick ascending limb of
loop of Henle
• Act by inhibiting Na+, K+, 2Cl- co-transporter
 contd
• Moderate-efficacy diuretics: are thiazides and
related drugs
• Thiazides include hydrochlorothiazide,
chlorothiazide
• Related drugs include metolazone,
chlorthalidone, indapamide
• All inhibit salt reabsorption in the distal
convoluted tubule
 contd
• Low-efficacy diuretics: include spironolactone,
epleronone, amiloride, triamterene
• Spironolactone is structurally similar to
aldosterone and competitively inhibits its
action in the late distal tubule and early
collecting duct
• Exchange of potassium for sodium inhibited
• Excessive secretion of aldosterone contributes
 contd
to fluid overload in hepatic cirrhosis, nephrotic
syndrome, congestive heart failure
• Estrogenic effects(e.g.gynecomastia) are the
major limitations to its long-term use
• Epleronone is spironolactone analogue which
is free of the estrogenic effects
Amiloride and triamterene block the sodium
channels in the distal tubule and collecting duct
 contd
Indications for diuretics:
1) Edema states associated with sodium
overload, e.g. cardiac, renal, hepatic disease,
and also without sodium overload, e.g. acute
pulmonary edema following MI
2) Hypertension, by reducing intravascular
volume and probably by other mechanisms, e.g.
reduction of sensitivity to noradrenergic
vasoconstriction
 contd
• Thiazides and related drugs are commonly
used but during normal renal function
• Loop diuretics are effective at a GFR below 10
mL./min
3) Hypercalcemia, furosemide reduces calcium
reabsorption at AscLH and reduces raised
plasma calcium combined with saline
 contd
4) Idiopathic hypercalcuria, a common cause of
renal stone, may be reduced by thiazides
5) The syndrome of inappropriate secretion of
antidiuretic hormone may be treated with
furosemide if there is a dangerous degree of
volume overload
6) Nephrogenic diabetes insipidus, paradoxically
may respond to diuretics which, by contracting
 contd
Plasma volume, increase salt and water
reabsorption in the proximal tubule, and thus
reduce urine volume
• Adverse effects of diuretics:
a) Potassium depletion- diuretics that act at PCT,
LH, and DCT cause more sodium to reach the
sodium-potassium exchange site
• Hypokalemia may cause cardiac arrhythmia in
patients at risk(e.g. receiving digoxin)
 contd
b) Hyperkalemia- may occur if potassium-
sparing diuretic is given for patient with
impaired renal function
• ACE inhibitors, ARBs and potassium
supplementation may also increase plasma
potassium levels, and thus combination cause
dangerous hyperkalemia
• With suitable monitoring combination can be
used
 contd
C) Hypovolemia can result from overtreatment
• Acute loss of excessive fluid leads to postural
hypotension and dizziness
d) Hyponatremia especially in patients ingesting
large amount of water while taking diuretics
e) Urate retention(hyperuricemia) especially
thiazides and loop diuretics
f) Magnesium deficiency
 contd
g) Carbohydrate intolerance especially thiazides
and loop diuretics which cause hypokalemia,
probably intracellular potassium is necessary for
insulin formation
h) Loop diuretics have ototoxicity potential, thus
combination with aminoglycosides, and other
nephrotoxins should be with caution
 contd
• Osmotic diuretics: are small molecular weight
substances that are filtered by the glomerulus
but not reabsorbed by the renal tubule
• Increase the osmolality of the tubular fluid
• Prevent reabsorption of water principally in
the PCT and also in the desc. LH
• Increase volume of urine
• Fall in to low-efficacy diuretics
 contd
• Mannitol is the prototype given by i.v route
• It encourages movement of fluid from inside
cells to the extracellular fluid before diuresis
occurs
• It is mainly used for rapid reduction of
intracranial or intraocular pressure and to
maintain urine flow to prevent renal tubular
necrosis
 contd
• Carbonic anhydrase(CA) inhibitors: Include
acetazolamide, dorzolamide
• CA facilitates the reaction b/n CO2 and water
to form carbonic acid, which then breaks
down to H+ and bicarbonate(HCO3 -) ions
• This process is fundamental for production of
either acid or alkaline secretions
 contd
• Rapid tolerance develops to their diuretic
effects(hence not used for this purpose)
• Used for reduction of intraocular pressure and
for high-altitude(mountain) sickness
• Reduction of intraocular action is not related
with diuresis, the formation of aqueous
humour is an active process requiring a
supply of bicarbonate, which depends on CA
 contd
• CA inhibitors reduce formation of aqueous
humour and lower intraocular pressure
• Acetazolamide p.o. or i.v used for acute
glaucoma but not recommended for long-term
use
• It causes hypokalemia and acidosis with long-
term use
• Dorzolamide can be given as eye drops and is
suitable for chronic use in glaucoma
 Alteration of urine pH
• Alteration of urine pH is sometimes desirable
• The most common reason is in the treatment
of poisoning
• Urine can be made alkaline by sodium
bicarbonate i.v. or by potassium citrate po
• Alkalinization of urine:
- Increases the elimination of acidic drugs such
as salicylates, phenobarbital, etc.
 contd
• Acidification of urine can be done with:
- Ammonium chloride, arginine hydrochloride,
ascorbic acid and calcium chloride by mouth
• Acidification of urine:
- Increase elimination of basic drugs such as
amphetamine, quinine, etc.
 Drug-Induced Renal Disease
• Drugs and other chemicals damage the kidney
by:
1. Direct biochemical effects, e.g. heavy metals
gold, mercury, lead; antimicrobials
aminoglycosides, amphotericin B, iodinated
radio contrast media, etc
2. Indirect biochemical effects, e.g. cytotoxic
drugs and uricosurics may cause urate to be
precipitated in the tubule
 contd
3. Immunologic effect,e.g penicillins, phenytoin,
hydralazine, penicillamine, etc
• Combination of the mechanisms possible
• The sites and pathological types of injuries
include:
- Glomerular damage(glomerulonephritis,
proteinuria and nephrotic syndrome may
result)
 contd
• Tubule damage(aminoglycosides, salicylates,
heavy metals, radiographic contrast media,
lithium,etc)
• Tubule obstruction by deposition of
crystals(methotrexate, sulfonamides precipitate
at acidic urine)
• Vasculitis caused by allopurinol,sulfonamides
• Allergic interstitial nephritis caused by
penicillins
 contd
• Drug-induced lupus erythematosus caused by
hydralazine, procainamide
• Drugs may thus induce any of the common
clinical syndromes of renal injury, namely:
 Acute renal failure,e.g. aminoglycosides
 Nephrotic syndrome e.g. penicillamine, gold
 Chronic renal failure e.g. NSAIDs
 Functional impairment –acid-base imbalance
e.g. acetazolamide
 Contd

• No effective remedy once these kidney

syndromes are established
• Non-pharmacological approach such as renal
replacement therapy, supportive medications
and drugs slowing disease progression may
improve quality of life and survival
• Avoidance of nephrotoxins is important to
improve outcome
 contd
• Acute kidney injury is a common complication
in hospitalized patients(critically ill patients)
• Loop diuretics have some advantages for both
prevention and treatment of AKI
• Chronic kidney disease is usually diagnosed
late(after complications occurred)
• ACEIs/ARBs are useful to slow disease
progression
 contd
• Treatment of complications of CKD(e.g.
anemia) can be done with epoietin alfa
• Iron, vitamin B12, folate are supplemented
• Glomerulonephritides managed by supportive
therapy to remove edema, control
hypertension, hyperlipidemia
• Corticosteroids(e.g. prednisolone) and
cytotoxic drugs(cyclophosphamide) can be
used to slow disease progression
 Prescribing in renal disease
• Drugs may:
 Exacerbate renal disease
 Be ineffective e.g. thiazides in moderate or
severe renal failure
 Be potentiated by accumulation due to failure
of renal excretion
• For drugs exacerbating renal disease, seek an
alternative drug that does not depend on renal
elimination
 contd
• Loop diuretics can substitute thiazides for use
in impaired renal function
• Potentiation of effect due to decreased renal
excretion can be corrected by dosage
adjustment
• Adjustment of maintenance dose involves
either reducing each dose given or
lengthening the time between doses
 contd
• Dose adjustment is made in proportion to
reduction in creatinine clearance
• Adjustment of initial dose is generally
unnecessary
• Adjustment of maintenance doses of those
drugs that are completely or largely
metabolized to inactive products may not be
necessary(assess effects nevertheless)
Drugs for urinary incontinence(UI)
• UI is an involuntary leakage of urine
• Frequently accompanied by urgency,
increased day time frequency and nocturia
• Affects significantly quality of life
• Patients with UI may have depression as a
result of perceived lack of self-control
• Stress, urge, mixed and overflow UI occur in
men and women
 contd
• Anticholinergic/antimuscarinic agents are first-
line therapies for overactive bladder or urge
incontinence
• Individual drugs include oxybutynin,
tolterodine, solifenacin
• Antagonize muscarinic receptors on detrusor
muscle of the bladder
• Suppress premature bladder contractions and
thereby enhance bladder storage
 contd
• All are equally effective and have similar
adverse effects profile(dry mouth,
constipation, headache, blurred
vision,tachycardia,etc)
• Sustained-release formulations have lesser
adverse effects
• Mirabegron, a beta3 -adrenergic agonist can
be considered as an alternative for those who
 contd
fail to achieve optimal efficacy or can not
tolerate the adverse effects of anticholinergics
• Duloxetine, and topical estrogens are the
drugs of choice for stress incontinence
• Overflow incontinence secondary to BPH is
also treatable with drugs
Drugs for Benign prostate hyperplasia(BPH)

• BPH is an androgen-driven growth in the size

of the prostate
• BPH symptoms are divided into obstructive
and irritative
• BPH symptoms can be exacerbated with
medications such as antihistamines,
phenothiazines, tricyclic antidepressants and
anticholinergic agents(avoid them)
 contd
• Drug therapy for BPH can be categorized in to
three types:
1) Agents that relax prostatic smooth muscle
2) Agents that interfere with testosterone’s
stimulatory effect on prostate gland
enlargement
3) Agents that relax bladder detrusor muscle
 contd
• Of the agents that relax prostatic smooth
muscle, second and third-generation alpha1 –
adrenergic antagonists are widely used
• Second-generation drugs: prazosin, terazosin,
alfuzosin, doxazosin
• Third-generation drugs: Tamsulosin, silodosin,
• These drugs relax the intrinsic urethral
sphincter and prostate smooth muscle,
 contd
thereby enhancing urinary outflow from the
bladder
• Do not reduce prostate size
• 5-alpha-reductase inhibitors such as
finasteride and dutasteride interfere with
testosterone’s stimulatory effect on prostate
gland
• Delay disease progression and decrease size
 contd
• 5-alpha-reductase inhibitors do not relax
prostatic smooth muscle
• May decrease libido and cause erectile
dysfunction as adverse effect
• Third-generation alpha1 –antiadrenergics have
lesser cardiovascular adverse effects than
second-generation ones
• Alpha1 –adrenergic antagonists, 5-alpha-
 contd
reductase inhibitors may improve urinary flow
rates and bladder emptying
• If patients complain of irritative voiding
symptoms(e.g. urinary frequency,
urgency,nocturia), antimuscarinic agents can
be added to alpha1 –antiadrenergics
• These agents reduce uninhibited detrusor
contractions