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Textbook of Pharmacotherapeutics
Clinical Manifestations
Open angle glaucoma is insidious in onset and shows no or minor symptoms like
headache or tired eyes. With disease progression, patients may report loss of
peripheral vision and presence of blind spots in the field of vision. Acute angle closure
glaucoma normally has a sudden onset of action and presents with signs and
symptoms of blurred vision, severe ocular pain, nausea and occasional vomiting. The
eye typically appears red, the cornea is cloudy, the pupil is mildly dilated, and IOP is
frequently greater than 50 mm of Hg. Complete blindness may occur in 2 to 5 days if
remains untreated.
Non-pharmacological Management
Surgery: Surgery involves creating collateral drainage from the anterior chamber. It
is reserved for the patients who cannot tolerate mono or combined therapy. It is
preferred for open angle glaucoma.
Laser therapy: Laser trabeculoplasty is considered for open angle glaucoma while
laser iridotomy is recommended for angle closure glaucoma.
Pharmacological Management
Immediate and sustained reduction in IOP to prevent deterioration of optic nerve and
loss of vision should be the aim of the glaucoma therapy. The medicines used in this
treatment either increases the elimination rate of aqueous humor or decreases its
formation. These drugs can be classified into six types as follows:
•
-blockers (adrenolytic agents): These drugs block the adrenoreceptors in the
ciliary body, thereby reducing the aqueous humor production by one-third.
Timolol, levobunolol, betaxolol, metipranolol, carteolol are the examples of this
category. All these drugs are available in solution form and administered two or
three times daily. Timolol is also available in gel form which can be given once in
a day.
• Miotics (cholinergic agents): These drugs can cause direct or indirect stimulation
of cholinergic nerves. Both the types of drugs facilitate the outflow of aqueous humor
and reduce the IOP. Examples of direct acting agents are pilocarpine and carbachol
while physostigmine and echothiophate are examples of cholinesterase inhibitors.
Pilocarpine is available in the form of solution, gel and ocular insert. It is associated
with typical side effects like myopia or fixed pupil. Systemic effects may include
nausea, vomiting, diarrhea and bradycardia. Carbachol has a longer duration of
action than pilocarpine and can be used as an alternative to pilocarpine.
Physostigmine has a short duration of action while organophosphate compounds
like echothiophate or demecarium have longer duration of action. They are used in
the treatment of open angle glaucoma but not advisable in angle closure glaucoma
or congenital glaucoma.
• Sympathomimetics (adrenergic agonist) drugs: These drugs stimulate either or
both - and -adrenergic receptors. Catecholamine including epinephrine,
norepinephrine, and dopamine act by both the mechanisms, i.e. decreased
production or increased elimination of aqueous humor. Local side effects include
mydriasis, hyperemia and ocular irritation. Epinephrine and its prodrug dipivefrin
should not be used in patients with narrow angle since they cause acute angle closure.
Systemic side effects include palpitations, hypertension and arrhythmia.
Ophthalmology
149
• Carbonic anhydrase inhibitors: Carbonic anhydrase catalyzes the reversible
conversion of carbon dioxide to bicarbonate, which is a significant step in aqueous
humor production. Inhibition of this enzyme reduces aqueous humor production.
They are available in topical and systemic preparations.
• Topical agents: Dorzolamide and brinzolamide are the drugs available from this
category. Dorzolamide is available as a solution and brinzolamide as suspension
for monotherapy or in combination with other drugs.
• Systemic agents: Acetazolamide is the drug of choice as a tablet, sustained release
capsule or for IV administration. Dichlorphenamide and methazolamide are the
other drugs of this category. These agents reduce IOP effectively but significant
adverse effects associated with it reserves its use to third or fourth line of treatment.
They are effective in acute angle closure glaucoma. Adverse effects include
paresthesias of the hands and feet, nausea, vomiting, weight loss, depression and
anorexia.
• Hyperosmotic agents: Hyperosmotic agents create an osmotic gradient which draws
water from vitreous humor, thus decreasing IOP. Mannitol, urea, glycerol and
isosorbide are examples of this class. These are rapid acting drugs. Headache and
thirst are common side effects with use of these drugs.
• Prostaglandin analogues: Latanoprost is the prostaglandin analogue, which reduces
IOP by increasing aqueous humor outflow through the uveoscleral pathway.
KEY POINTS
• Increased intraocular pressure is the highest risk factor for glaucoma
• It causes damage to the ganglionic cells and optic nerves
• It can be classified as open angle or angle-closure glaucoma
• -blockers, miotics, sympathomimetics, carbonic anhydrase inhibitors are the classes of medicines
useful for glaucoma.
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Textbook of Pharmacotherapeutics
13
Anti-microbial
Resistance
The ability of microorganisms to grow in presence of antimicrobial agents which are
designed to inhibit their growth or kill them is called antimicrobial resistance.
The antibiotic era started around 70 years ago. The quest for new antibiotics is
still going on but probably the effective antibiotics have already been discovered.
Table 13.1 shows the timeline of antibiotic discovery and development of resistance.
Drug resistant pathogens have already been discovered for a long time. The spread
of pathogens is a threat to the health of the society. The ‘superbug’ was discovered in
the year 2002. The resistant strain of S aureus was first isolated from a diabetic patient
suffering from foot ulcers in Detroit. Another strain that is vancomycin-resistant
enterococci (VRE) was also isolated from the same patient.
There are many sources of antibiotic resistance
• Improper prescribing practices
• Use of suboptimal doses of antibiotics
• Failure of patient compliance
• Unregulated sale of antibiotics
• Use of antibiotics as growth enhancers in animal feeds
• Bacterial genetic factors
Table 13.1: Timeline of antibiotic discovery and development of resistance
Antibiotic Reported or discovered Resistance identified Organism involved
Sulphonamide 1935 1939 S. pneumoniae
Penicillin G 1928 1942 S. aureus
Methicillin 1960 1961 S. aureus
Oxyimino- lactams 1978 1983 K. pneumoniae
Streptomycin 1944 1946 E. coli
Tetracycline 1948 1959 S. dysenteriae
Erythromycin 1952 1957 S. aureus
Vancomycin 1956 1987 E. faecium
Gentamicin 1963 1970 K. pneumoniae
Ref: Antimicrobial Drug Resistance—Mechanism of Drug Resistance, volume 1, second edition by Douglas L
Mayers, Jack D Sobel, Marc Ouellette, Keith S Kaye, Dror Marchaim.
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Anti-microbial Resistance
151
Mechanism of Antimicrobial Resistance
There are various mechanisms by which microorganisms develop resistance. The
mechanisms used by two bacteria to develop resistance for the same antibiotic may be
different.
Pharmacologic parameters influencing antimicrobial resistance can be drug-
specific, organism-specific, or host-specific.
Pathogens often prevent entry of the drugs and thereby become resistant. Penicillin
G cannot affect many Gram-negative bacteria because of its inability to penetrate the
outer membrane of the bacteria cell. Sulphonamide resistance can also develop due to
decrease in permeability of the cell. Mycobacteria contain high mycolic acids in their
complex lipid layer which is impermeable to many water-soluble drugs.
A second way of developing resistance is to pump the drug out with the help of
efflux pumps by the pathogens. Translocases may be present in the plasma membrane
of pathogens and can expel drugs. These efflux pumps are mostly non-specific and
can act as multidrug resistant pumps. Such systems are present in E. coli, P. aeruginosa,
and S. aureus.
Many pathogens may show resistance by drug inactivation. This may be done
by chemical modification of the drug, e.g. enzyme penicillinase hydrolyses the betalactam ring of penicillins. The addition of chemical groups also leads to
inactivation of drugs, e.g. chloramphenicol can be modified by addition of acetylCoA. This reaction is catalysed by the enzyme chloramphenicol acetyltransferase.
The modification and inactivation of aminoglycosides can be carried out in several
ways, e.g. the addition of hydroxyl group may be done by certain enzymes or the
acetylation of amino group is catalysed by acetyltransferases.
Target modification may lead to development of resistance to the chemotherapeutic
agents, e.g. the ribosomal affinity for erythromycin and chloramphenicol can be
decreased by a change in the rRNA to which they bind. This leads to reduction in
antibiotic binding. Also, resistance to anti-metabolites occurs through alteration of
susceptible enzymes, e.g. bacteria which use para-aminobenzoic acid during folic acid
synthesis have low affinity for sulphonamides.
Use of alternate pathways by resistant bacteria is to bypass the sequence inhibited
by the agent or increasing the production of target metabolite, e.g. bacteria resistant
to sulphonamides use preformed folic acid instead of synthesizing it. Other strains
increase the folic acid preparation and resist inhibition by sulphonamides.
Origin and Transmission of Drug Resistance
Penicillin-resistant bacteria were found within three years of use of penicillin. The
microorganisms which produce antibiotics contain the genes called immunity genes
which encode resistance proteins. The genes which encode antibiotic resistance in
bacteria may undergo horizontal gene transfer from antibiotic producer to nonproducer thereby giving rise to a large pool of resistance encoding genes. The drug
resistant genes may be present on non-producing bacterial chromosomes, transposons,
plasmids, and other genetic material.
Sometimes spontaneous mutation in bacterial chromosomes can lead to drug
resistant bacteria (exception is M. tuberculosis undergoes frequent mutation). If the
patient does not comply with the prescribed antibiotics as directed, the resistant
mutants flourish. The objective of DOTS is to prevent such mutation in TB patients.
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Textbook of Pharmacotherapeutics
Presence of R plasmids or resistance plasmids frequently leads to development of
drug resistance in bacterial pathogens. R plasmids are responsible for code for
enzymes that modify or destroy the drugs, e.g. hydrolysis of penicillin acetylation of
chloramphenicol and aminoglycosides. These plasmid resistance genes (could not find
these three words together in google, it is antibiotics resistance genes) are involved in
resistance to aminoglycosides, chloramphenicol, penicillins, cephalosporins,
erythromycin, tetracyclines, sulphonamides, and other drugs. The R plasmids may
be transferred to other bacteria through processes like conjugation, transduction, and
transformation. The pathogens can become resistant to several drugs at a time as a
single plasmid may carry genes for resistance to several drugs.
Transposons containing antibiotic resistance genes can move between plasmids in
bacteria, both Gram-positive and Gram-negative.
Gene cassettes contain several resistance genes together.
An integron consists of an integrase gene and sequences for recombination. It can
capture genes and gene cassettes, so these are important in spreading resistance
genes.
Conjugative transposons containing resistance genes can move between bacteria by
conjugation and can spread resistance.
Overcoming Drug Resistance
The strategies for overcoming drug resistance are:
• Administration of drugs in proper concentration
• Administration of two or three different drugs simultaneously
• Adequate therapy
• Use of antibiotics only when prescribed by certified health professional
• Patient compliance
• Neither use or share leftover medicines
• Prevent infections by regularly washing hands
• Avoid close contact with infected people and practise safe sex
• Take vaccinations on time
• Prepare food hygienically. Follow the WHO Five Keys to Safer Food (keep clean,
separate raw and cooked, cook thoroughly, keep food at safe temperatures, use
safe water and raw materials). Choose foods that have been produced without the
use of antibiotics for growth promotion or disease prevention in healthy animals
• Ensure a national action plan to tackle antibiotic resistance
• Administer antibiotics to animals only under veterinary supervision.
• Vaccinate the animals to avoid use for antibiotics
Antimicrobial Resistance—A Global Concern
Bacteria, not humans or animals, become antibiotic-resistant. AMR occurs naturally
over time, usually through genetic changes. Antimicrobial resistant organisms are
found in people, animals, food, plants and the environment (in water, soil and air).
They can spread from person to person or between people and animals, including
from food of animal origin. New resistance mechanisms acquired by pathogens are
leading to antimicrobial resistance and thus threatening our ability to treat common
infections. There is an alarming global spread of multi- and pan-resistant bacteria
Anti-microbial Resistance
153
(“superbugs”) that cause infections that cannot be treated with existing antimicrobial
medicines like antibiotics.
Antibiotics are becoming increasingly ineffective as drug-resistance spreads
globally leading to more difficult to treat infections and death. The cost of AMR to
economies of the nations and their healthcare systems is significant as it affects the
productivity of patients, their caretakers due to prolonged hospital stays and the need
for more expensive and intensive care.
A growing number of infections—such as pneumonia, tuberculosis, gonorrhoea,
and salmonellosis—is becoming harder to treat as the antibiotics used to treat them
are becoming less effective. Even medical procedures like caesarean sections or hip
replacements, cancer chemotherapy, and organ transplantation, will become riskier.
Need for Coordinated Action
AMR is a complex problem that requires a united multisectoral approach. The one
health approach brings together multiple sectors and stakeholders engaged in
human, terrestrial and aquatic animal and plant health, food and feed production and
the environment to communicate and work together in the design and implementation
of programmes, policies, legislation and research to attain better public health
outcomes.
Greater innovation and investment is required in operational research, and in research
and development of new antimicrobial medicines, vaccines, and diagnostic tools
especially those targeting the critical Gram-negative bacteria such as carbapenemresistant Enterobacteriaceae and Acinetobacter baumannii.
Since 2020, World Antimicrobial Awareness Week (WAAW) (previously called
World Antibiotic Awareness Week) is observed from 18 to 24 November each year.
WAAW includes all antimicrobials including antibiotics, antifungals, antiparasitics,
and antivirals. Held annually since 2015, WAAW is a global campaign with the
objective to raise awareness of antimicrobial resistance worldwide and encourage best
practices among the general public, health workers and policy makers to slow the
emergence and spread of drug-resistant infections. The slogan used for the last 5 years
was “Antibiotics: Handle with Care.” This has been changed to “Antimicrobials:
Handle with Care” in 2020.
KEY POINTS
• The ability of microorganisms to grow in presence of antimicrobial agents which are designed to
inhibit their growth or kill them is called antimicrobial resistance.
• Antimicrobial resistance (AMR) is a global health threat. It requires urgent multisectoral action in
order to achieve the Sustainable Development Goals
• The main drivers in the development of drug-resistant pathogens are misuse and overuse of
antimicrobials.
• Antimicrobial resistance is a global threat which has to be tackled at the level of individuals, policy
makers, healthcare professionals, industry and agriculture sector.
• Strategies for overcoming drug resistance include administration of medicines by healthcare
professionals in proper concentrations, preventing infections, and timely vaccinations.
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14
Women’s Health
14.1 POLYCYSTIC OVARY SYNDROME
Polycystic ovary syndrome (PCOS) is a hormonal condition that affects a large number
of women of reproductive age. Women with PCOS may have irregular or prolonged
menstrual cycles or high levels of male hormone (androgen) levels. The ovaries may
develop numerous small collections of fluid (follicles) and fail to release eggs
regularly.
Aetiology
There is no clear aetiology of polycystic ovary syndrome, but studies have shown
an association of polycystic ovary syndrome with anovulation, insulin resistance,
increase in androgen levels which can lead to cardiovascular problems, and
heredity.
Clinical Manifestations
The most common signs of PCOS are infrequent, irregular, or prolonged menstrual
cycles. Hirsutism (excess facial and body hair) is very common and is accompanied by
severe anxiety, social stress, and acne. This is characterised by multiple small cysts
within the ovary and by excess androgen production from the ovaries and, to a lesser
extent, from the adrenals.
Non-pharmacological Management
Lifestyle changes for weight loss through a low-calorie diet combined with moderate
exercise activities are recommended.
Pharmacological Management
For Regulation of the Menstrual Cycle
• Combination birth control pills: Oestrogen and progestin-containing pills decrease
androgen production and regulate oestrogen. Hormone regulation can lower the
risk of endometrial cancer and correct abnormal bleeding, excess hair growth, and
acne. Instead of pills, a skin patch or vaginal ring that contains a combination of
oestrogen and progestin may be used.
• Progestin therapy: Progestin therapy for 10 to 14 days every one to two months
helps to regulate periods and gives protection against endometrial cancer. Progestin
therapy does not improve androgen levels and will not prevent pregnancy. The
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Women’s Health
155
progestin-only minipill or progestin-containing intrauterine device is a better choice
if the patient also wishes to avoid pregnancy.
For Treatment of Fertility
• Clomiphene 50–200 mg can be given daily on days 2 to 6 of the cycle. This oral antioestrogen medication is taken during the first half of the menstrual cycle.
• Metformin is added to lower insulin levels, which helps with menstrual irregularity
and difficulties in ovulation.
• Gonadotropins are given by injection to stimulate ovulation.
For Hirsutism
• Oestrogens (e. g. oral contraceptives) suppress ovarian androgen production, which
can cause excessive hair growth.
• Spironolactone (Aldactone) 200 mg daily has an antiandrogen effect and can help
improve hirsutism.
• Plucking, bleaching, depilatory cream or wax, and shaving may help to remove the
excess hair. Electrolysis is effective but costly.
KEY POINTS
• Polycystic ovary syndrome (PCOS) is a hormonal condition that affects many women of
reproductive age.
• PCOS may cause irregular or prolonged menstrual cycles or high levels of male hormone
(androgen) levels.
• Hirsutism (excess facial and body hair) is very common and is accompanied by severe anxiety,
social stress, and acne.
14.2 DYSMENORRHOEA
Dysmenorrhoea is characterised by severe and frequent menstrual cramps and pain
during the periods which may be primary or secondary.
• Primary or spasmodic dysmenorrhoea: This starts with the first menstrual cycle
and is a uterine problem and can cause severe menstrual cramping.
• Secondary dysmenorrhoea: This type is due to some underlying medical condition,
such as pelvic inflammatory disease or endometriosis.
Aetiology
Studies suggest that women suffering from primary dysmenorrhoea have greater
concentrations of prostaglandins that lead to increased myometrial contractility.
Secondary dysmenorrhoea is seen in women in their late 30s and 40s and is due to
some pelvic pathology like pelvic inflammatory disease, endometriosis, uterine
fibroids or infection or tumours in the pelvic cavity.
Clinical Manifestations
The most common symptoms are spasmodic pain in the lower abdomen that can
radiate to the back and down the legs. The pain is accompanied by one or more
symptoms, like nausea, vomiting, diarrhoea, lower backache, and headache.
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Textbook of Pharmacotherapeutics
Non-pharmacological Management
This Includes
• Changes in the diet (to increase protein and decrease sugar and caffeine intake)
• Vitamin supplements
• Regular exercise
• A heating pad across the abdomen
• Hot bath or shower
• Abdominal massage
• Acupuncture
Pharmacological Management
For the treatment of pain in primary dysmenorrhoea, the most rational choice would
be a non-steroidal anti-inflammatory drug (NSAID) as these drugs decrease
prostaglandin biosynthesis by inhibiting cyclooxygenase. Mefenamic acid is
frequently used to manage pain associated with dysmenorrhoea. Recently, the
cyclooxygenase (COX-2) inhibitor rofecoxib has been approved for the treatment. of
dysmenorrhoea. The combined oral contraceptives (COC) inhibit ovulation, thereby
preventing increased prostaglandin synthesis and so decreasing uterine contractility
and pain, but not all women are suitable candidates for COC.
For secondary dysmenorrhoea, the best treatment is to find the underlying
pathology and treat it.
KEY POINTS
• Dysmenorrhoea is characterised by severe and frequent menstrual cramps and pain.
• The most common symptoms are spasmodic pain in the lower abdomen that can radiate to the
back and legs.
• The most rational choice would be a non-steroidal anti-inflammatory drug (NSAID) for the
treatment of pain in primary dysmenorrhoea.
14.3 PREMENSTRUAL SYNDROME
Premenstrual syndrome (PMS) has both mood changes and physical symptoms. The
symptoms may start a few days before menstruation and disappear at the onset of
shortly after menstruation.
Aetiology
PMS signs and symptoms change with hormonal fluctuations and disappear with
pregnancy and menopause. Fluctuations of serotonin, a brain chemical (neurotransmitter)
that’s thought to play a crucial role in mood states, could trigger PMS symptoms.
Serotonin deficiency may contribute to premenstrual depression, as well as to fatigue,
food cravings, and sleep disturbances.
The mineralocorticoids, prolactin, androgens, prostaglandins, endorphins,
nutritional factors, e. g. pyridoxine, calcium, and essential fatty acids) and hypoglycaemia
may be involved. The CNS function has been implicated as cerebral blood flow in the
temporal lobes is decreased premenstrually in women with PMS. There could be many
other aetiological factors as the symptoms vary from individual to individual.
Women’s Health
157
Clinical Manifestations
Symptoms occur 1–14 days before menstruation begins and disappear at the onset
shortly after menstruation begins. The common symptoms of PMS are tension, low
mood, mood swings and irritability or anger, changes in appetite and sleep, joint or
muscle pain, headache, abdominal bloating, breast tenderness, fluid retention, acne
flare-ups, and constipation or diarrhoea.
Non-pharmacological Management
Maintenance of good general health especially the intake of calcium and pyridoxine
has been found to be beneficial. Dietary modifications like restricting caffeine and
alcohol intake may be helpful. Increasing intake of natural diuretics like prunes, figs,
celery, cucumber, parsley, and foods high in potassium such as bananas, oranges,
dried fruits, nuts, soya beans, and tomatoes may be useful.
Pharmacological Management
Combined oral contraceptives: These are helpful in some women because these pills
prevent ovulation which brings relief from PMS symptoms.
Bromocriptine: It stimulates central dopamine receptors and thus inhibits the
release of prolactin, hence may be useful for breast tenderness, fluid retention, and
mood changes.
Antidepressants: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine
(Prozac, Sarafem), paroxetine (Paxil, Pexeva), sertraline (Zoloft), and others have been
shown to reduce mood symptoms.
Diuretics: When exercise and limiting salt intake are not enough to reduce the
weight gain, swelling, and bloating of PMS, taking diuretics like spironolactone can
help the body excrete excess fluid through the kidneys.
Prostaglandin synthesis inhibitors: Mefenamic acid, a cyclooxygenase inhibitor
and antagonist at prostaglandin E receptors, has shown improvement in tension,
irritability, depression, headache, and general aches and pain in women with PMS.
KEY POINTS
• In premenstrual syndrome (PMS), the symptoms may start a few days before menstruation which
includes both mood changes and physical symptoms.
• The common symptoms of PMS are tension, low mood, mood swings and irritability or anger.
• Good general health along with proper diet is helpful.
• Different medications like oral contraceptives, bromocriptine and prostaglandin synthesis
inhibitors help to bring relief from PMS symptoms.