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58
Textbook of Pharmacotherapeutics
If hypothyroidism remains untreated, conditions may worsen to cause myxoedema
coma. It is a rare but life-threatening condition.
Aetiopathogenesis
Hypothyroidism can be of three types:
• Primary hypothyroidism: Primary hypothyroidism is caused due to dysfunction
of thyroid. It may occur due to autoimmune destruction or effect of treatment of
thyrotoxicosis. It contributes to about 95% of adult cases. Women are more
susceptible to the disease than men.
Congenital hypothyroidism (cretinism) is deficiency of thyroid hormone at birth. It
may occur due to underdeveloped gland or defective hormone synthesis or lack of
iodine in the mother’s diet during pregnancy.
• Secondary hypothyroidism: Secondary disease is due to hypopituitarism or lack
of TSH hormone. It is a rare phenomenon.
• Tertiary hypothyroidism: This condition is due to failure of hypothalamus.
Sometimes it can also be drug induced. Iodides and iodide containing compounds
like amiodarone, povidone-iodine and iodinated contrast media are not able to escape
from the Wolff-Chaikoff block to resume hormone synthesis. Wolff-Chaikoff effect is
the mechanism by which a large amount of ingested iodine acutely inhibits thyroid
hormone synthesis within the follicular cells irrespective of the serum level of thyroidstimulating hormone. Unfortunately, this type of hypothyroidism may not always be
reversible after the iodides and amiodarone are stopped.
Clinical Manifestations
Symptoms of hypothyroidism include:
• Weakness
• Fatigue
• Lethargy
• Cold intolerance
• Constipation
• Weight gain
• Hair loss
• Difficulty in concentrating and poor memory
• Menorrhagia
• Hearing loss
• Macrocytic anaemia
These symptoms are frequently vague particularly in the initial stage. Hence, it can
be incorrectly attributed to normal aging. Sometimes, these symptoms may be
confused with normal obesity and depression.
Signs of Hypothyroidism
• Dry, cool, flaking, thickened skin
• Puffy face, eyes, hands and feet
• Yellowish complexion
Disorders of Endocrine System
59
• Coarse dry hairs
• Brittle nails
• Bradycardia
• Carpal tunnel syndrome
• Delayed tendon reflexes relaxation
• Depression, psychiatric disturbances
• Raised total and LDL cholesterol
Clinical presentation of congenital hypothyroidism includes pig-like appearance of
eyes, hypothermia, prolonged jaundice, umbilical hernia, hoarseness, thick tongue,
feeding problem, protuberant abdomen, constipation, etc. If the condition of the child
is not detected and treatment is delayed, irreversible neurological damage may occur.
Non-pharmacological Management
Since hypothyroidism is not a curable disease, one has to take medications. But there
are some lifestyle changes which can help maintain normal levels of thyroid hormones.
1. Consuming food rich in iodine definitely helps. It includes:
• Eggs
• Dairy products
• Meat, poultry and seafood
• Edible seaweed
• Iodized salt
Healthy food especially containing more fibers and vitamins helps to keep check
on weight gain, which is one of the symptoms of hypothyroidism.
2. Regular exercise with meditation helps to keep away stress and depression.
3. Adequate sleep helps to get rid of tiredness.
Pharmacological Management
Thyroxin is a drug of choice for hormone replacement therapy. The starting dose of T
may vary with the patient’s age, severity and duration of disease. However, this may
not be possible in cardiac patients in whom angina or MI may get precipitated or
aggravated by thyroxine. Thyroxin has a longer half-life which maintains a substantial
peripheral pool of thyroxin from which T
effect against lapses in treatment. T
buffering effect. Combinations of T
and T4 are also available but not as substantial as T4.
3
is slowly formed. This provides a buffering
3
has a shorter half-life and hence lacks this
3
Thyroxin and levothyronine both are available in tablets and injections form.
Hyperthyroidism
Hyperthyroidism is defined as excessive release of thyroid hormones by thyroid gland.
Prolonged exposure to elevated levels of thyroid hormones results in a condition
known as thyrotoxicosis.
Etiopathogenesis
Hyperthyroidism could be the result of:
• Graves’ disease
• Toxic nodules (multinodular goiter)
4
60
Textbook of Pharmacotherapeutics
• Toxic adenoma
• Drug induced
• Neonatal thyrotoxicosis
Graves’ Disease
It is an autoimmune disease where abnormal IgG immunoglobulin is produced. It
mimics the effect of TSH and stimulates the secretion of thyroid hormone.
These stimulatory immunoglobulins are called thyroid receptor antibodies
(TRabs)
Toxic Nodules
Toxic multinodular goitre is more common in older women. Individual nodules
become autonomous and secrete T
It is observed that often, only T
and T4. It is less severe and more gradual in onset.
3
levels are elevated, though the TSH is suppressed in
3
all cases.
Toxic Adenoma
Toxic adenomas are single, autonomous benign, well-differentiated tumours that
secrete excessive hormones.
Drug induced
Certain drugs like iodides, amiodarone, lithium, etc. can induce hyperthyroidism.
Iodine induced hyperthyroidism is known as Jod-Basedow disease. Iodides
normally produce thyrotoxicosis in an abnormal thyroid gland that has lost the
protective Wolff-Chaikoff block. It has also been reported after injections of
radiocontrast material or iodinated topical preparations.
Amiodarone contains iodine and causes 2 types of hyperthyroidism. Type I disease
occurs in patients with predisposing risk factors and is related to high iodine content
of amiodarone and loss of protective Wolff-Chaikoff block. Type II disease is caused
due to leakage of large quantities of hormone into circulation as a result of
inflammatory type of thyroiditis.
Neonatal Thyrotoxicosis
Neonatal hyperthyroidism is the result of transplacental passage of TRab.
Clinical Manifestations
Symptoms of hyperthyroidism include:
• Hyperactivity, irritability
• Nervousness, psychosis
• Heat intolerance, sweating
• Palpitations
• Fatigue, weakness
• Weight loss with increased appetite
• Diarrhoea, polyurea
• Amenorrhoea, osteoporosis
Disorders of Endocrine System
61
Signs of hyperthyroidism:
• Tachycardia, atrial fibrillation
• Lid retraction
• Tremor
• Goitre
• Warm and moist skin
Non-pharmacological Management
Along with the effective treatment, patients should also get counselled for the
importance of regular clinical attendance. It is required to monitor therapeutic outcome
and development of adverse reactions. Following points shall be covered in counselling:
• Differences between specific anti-thyroid therapy and symptomatic treatment
• Anticipated duration of treatment and dose schedule
• Explain use of adjuvant therapy, e.g. -blockers
• Encourage reporting adverse effects like skin rashes, sore throat or mouth ulcers
• Encourage monitoring of therapy by regular visit to the clinic
• Understanding relapse may occur and its management.
Pharmacological Management
Hyperthyroidism can be managed with thioamides, RAI (radioactive iodine) therapy and
surgery. Each one of these has its own advantages and disadvantages, so treatment must
be individualized. The etiology of hyperthyroidism, its severity, the patient’s age, size of
goitre, and any complication if present should be considered for selection of treatment.
Treatment with thioamides is preferred in patients with small goitres and mild
diseases. Benefit with thioamide is it does not destroy the gland but control the
disease. Sometimes, it also has a risk of adverse reactions which include rashes,
agranulocytosis or rarely hepatitis.
Adrenergic antagonist: Sympathetic nervous system mediates the signs and
symptoms of thyrotoxicosis hence adrenergic antagonist particularly -blockers
blocks the effects of thyroid hormone and gives symptomatic relief.
RAI therapy is advised in older patients with cardiac disease and in those with TMG
(toxic multinodular goitre). Two types of isotopes can be used
131
I and
125
I. Pretreatment
with thioamides for approximately 1 month or with -blocker before and after RAI
therapy is necessary. RAI is strictly contraindicated in pregnancy as it crosses the
placenta and may destroy the thyroid gland of the fetus.
Surgery for thyroidectomy or complete removal of thyroid gland is advised only, if
previous two ways of treatment are not effective. Carrying out surgery is difficult for
the patients with severe cardiac, respiratory or debilitating diseases, and women in
the third trimester of pregnancy. Major nonacceptance for surgery includes high cost,
hospitalization, fear of surgery, risk of anesthesia and postoperative complications.
KEY POINTS
• Thyroid is an endocrine gland which produces T3 and T4.
• Hypothyroidism is the condition where there is deficiency of thyroid hormones.
• Hyperthyroidism is defined as excessive release of thyroid hormones by thyroid gland.
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Textbook of Pharmacotherapeutics
5
Disorders of
Central Nervous System
5.1 EPILEPSY
Epilepsy is a chronic neurologic disorder that affects people of all ages. It affects
around 50 million people around the world. An epileptic seizure or convulsion is a
transient abnormal event caused by a paroxysmal release of cerebral neurons that is
visible to a person experiencing the seizures and/or a spectator. The term “epilepsy”
is used to describe a variety of conditions that have the potential to cause seizures. About
70–80% of those who develop epileptic seizures become seizure-free after therapy, and
about half will be able to discontinue their medications successfully in the long run.
Aetiology
Epilepsy is not contagious. Even though it can be caused due to many underlying
disease conditions, the exact cause of the disease is still unknown in about 50% of cases
worldwide. The causes of epilepsy include brain damage from prenatal or perinatal
causes (e.g. a loss of oxygen or trauma during birth, low birth weight), congenital
abnormalities or genetic conditions with associated brain malformations, a severe
head injury, a stroke that reduces the amount of oxygen to the brain, an infection of
the brain such as meningitis or encephalitis, metabolic abnormalities like hyponatremia,
hypoglycaemia, uraemia, and others, brain tumour, and pyrexia.
Pathogenesis
Neurons are linked together in a complex network through synapses. A small electric
current is discharged by neurons to release neurotransmitters at the synapse to allow
communication with each other. There are two types of neurotransmitters: Inhibitory
and excitatory. As a result, a neuron discharging can either excite or inhibit neurons
connected to it. This information is transmitted and processed through the central
nervous system in this manner.
A normal neuron discharges electric current at a low baseline frequency, and this
can be recorded in a typical EEG. If neurons are damaged or injured, a shift in
discharge pattern may develop. In the case of epilepsy, regular low-frequency
discharges are replaced by high-frequency discharges, usually followed by periods of
inactivity (mediated by the inhibitory neurotransmitter GABA or by potassium
channels). These bursts are caused by an influx of extracellular calcium followed by
the activation of voltage-dependent sodium channels. This abnormal discharge may
remain localised or it may spread to adjacent areas involving more neurons. The area
from which the abnormal discharge originates is called the epileptic focus. An EEG
62
Disorders of Central Nervous System
63
recording carried out during one of these abnormal discharges may reveal a variety
of atypical signs depending on which area of the brain is involved and its
progression.
Clinical Manifestations
The clinical manifestations of a seizure will depend on the location of the focus and
the pathways involved in its spread. The seizures are of two types, depending on
the area of the brain from which the abnormal discharge originates. Seizures are
termed “generalized” when both the hemispheres are activated at the same time. If
a discharge starts in a localized area of the brain, the seizures are termed partial or
focal.
Generalized seizures: These occur when there is widespread seizure activity in
the left and right hemispheres of the brain. There are various types of generalised
seizures.
Tonic-clonic seizures (grand mal epilepsy): These are the most common of all
epileptic seizures. These seizures begin with tonic (rigid) flexion of the
extremities followed by an extension. During this phase, air is forced from the
larynx to produce an audible cry. This phase lasts for 15 to 20 seconds and is
followed by the clonic (jerking) phase during which there are spasms of the trunk
and extremities and often tongue biting. The convulsion stops after a few
minutes and may be followed by a period of drowsiness, confusion, headache,
and sleep.
Absence seizures (petit mal epilepsy): These primarily occur in childhood and
early adolescence. These are characterised by an abrupt interruption of consciousness
followed by a fixed glare. Involuntary movements like lip-smacking, fluttering of
eyelids, or flopping of the head may occur.
Myoclonic seizures: These are abrupt, very brief, involuntary shock-like jerks that
may involve the whole body, the arms, or the head. They may occasionally cause the
person to fall, but they recover quickly.
Atonic seizures: These are characterised by a sudden loss of muscle tone, causing
the person to collapse, but recovery is quick.
Partial or focal seizures: These are limited to one hemisphere of the brain.
Simple partial seizures: Localised jerking of a limb or the face, stiffness or twitching
of one part of the body, numbness, or abnormal sensations may occur during a simple
partial seizure. The consciousness is fully preserved.
Complex partial seizures: These seizures comprise impaired consciousness with
abnormal behaviours like lip-smacking, buttoning or unbuttoning of clothing, or
wandering behaviour.
Secondarily generalised seizures: These are partial seizures in which the discharge
spreads to the entire brain which leads to a convulsive attack with the same
characteristics as a generalised tonic-clonic seizure.
General Principles of Treatment
The goals of AED (anti-epileptic drugs) pharmacotherapy are to completely control
seizures with the fewest side effects possible.
64
Table 5.1: Antiepileptic drugs for different types of seizures
Seizure type First-line treatment Second-line treatment
Generalised seizures
Tonic clonic Sodium valproate Lamotrigine
Absence Ethosuximide Clonazepam
Myoclonic Sodium valproate Levetiracetam
Atonic Clonazepam Lamotrigine
Partial seizures
Source: Roger Walker and Cate Whittlesea, 2012, Clinical Pharmacy and Therapeutics, Fifth edition, reprinted
2015, Churchill Livingstone, Elsevier, UK
Textbook of Pharmacotherapeutics
Sodium valproate Lamotrigine
Clonazepam Acetazolamide
Topiramate
Clobazam Carbamazepine
Phenytoin
Acetazolamide
Topiramate
Carbamazepine Topiramate
Phenytoin Sodium valproate
Lamotrigine Clobazam
Oxcarbazepine Zonisamide
Levetiracetam Pregabalin
Phenytoin
Gabapentin
Lacosamide
Acetazolamide: It can be used as a second-line drug for most of the seizure types
but is mostly used for partial seizures, absence seizures, and myoclonic seizures. It has
limited use as long-term therapy due to the development of tolerance. Side effects
include skin rashes, weight loss, paraesthesia, drowsiness, and depression.
Carbamazepine: It is a drug of first choice in partial seizures and tonic-clonic
seizures secondary to focal discharge seizures, and it is effective in trigeminal
neuralgia. Tolerance usually does not develop. Sedation, ataxia, giddiness, nystagmus,
diplopia, blurred vision, and slurred speech occur in 50% of patients with plasma
levels over 8.5 mg/L.
Sodium valproate: It is effective against many forms of epilepsy, including tonic-
clonic, absence, partial seizures, and myoclonic epilepsy. The adverse effects
include tremors, ataxia, and incoordination (dose-related), nausea, vomiting, and
abdominal pain (reduced by using enteric-coated tablets), hair loss (temporary),
thrombocytopenia, etc.
Phenytoin: It is a second-line drug for partial seizures, tonic-clonic, and atonic
seizures. Dose-related adverse effects include nystagmus, ataxia, and lethargy.
Cosmetic effects like gum hypertrophy, hirsutism, and acne are also well-recognized
adverse effects.
Disorders of Central Nervous System
65
Phenobarbital: It may be used for the treatment of tonic-clonic and partial seizures.
Rebound seizures may occur on withdrawal.
Benzodiazepines (e.g. diazepam, clobazam, and clonazepam) have anticonvulsant
properties in addition to their anxiolytic and other actions. Chronic usage is limited
due to the tolerance to their anti-epileptic properties. Adverse effects are common, and
about 50% of patients experience lethargy and dizziness. Clobazam may produce less
sedation as compared to other benzodiazepines.
Ethosuximide: It is the drug of first choice for generalised absence seizures.
Gastrointestinal symptoms are the most common side effects. Behavioural disorders,
anorexia, fatigue, sleep disturbances, and headaches may also occur.
Gabapentin: It is occasionally used as a second-line treatment of partial seizures.
The most frequently reported side effects are drowsiness, dizziness, diplopia, ataxia,
and headache.
Topiramate: It is used as a second-line drug for patients with partial seizures. Side
effects include dizziness, drowsiness, nervousness, impaired concentration,
paraesthesia, and fatigue.
Tiagabine: It is used as a second-line drug in patients with partial seizures. The
most common side effects are sedation, tremors, headaches, mental slowing, tiredness,
and dizziness.
Pregabalin: It has been licenced for the adjunctive treatment of refractory partial
seizures. Dizziness, drowsiness, ataxia, tremors, and diplopia are the most common
side effects.
Table 5.2: Commonly used starting and maintenance doses of AEDs for adults
Antiepileptic drug Starting dose (mg) Average maintenance (mg) Doses/day
Acetazolamide 250 mg 500–1500 mg 2
Carbamazepine 100 mg 600–2400 mg 2–4
Sodium valproate 500 mg 2000–2500 mg 1–2
Phenytoin 200–300 mg 200–400 mg 1–2
Phenobarbital 60 mg 60–180 mg 1
Clobazam 10 mg 10–30 mg 1–2
Clonazepam 0.5 mg 0.5–3 mg 1–2
Ethosuximide 250 mg 500–1500 mg 1–2
Gabapentin 300 mg 900–1200 mg 3
Lamotrigine 50 mg 100–500 mg 2
Levetiracetam 1 g 2–3 g 2
Oxcarbazepine 300 mg 900–1800 mg 2–3
Lacosamide 50 mg 200–400 mg 2
Zonisamide 50 mg 300–500 mg 2
66
Textbook of Pharmacotherapeutics
Lamotrigine: It is a second-line drug for partial epilepsy. Its most common side
effects are drowsiness, headaches, nausea, and diplopia.
Levetiracetam: This drug is indicated for the treatment of refractory partial
epilepsy. It is well tolerated and the adverse effects are dizziness, irritability, asthenia,
and sedation.
Oxcarbazepine: It is an analogue of carbamazepine. Two-thirds of patients who are
allergic to carbamazepine can tolerate oxcarbazepine.
Lacosamide: It is a second-line drug for partial epilepsy in patients over the age of
16 years. Its most common side effects are dizziness, headaches, nausea, and diplopia.
Zonisamide: It is used as a second-line drug for patients with partial seizures.
Dizziness, drowsiness, headache, hyporexia, nausea and vomiting, weight loss,
irritability, impaired concentration, and fatigue.
Febrile Seizures
These are defined as generalised tonic-clonic seizures associated with temperatures
greater than 38°C that occur in the absence of other identifiable causes. These are
common forms of epilepsy in children. Only the temperature needs to be treated in
febrile seizures (tepid sponging and paracetamol). If a febrile convulsion lasts longer
than 15 minutes, intravenous or rectal administration of diazepam is usually effective.
Status Epilepticus
This medical emergency means rapidly recurring seizures without any return of
consciousness between seizures. Lorazepam IV is considered the treatment of choice
for controlling seizures. In cases where lorazepam is not available, diazepam can be
administered intravenously or rectally. Lorazepam/diazepam should be immediately
followed by IV phenytoin or fosphenytoin. The patient is intubated and IV sodium
valproate is started if seizures persist. General anaesthesia with a short-acting
barbiturate like propofol or midazolam is induced in case the seizures still persist.
Phenobarbitone can be injected where facilities for intubation are not available.
KEY POINTS
• An epileptic seizure or convulsion is a transient abnormal event caused by a paroxysmal release
of cerebral neurons.
• There are various types of generalised seizures as well as partial or focal seizures.
• Antiepileptic drugs aim to completely control seizures with the fewest side effects possible.
5.2 PARKINSON’S DISEASE
After Alzheimer’s disease, Parkinson’s disease is the second most common degenerative
disease. Its clinical features were first fully documented by James Parkinson in 1817.
This disease, affecting 1% of the population over the age of 65, is characterised by
tremors, rigidity, bradykinesia, and postural instability.
Aetiology
Both genetic and environmental factors have been involved in the development
of Parkinson’s disease. Ingestion or inhalation of MPTP (1-methyl-4-phenyl-
Disorders of Central Nervous System
67
1,2,3,6-tetrahydropyridine), a toxin produced during the manufacture of pethidine by
drug addicts, has produced a severe Parkinsonian state in some cases. A major
component in the pathology of Parkinson’s disease is alpha-synuclein (a mutation in
the gene coding for a synaptic protein).
Pathogenesis
There is a neuronal loss in pigmented brainstem nuclei together with the presence of
eosinophilic inclusion bodies called Lewy bodies in surviving cells. The pars compacta
of the substantia nigra in the midbrain is partially affected. Dopaminergic neurons
within this nucleus project to the striatum, which is therefore deprived of the
neurotransmitter dopamine. There is a loss of over 80% of nigral neurons before
symptoms manifest in Parkinson’s disease.
Cholinergic neurons within the pedunculopontine nucleus also degenerate, leading
to postural instability, difficulty swallowing, and sleep disturbances. Changes occur
within GABA-containing neurons that cause involuntary movements (dyskinesia).
The loss of adrenergic and serotonergic neurons within the locus coeruleus and the
raphe nucleus, respectively, may provide a pathophysiological basis for depression,
which is common in Parkinson’s disease.
Clinical Manifestations
The chief clinical features of Parkinson’s disease (PD) are tremors at rest, rigidity,
akinesia or dyskinesia, and postural instability (represented by the acronym TRAP).
The resting tremor often disappears during sleep and is exacerbated by stress.
Patients may also demonstrate postural tremor (which occurs when arms are
outstretched) or action tremor (which occurs when an object is held). Stiffness
develops that can be felt during limb movements. The masking of facial expressions is
an early symptom of PD and may be misinterpreted as apathy or depression. Akinesia
and dyskinesia are the absence and slowness of movement, respectively. The
combination of dyskinesia and rigidity contributes to a slow and shuffling gait.
Postural instability is a late feature of PD and comprises impairment of righting
reflexes with a tendency to fall. Writing becomes small and barely legible. In addition
to primary motor features, nonmotor symptoms are also very common and affect the
quality of life. Bladder incontinence, constipation, dementia, depression, drooling,
dysphagia, erectile dysfunction, sweating, and temperature intolerances are some of
the examples.
Non-pharmacological Management
Non-pharmacological interventions include education, physical therapy, speech
therapy, and nutrition. Education should be selective as disease progression and
severity, presence of various symptoms, and response to drug therapy differ from
patient to patient. Patients and family members should understand how symptoms
affect personal and social activities and that lifestyle adjustments are needed.
Consultation with a physiotherapist or an occupational therapist is often helpful for
developing exercises for improving safety in the workplace and home. Consultation
with a dietitian and a speech therapist may be helpful as patients often experience
difficulty chewing and swallowing food and have speech problems. Adequate calcium
intake and sunlight exposure can help reduce the long-term risk of osteoporosis and