Definition, Epidemiology, Etiology, Classification, Pathophysiology, Clinical presentation, Risk factors, Diagnosis and Management of stroke (Pharmacotherapeutics-III) Pharm.D

1. STROKE
T. SOUJANYA
PHARM.D

2. OUTLINE:
• Definition
• Epidemiology
• Classification
• Etiology
• Types of stroke
• Pathophysiology
• Clinical presentation
• Risk factors
• Diagnosis
• Management

3. DEFINITION:
According to WHO, stroke is defined as a neurological deficit of
cerebrovascular cause that persists beyond 24 hours or is interrupted by
death within 24 hours. Therefore, stroke can be explained as death or
dysfunction of brain tissue due to occlusion or haemorrhage of brain’s
arteries. The pattern of resulting neurological damage differs according
to whether the supply to the posterior or anterior artery has interrupted.
Transient ischaemic attack (TIA):
This means a focal deficit, such as a weak limb, aphasia or loss of
vision lasting from a few seconds to 24 hrs. there is complete recovery,
the attack is usually sudden. TIAs have a tendency to recur, and may
herald thromboembolic stroke.

4. EPIDEMIOLOGY:
There are currently 4.6 million stroke survivors in the United States,
stroke is the leading cause of adult disability.
Approximately 20% of patients in nursing homes have had a stroke
and stroke is also a leading diagnosis in inpatient rehabilitation.
Stroke risk is increased above that of the general population in the
elderly male individuals and in African-Americans.1 In addition,
geographic disparity in stroke incidence exists, such that several areas
of the southeastern United States have stroke mortality rates more than
twice that of the national average.
This phenomenon, originally describing areas of the coastal Carolinas
and Georgia, has been named the “Stroke Belt.”

5. CLASSIFICATION:
1. Clinical classification:
• Transient Ischaemic attack (TIA)
• Progressing stroke
• Completed stroke
2. Classification by mechanism:
• Ischaemic stroke (85%)
• Haemorrhagic stroke (15%)

6. ETIOLOGY:
1. Ischaemic stroke: Thrombus formation, embolic phenomenon,
atherosclerosis.
2. Haemorrhagic stroke:
a) Sub arachnoid haemorrhage: Trauma, rupture of intracranial
aneurysm, rupture of arteriovenous malformation.
b) Intracerebral haemorrhage: Trauma, disruption of bridging vein.
c) Subdural haematoma: Blood vessel rupture within brain
parenchyma, uncontrolled high blood pressure.

7. TYPES OF STROKE:
Strokes can be classified into
two main categories, including the
following:
1. Ischaemic strokes (incidence-
85%)-strokes caused by blockage
of an artery.
2. Haemorrhagic stroke (incidence
15%)-strokes caused by bleeding.

8. 1. ISCHAEMIC STROKE:
An ischaemic stroke occurs when a blood vessel
that supplies the brain becomes blocked or “clogged”
and impairs blood flow to the part of the brain. The
brain cells and tissues begin to die within minutes from
lack of oxygen and nutrients. The area of tissue death
is called an “infarct”.
About 85% of stroke fall into this category.
Ischaemic strokes are further divided into two groups
including the following:
a) Thrombotic stroke
b) Embolic stroke

9. CONTD…
a) Thrombotic stroke:
It is caused by a blood clot
that develops in the blood vessels
inside the brain.
b) Embolic stroke:
It is caused by blood clot or
plaque debris that develops
elsewhere in the body and then
travels to one of the blood vessels in
the brain via the blood stream.

10. 2. HAEMORRHAGIC STROKE:
Haemorrhagic strokes occur when a blood vessel that supplies the
brain ruptures and bleeds. Haemorrhagic strokes are divided into three
main categories, including the following:
a) Subarachnoid haemorrhage
b) Intracerebral haemorrhage
c) Subdural haematomas

11. CONTD…
a) Subarachnoid haemorrhage:
It occurs when blood enters the subarachnoid space (where
cerebrospinal fluid is housed) owing to either trauma, rupture of an
intracranial aneurysm, or rupture of an arteriovenous malformation
(AVM).
b) Intracerebral haemorrhage:
It occurs when a blood vessel ruptures within the brain
parenchyma itself, resulting in the formation of a hematoma. These
types of haemorrhages very often are associated with uncontrolled high
blood pressure and sometimes antithrombotic or thrombolytic therapy.

12. CONTD…
c) Subdural haematomas:
It refers to collections of blood below the dura (covering of the
brain), and they are caused most often by trauma.
Haemorrhagic stroke, although less common, is significantly
more lethal than ischemic stroke, with 30-day case-fatality rates that are
two to six times higher.

13. PATHOPHYSIOLOGY:
Brain requires continuous supply of O2 and glucose for neurons to
function. If blood flow is interrupted neurologic metabolism is altered in
30 seconds, metabolism stops in 2 minutes, cell death occurs in 5
minutes. Atherosclerosis is a major cause of stroke that can lead to
thrombus formation and contribute to emboli.
In carotid atherosclerosis, progressive accumulation of lipids and
inflammatory cells in the intima of the affected arteries, combined with
hypertrophy of arterial smooth muscle cells, results in plaque formation.
Eventually, sheer stress may result in plaque rupture, collagen exposure,
platelet aggregation, and clot formation.

14. CONTD…
The clot may remain in the vessel, causing local occlusion, or
travel distally as an embolism, eventually lodging downstream in a
cerebral vessel. In the case of cardiogenic embolism, stasis of blood in
the atria or ventricles of the heart leads to the formation of local clots
that can become dislodged and travel directly through the aorta to the
cerebral circulation.
The final result of both thrombus formation and embolism is an
arterial occlusion, decreasing cerebral blood flow and causing ischemia
distal to the occlusion.

15. Accumulation of lipids and inflammatory cells in intima of affected arteries
Carotid atherosclerosis
Hypertrophy of arterial smooth muscles
Plaque formation
Sheer stress may result in
Plaque rupture, collagen exposure, platelet aggregation, clot formation
Clot rupture
Embolus
Arterial occlusion
Reduced blood flow
“Ischaemia/ischaemic stroke”
Cell necrosis

16. CLINICAL PRESENTATION:
General:
The patient may not be able to reliably report the history owing to
cognitive or language deficits. A reliable history may have to come from
a family member or another witness.
Symptoms:
The patient may complain of weakness on one side of the body,
inability to speak, loss of vision, vertigo, or falling. Ischemic stroke is
not usually painful, but patients may complain of headache, and with
haemorrhagic stroke, it can be very severe.

17. CONTD…
Signs:
• Patients usually have multiple signs of neurologic dysfunction, and the
specific deficits are determined by the area of the brain involved.
• Hemi- or monoparesis occurs commonly, as does a hemisensory
deficit.
• Patients with vertigo and double vision are likely to have posterior
circulation involvement.
• Aphasia is seen commonly in patients with anterior circulation strokes.
• Patients also may suffer from dysarthria, visual field defects, and
altered levels of consciousness.

18. RISK FACTORS:
i) Non modifiable risk factors:
• Age (more than 60 years)
• Gender (women are more likely to die)
• Race (African Americans)
• Heredity

19. CONTD…
ii) Modifiable risk factors:
• Asymptomatic carotid stenosis or other artery diseases
• Diabetes mellitus, atrial fibrillation and other heart disease
• Heavy alcohol consumption, smoking, stress
• Hypercoagulability, hyperlipidaemia (high blood cholesterol)
• Hypertension
• Oral contraceptive use
• Physical inactivity and obesity
• Sickle cell disease

20. DIAGNOSIS:
Laboratory tests:
Tests for hypercoagulable states (proteins S and C deficiency,
antiphospholipid antibody).
Other diagnostic tests:
1. CT scan: reveals an area of hyperintensity (white) in the area of
haemorrhage and will be normal or hypointense (dark) in the area of
infarction. The CT scan may take 24 hours (and rarely longer) to reveal the
area of infarction.
2. MRI: reveals areas of ischemia with higher resolution and earlier than the
CT scan.
3. Diffusion-weighted imaging (DWI): reveals an evolving infarct within
minutes.
4. Carotid Doppler (CD): determines whether the patient has a high degree of
stenosis in the carotid arteries supplying blood to the brain (extracranial
disease).

21. CONTD…
5. Electrocardiogram (ECG): determines whether the patient has atrial
fibrillation, a potent etiologic factor for stroke.
6. A transthoracic echocardiogram (TTE): determines whether valve
abnormalities or wall motion abnormalities are sources of emboli to the
brain.
7. A transoesophageal echocardiogram (TEE): more sensitive test for
thrombus in the left atrium. It is effective at examining the aortic arch
for atheroma, a potential source of emboli.
8. Transcranial Doppler (TCD): determines whether the patient is
likely to have intracranial arterial sclerosis (e.g., middle cerebral artery
stenosis).

22. MANAGEMENT OF STROKE:
Goals of treatment:
The goals of treatment of acute stroke are:
1. To reduce the ongoing neurologic injury and decrease mortality and
long-term disability.
2. Prevent complications secondary to immobility and neurologic
dysfunction.
3. Prevent stroke recurrence

23. GENERALAPPROACH FOR TREATMENT:
1. The initial approach to the patient with a presumed acute stroke is to
ensure that the patient is supported from a respiratory and cardiac
standpoint.
2. Quickly determine whether the lesion is ischaemic or haemorrhagic based
on a CT scan.
3. Ischaemic stroke patients presenting within hours of the onset of their
symptoms should be evaluated for reperfusion therapy.
4. Patients with elevated blood pressure should remain untreated unless their
blood pressure exceeds 220/120 mm Hg or they have evidence of aortic
dissection, acute myocardial infarction (AMI), pulmonary edema, or
hypertensive encephalopathy.
5. If blood pressure is treated, short acting parenteral agents, such as
labetalol, nicordipine and nitroprusside are favoured.

24. NON-PHARMACOLOGICAL TREATMENT:
1. Ischaemic stroke:
• In certain cases of ischaemic cerebral edema owing to a large infarction,
craniectomy to release some of the rising pressure has been tried.
• In cases of significant swelling associated with a cerebellar infarction,
surgical decompression can be lifesaving.
• In secondary prevention, carotid endarterectomy of an ulcerated and/or
stenotic carotid artery is a very effective way to reduce stroke incidence and
recurrence in appropriate patients.
• In patients in whom the risk of endarterectomy is thought to be excessive,
carotid stenting may be effective in reducing recurrent stroke risk but is less
invasive.

25. CONTD…
2. Haemorrhagic stroke:
In patients with subarachnoid haemorrhage owing to a ruptured
intracranial aneurysm or an AVM, surgical intervention to either clip or
ablate the offending vascular abnormality substantially reduces
mortality owing to rebleeding.

26. PHARMACOLOGICAL TREATMENT:
1. Thrombolytics: Streptokinase, urokinase, alteplase, reteplase,
tenecteplase.
2. Anti platelet agents: Aspirin, dipyridamole, clopidogrel,
ticlopidine.
3. Oral anticoagulants: Warfarin
4. HMG CoA reductase inhibitors: Atorvastatin, rosuvastatin,
simvastatin.
5. ACE inhibitors: Perindopril, enalapril, captopril.
6. Angiotensin receptor blockers: Losartan.

27. 1. THROMBOLYTICS:
MOA:
They promote the conversion of plasminogen to plasmin. Plasmin
degrades fibrin into fibrin degradation products and thus rapidly
dissolve the blood clot.
Uses:
They are commonly used in the treatment of stroke, peripheral
arterial occlusion, acute MI, deep-vein thrombosis, pulmonary
embolism etc.

28. CONTD…
ADRs:
Bleeding due to activation of circulating plasminogen, other
effects include nausea, vomiting, hypotension, anaphylactic reactions,
cardiac dysrhythmias can be dangerous.
Dose:
• Streptokinase: 7.5-15 lac IU infused over 1 hour
• Alteplase (rt-PA): 15mg IV bolus inj, followed by 50mg over 30 min,
then 35mg over the next 1 hour,
• t-PA (tissue plasminogen activator): 0.9mg/kg IV (maximum 90kg)
over 1 hour in selected patients within 3 hours of onset.

29. 2. ANTI PLATELET AGENTS:
MOA:
Aspirin irreversibly inhibits COX1, the enzyme which is
responsible for the conversion of arachidonic acid to thromboxane
whereas clopidogrel and ticlopidine inhibits ADP pathway i.e., inhibits
activation of ADP receptors on platelets.
Uses:
They are commonly used in the treatment of transient ischaemic
attack (TIA), acute MI, unstable angina, angioplastic coronary
interventions, prosthetic heart valves etc.

30. CONTD…
ADRs:
Common effects include nausea, vomiting, diarrhoea, serious
adverse effects are severe neutropenia, fatal agranulocytosis with
thrombocytopenia has occurred within the first 3 months of therapy.
Dose:
• Aspirin: 75-325mg OD
• Dipyridamole + aspirin: 200mg + 25mg 1 capsule BID
• Clopidogrel: 75mg OD
• Ticlopidine: 250mg BID

31. 3. ORALANTICOAGULANTS:
MOA:
They interfere with the synthesis of vitamin K dependent clotting
factors in liver. Clotting factors II, VII, IX and X are synthesized in liver
as inactive proteins. These factors are rich in glutamic acid residues and
are carboxylated in liver where vitamin K acts as a cofactor. Vitamin K
is converted to inactive epoxide from by oxidation and is regenerated to
its active form by epoxide reductase enzyme. Warfarin is structurally
similar to vitamin K, hence it competitively inhibits the synthesis of
vitamin K-dependent factors by inhibiting epoxide reductase enzyme
and thus produces anticoagulant effect.

32. CONTD…
Uses:
They are commonly used in the treatment of cerebrovascular
diseases, deep vein thrombosis and pulmonary embolism, myocardial
infarction, unstable angina, atrial fibrillation, disseminated intravascular
coagulation etc.
ADRs:
Bleeding, skin necrosis, purple toe syndrome, teratogenicity,
osteoporosis, other effects include agranulocytosis, leukopenia,
diarrhoea, nausea, anorexia etc.
Dose:
• warfarin-5mg daily, maintenance dose: 2-10mg for 2 days.

33. 4. HMG COA REDUCTASE INHIBITORS:
MOA:
Statins competitively inhibit HMG-CoA reductase, the rate
limiting step in cholesterol biosynthesis (i.e., the conversion of HMG-
CoA to mevalonate). This results in a decreased blood LDL and VLDL
levels. Thus, statins are very effective in reducing the risk of stroke in
patients with coronary artery disease and elevated plasma lipids. They
also reduce triglycerides (TGs) and increase HDL cholesterol levels in
plasma.

34. CONTD…
Uses:
They are commonly used in the treatment of stroke, primary
hyperlipidaemias with increased LDL and cholesterol levels. They are
also used in secondary hyperlipidaemias due to diabetes or nephrotic
syndrome.
ADRs:
Hepatotoxicity, headache, sleep disturbances myopathy, anorexia,
nausea, vomiting, diarrhoea etc.
Dose:
• Atorvastatin: 10-20mg OD
• Rosuvastatin: 10mg OD
• Simvastatin: 40mg OD

35. 5. ACE INHIBITORS:
MOA:
They mainly act by lowering blood pressure by reducing
peripheral vascular resistance (PVR). They block the angiotensin
converting enzyme (ACE) that cleaves angiotensin I to from the potent
vasoconstrictor angiotensin II. ACE inhibitors decrease angiotensin II
and increase bradykinin levels. They also decrease the secretion of
aldosterone, resulting in decreased sodium and water retention.

36. CONTD…
Uses:
They are commonly used in the treatment of hypertension,
congestive cardiac failure, acute MI, diabetic nephropathy, stroke etc.
ADRs:
Cough, angioedema, proteinuria, teratogenic effect, neutropenia,
rashes, itching, loss of sensation, nausea etc.
Dose:
• Perindopril: 4mg OD
• Enalapril: 5mg OD
• Captopril: 25mg OD

37. 6. ANGIOTENSIN RECEPTOR BLOCKERS
(ARBs):
MOA:
ARBs competitively inhibit the binding of angiotensin II to AT1
receptor subtype and block its effects. ARBs produce effects similar to
those of ACE inhibitors.
Uses:
They are used in hypertension, CCF, MI, diabetic nephropathy.
They are mainly indicated in patients who develop cough with ACE
inhibitors.

38. CONTD…
ADRs:
They are better tolerated as compared to ACE inhibitors. They
cause headache, hypotension, weakness, rashes, rashes, nausea,
vomiting and teratogenic effects. They are less likely to produce cough
or angioedema than ACE inhibitors.
Dose:
• Losartan-50mg OD

39. SURGICAL MANAGEMENT:
1. Carotid endarterectomy
2. Craniotomy
3. Extracranial-intracranial arterial bypass

40. PREVENTION:
1. Diet (low fat, high fibre)
2. Quit smoking and alcohol intake
3. Controlling diabetes
4. Maintain healthy weight
5. Exercise
6. Avoiding illicit drugs

41. REFERENCE/BIBLIOGRAPHY:
Textbook of Pharmacotherapy: A
Pathophysiologic approach by
Joseph T. Dipiro.