1. PHARMACOTHERAPY - I PHCY 310
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY - I
PHCY 310
Lecture -9 Neurologic Disorders Cerebrovascular Disorders “Stroke” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
Differentiate between transient ischemic attack(TIA) and stroke,
Describe the risk factors, clinical presentation, pathophysiology and diagnosis of stroke,
Relate the general principles of treating ischemic stroke and hemorrhagic stroke,
Individualize the treatments based on diagnosis, evaluation of therapeutic outcome.

3. Cerebrovascular disease
It is a broad term covering many disorders of the blood vessels of the central nervous system (CNS).
These disorders result from either
inadequate blood flow to the brain (i.e., cerebral ischemia) with subsequent infarction of the involved portion of the CNS Or
from hemorrhages into the parenchyma or subarachnoid space of the CNS and subsequent neurologic dysfunction.

4. Transient ischemic attacks (TIAs) are focal ischemic neurologic deficits lasting less than 24 hours and usually less than 30 minutes.
TIA describes the clinical condition in which a patient experiences a temporary focal neurologic deficit such as slurred speech, aphasia, weakness or paralysis of a limb, or blindness.
Symptoms appear rapidly and are temporary, lasting <24 hours (usually only 2 to 15 minutes).
A cerebral infarction is a permanent neurologic disorder characterized by symptoms similar to a TIA caused by the death of neurons in a focal area of the brain.
Cerebral hemorrhage is a cerebrovascular disorder that involves escape of blood from blood vessels into the brain and its surrounding structures.
Aphasia is a disorder caused by damage to the parts of the brain that control language.  It can make it hard for you to read, write, and say what you mean to say.

5. Stroke is a term used to describe an sudden onset of focal neurologic deficit (insufficiency) that lasts at least 24 hours and is assumed to be of vascular origin.
RISK FACTORS FOR STROKE
Non-modifiable risk factors for stroke include increased age, male gender, race and heredity.
The major modifiable risk factors include hypertension and cardiac disease (e.g., coronary artery disease, heart failure, left ventricular hypertrophy, atrial fibrillation).
Other major risk factors include transient ischemic attacks, diabetes mellitus, dyslipidemia, and cigarette smoking.

6. Risk Factors
Non-modifiable risk factors for stroke include increased age, male gender, race (African American, Asian, Hispanic), family history of stroke, and low birth weight.
The major modifiable risk factors include hypertension and cardiac disease (especially atrial fibrillation).
Other major risk factors include diabetes mellitus, dyslipidemia, alcohol, sickle cell disease, lifestyle factors(obesity, physical inactivity, diet) and cigarette smoking.

7. PATHOPHYSIOLOGY
The neurologic sequelae of cerebral ischemia or infarction directly result from an embolic or thrombotic source.
If the clot is located near infarction, it is considered to be a thrombus; when the clot has migrated to brain from a distant source, it is considered an embolus.
ISCHEMIC STROKE
Ischemic strokes account for 88% of all strokes and are due either to local thrombus formation (Cerebral atherosclerosis) or to emboli that occlude a cerebral artery and causing ischemia and ultimately infarction.
Emboli can arise either from intra- or extra-cranial arteries, 20% of which arise from heart.
In the case of cardiogenic embolism, stasis of blood flow in the atria or
ventricles leads to formation of local clots that can dislodge and travel
through the aorta to the cerebral circulation.
• The final result of both thrombus formation and embolism is arterial
occlusion, decreasing cerebral blood flow and causing ischemia and
ultimately infarction distal to the occlusion.

8. HEMORRHAGIC STROKE
Hemorrhagic strokes account for 12% of strokes, and include subarachnoid hemorrhage, intracerebral hemorrhage, and subdural hematomas.
Subarachnoid hemorrhage may result from trauma or rupture of an intracranial aneurysm or arteriovenous malformation.

9. Intracerebral hemorrhage occurs when a ruptured blood vessel within the brain parenchyma causes formation of a hematoma.
Subdural hematomas are most often caused by trauma.

10. Clinical Presentation
The patient may experience weakness on one side of the body, inability to speak, loss of vision, vertigo, or falling.
Ischemic stroke is not usually painful, but headache may occur and may be severe in hemorrhagic stroke.
Patients usually have multiple signs of neurologic dysfunction on physical examination.
The specific deficits observed depend upon the area of the brain involved.
Hemi- or monoparesis and hemisensory deficits are common.
Clinical Presentation
Hemiparesis is weakness on one side of the body. It is less severe than hemiplegia — the total paralysis of the arm, leg, and trunk on one side of the body. 

11. Diagnosis
Computerized tomography (CT) head scan will reveal an area of hyperintensity (white) in an area of hemorrhage and will be normal or hypointense (dark) in an area of infarction.
The area of infarction may not be visible on CT scan for 24 hours (and rarely longer).
Magnetic resonance imaging (MRI) of the head will reveal areas of ischemia with higher resolution and earlier than the CT scan.
The electrocardiogram will determine whether atrial fibrillation is present.

12. Computerized Tomography (CT) Head Scan
Hemorrhage
Infarction

13. GENERAL PRINCIPLES OF TREATMENT
An accurate diagnosis to differentiate between the ischemic or hemorrhagic stroke is vital.
Initial approach is to ensure adequate respiratory and cardiac support and to determine quickly whether the lesion is ischemic or hemorrhagic based on a CT scan.
Ischemic stroke patients presenting within hours of symptom onset should be evaluated for reperfusion therapy.
Patients with hemorrhagic stroke should be assessed to determine whether they are candidates for surgical intervention through an endovascular or craniotomy approach.
After the hyperacute phase has passed, attention is focused on preventing progressive deficits, minimizing complications, and starting appropriate secondary prevention strategies.

14. PHARMACOLOGIC THERAPY
ISCHEMIC STROKE
Alteplase initiated within 3 hours of symptom onset, reduce the ultimate disability due to ischemic stroke.
A head CT scan must be obtained to rule out hemorrhage before beginning therapy.
Anticoagulant and antiplatelet therapy should be avoided for 24 hours, and the patient should be monitored closely for hemorrhage.
Aspirin 50 to 325 mg/day started between 24 and 48 hours after completion of alteplase has been shown to reduce long-term death and disability.
Aspirin, clopidogrel, and extended-release dipyridamole plus aspirin are all considered first-line antiplatelet agents.

15. Combination of aspirin and clopidogrel can only be recommended in patients with ischemic stroke and a recent history of myocardial infarction or other coronary events and then only with ultra-low-dose aspirin to minimize bleeding risk.
Elevated blood pressure is common after ischemic stroke, and its treatment is associated with a decreased risk of stroke recurrence.
The Joint National Committee and AHA/ASA guidelines recommend an angiotensin- converting enzyme inhibitor and a diuretic for reduction of blood pressure in patients with stroke or TIA after the acute period (first 7 days).
Angiotensin II receptor blockers have also been shown to reduce the risk of stroke and should be considered in patients unable to tolerate ACEIs.

16. Use of statins to achieve a low-density lipoprotein cholesterol concentration of less than 100 mg/dL.
Low-molecular-weight heparin or low-dose subcutaneous unfractionated heparin (5,000 units twice daily) recommended for prevention of deep venous thrombosis in hospitalized patients with decreased mobility due to stroke.
Low-molecular-weight heparin or
low-dose subcutaneous unfractionated
heparin
(5,000 units twice daily) is recommended for prevention of
deep venous thrombosis in hospitalized patients with decreased mobility
due to stroke and should be used in all but the most minor strokes.

17. PHARMACOLOGIC THERAPY
HEMORRHAGIC STROKE
Managing blood pressure, increased intracranial pressure, and other medical complications in acutely ill patients in neurointensive care units should be followed.
Vasospasm of the cerebral vasculature is thought to be responsible for the delayed ischemia and occurs between 4 and 21 days after the bleed.
The calcium channel blocker nimodipine is recommended to reduce the incidence and severity of neurologic deficits resulting from delayed ischemia.
Nimodipine 60 mg every 4 hours should be initiated on diagnosis and continued for 21 days in all subarachnoid hemorrhage patients.

18. EVALUATION OF THERAPEUTIC OUTCOMES
Patients with acute stroke should be monitored intensely for the development of neurologic worsening, complications of thromboembolism or infections, and adverse effects from pharmacologic or non-pharmacologic interventions.
Question to Answer
Inclusion and Exclusion Criteria for Alteplase Use in Acute Ischemic Stroke
Monitoring Hospitalized Acute Stroke Patients
Reference:
Richard A. Helms, David J. Quan, Eric T. Herfindal, Dick R.Gourley. Textbook of Therapeutics. Drug and Disease Management. 8th Edition. Lippincott Williams and Wilkins.
Barbara G.Wells, Joseph T. Dipirio et al. Pharmacotherapy Hand Book-7th Edition. McGraw-Hill (2009).