Assignment 2 Pathophysiology and Pharmacology STROKE Submitted By

Assignment 2
Pathophysiology and Pharmacology
STROKE
Submitted By: Ruja SubbaStudent ID: 2194785
Tutor: Beatrice ReschSubmitted On: 19th April 2018
Word Count: 1973
The case world involves Greta Balodis, 75 year-old widow diagnosed as right-sided Cerebro Vascular Accident (CVA) or Stroke and had a medical condition of atrial fibrillation (AF) who returned home from rehabilitation. She had medical history of transient- ischemic attack (TIA) 5 years back, hypertension and had 3 falls in the last 6 months. Greta was in the high risk of CVA due to all her medical history. In this assignment, the pathophysiology of CVA will be explained in brief and the pharmacology of drugs prescribed in her treatment will be described in depth explaining the pharmacokinetics, pharmacodynamics, doses, its indications and contraindications. Aspirin, clopidogrel and digoxin are the drugs that are prescribed at the time of discharge which she will be taking life long as indicated. The signs and symptoms that she presents will only be stated as the pharmacology of the drugs are not related to the symptoms she presents with as they are managed by regular physiotherapy.
CVA/ Stroke
Pathophysiology
Ischemic stroke presents in the form of thrombotic and embolic stroke. Due to the certain thrombus or emboli, there will be completely or partially discontinuation of blood supply in the brain. Thus there will be lower oxygen supply and brain depends on aerobic metabolism which makes brain tissue potential to ischemic effects. Inflammation occurs in the affected part of brain as a result the part goes sudden death (Deb et al. 2009).
Signs and Symptoms
The clinical symptoms of stroke are face drooping, unclear speech, and weakness of extremities, blurred vision and sudden severe headache, dizziness (Kanyal 2015). Among those symptoms, Greta has face drooping, weakness of left sided extremities, nausea and dizziness. These clinical symptoms have been managed by continuous physiotherapy.

Pharmacology
Aspirin:
Aspirin falls under the Salicylates groups of drug and is anti- platelet drug used for pain relief and aches. It belongs to non- steroidal anti-inflammatory drugs (NSAIDs) class. It is also used for secondary prevention of vascular disease as it reduces the risk of stroke and other heart diseases. Aspirin is used as prophylaxis as it does not dissolve the formed clots but only helps to prevent new clots formation (Caplan 2018). In the case of Greta, Aspirin is used for prevention of further stroke.

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Pharmacodynamics
Aspirin is anti-platelet agent known for its anti-platelet aggregation which inhibits the synthesis of prostaglandin and produces analgesic and anti-inflammatory activity on peripheral and central nervous system (Sankar et al. 2012). The aggregation of platelets is promoted by synthesis of Thromboxane A2 (TXA2). Aspirin causes irreversible inactivation of Cyclooxygenase 1 (COX-1), a key platelet enzyme which produces TXA2 in platelets by diffusing it into the COX channel resulting in suppression of platelets aggregation (Lehne 2010). Furthermore, aspirin has unique vasodilation effect which lowers the blood pressure. This effect is independent to COX inhibition. Vasodilatation effect of aspirin is due to the inhibition of critical components (RhoA/Rho-kinase) that are responsible for vascular tone regulation (Ying et al. 2009). Greta being a hypertensive patient, aspirin helps to lower and regulate her blood pressure.

Pharmacokinetics
When taken in oral form, it is rapidly absorbed in upper gastro intestinal tract. The absorption of aspirin follows first-order kinetics in which absorption of half -life occurs within 5-6 minutes. The chemical reaction to change in salicylic acid in reaction to water occurs in the liver and 68% of Aspirin reaches to systemic circulation (Hall & Mazer 2011). Furthermore, salicylic acid binds with serum albumin and undergoes distribution to tissues and fluids all over the body and the central nervous system. The salicylic acid and its metabolites are excreted by the kidneys (Lehne 2010).

Dose
The dose of aspirin has a wide range varying from 30-1300mg per day for the prevention of ischemic stroke in patients who had previous history of TIA or stroke (Ansara et al. 2010). Intake of 81 mg of aspirin daily produces successful effect on inhibition of platelet cyclooxygenase to suppress platelet function (Lehne 2010). Aspirin 75–150 mg is indicated for the long-term treatment of cerebro- vascular diseases (Hankey and Eikelboom 2003). Greta has been ordered 100 mg of aspirin to have therapeutic effect. The effectiveness of high dose of 325mg per day and low dose of 50-166mg per day are similar for the prevention of vascular diseases such as stroke. Meanwhile, it is also important to take into consideration that high dose of aspirin are associated with various adverse effects such as gastrointestinal bleeding (Dickerson, Carek & Quattlebaum 2007). In the case study, Greta has been prescribed low dose aspirin thus preventing from bleeding disorders.
Side effects:
The use of aspirin can result in some serious side effects, such as Gastro- intestinal bleeding and ulcers, renal impairment, severe stomach pain or problems in hearing such as tingling ears (Lehne 2010). GI upset, heartburn, drowsiness or headache comes under less serious side effects and nausea and vomiting can occur when orally taken (Hankey and Eikelboom 2003). Among above mentioned side effects, Greta is having nausea, headache and dizziness which are less serious that can be reduced by taking the drug with food or with full glass of water.
Indication
Aspirin can be used as secondary prevention for those who had history of Transient- Ischemic attack (TIA) or stroke (Hung 2003). In vascular diseases, aspirin are used as prophylactic to reduce morbidity as well as mortality (Lehne 2010). In the case of Greta, low dose aspirin inhibits thromboxane formation thus preventing platelet aggregation. In contrast to the action of all other NSAIDs, as explained in pharmacodynamics, aspirin has vasodilatation effect. Greta being a hypertensive patient, this drug maintains her blood pressure.

Contraindication
It is contraindicated to those patients with bleeding disorders and severe ulceration in gastro intestinal (GI) tract. The use of aspirin should be stopped a week prior to major surgery except the condition if there is need of antithrombotic (Hung 2003).
Clopidogrel:
Clopidogrel is anti-platelet drug and falls under adenosine diphosphate (ADP) receptor antagonist group of drug that is used as the primary drug for the prevention of vascular diseases (Hall & Mazer 2011).
Pharmacokinetics
After oral administration, Clopidogrel is absorbed from gastrointestinal tract in the presence and absence of food which approximately 50% reaches the site for physiological action (Lehne 2010). The absorbed drug undergoes hydrolysis to form carboxylic acid which is inactive metabolites that are converted in active form metabolites in the liver. In the liver, clopidogrel is metabolized into short lived active metabolite (R130964) which is responsible for platelet aggregation (Hall & Mazer 2011). The drug is equally eliminated by kidneys in the form of feces and urine.

Pharmacodynamics
The anti-thrombotic effect of Clopidogrel is associated with the variability of drug absorption and hepatic metabolism. The active metabolites formed in liver bind to the platelet P2Y12 receptors and irreversibly inhibit ADP receptor thus preventing ADP induced platelet aggregation. The possibility of returning of previous form of platelet activity increases once clopidogrel therapy is discontinued (Hall & Mazer 2011).

Dose
Clopidogrel 300-600mg orally as loading dose is capable of producing adenosine disphospate inhibition which prevents in platelet formation and aggregation that takes 2 hours to show the significant effect by reaching the peak level after 6 hours of administration whereas 75mg is to be repeated daily as maintenance dose to get platelet inhibition action (Hankey and Eikelboom 2003). Doses need not to be changed for elderly patients or for those who has impaired renal function (Lehne 2010). Greta being elderly patient was ordered clopidogrel 75 mg per day as she is taking the drug for long term as maintenance dose which is the appropriate dose in her case.

Side Effects
Despite of various clinical benefits in patients with vascular diseases, there are some side effects of clopidogrel and few of them may be life threatening (Almsherai, Mclachlan &Sharef 2007). The common side effects are diarrhea, skin rashes and dyspepsia. The adverse effect of clopidogrel is increased risk of GI bleeding (Lehne 2010). If the side effects persist, medical consultation should be taken and if symptoms such as severe abdominal pain, uncontrolled bleeding gum and nose, severe headache, purple skin patches appeared, urgent medical help should be taken (Hall & Mazer 2011). None of these side effects are found in Greta.

Indication
Patient who has history of previous stroke and other vascular diseases can take clopidogrel. It is indicated for those who had TIA to prevent from recurrent stroke (Rang & Dale 2007, pp. 305). Patient with atrial fibrillation (AF), are in high risk of formation of thrombus therefore antiplatelet drugs inhibit the process of thrombus formation by preventing platelet adhesion and reduces the risk of ischemic stroke (Karlson, Jensen & Jakobsen 2016). Greta being an elderly female patient of AF and previous TIA is in the risk of another stroke, clopidogrel is prescribed for her as prophylactic to prevent thrombus formation. The therapeutic effect of clopidogrel is optimal when taken with aspirin (Rang & Dale 2007). Greta is taking both clopidogrel and aspirin.

Contraindication
As clopidogrel are anti-platelet drugs those who are have bleeding disorders and other gastro intestinal diseases should not take this medicine.
Digoxin:
Digoxin is cardiac glycosides which are also known as digitalis glycosides. It is frequently used to treat atrial fibrillation by decreasing the ventricular rate (Reynolds 2014).

Pharmacokinetics
When orally taken more than half (70-80 %) of digoxin is absorbed as soon as it reaches the small intestine. In the proximal part of small intestine it binds with serum albumin. It is distributed extensively in the muscles of heart and kidney with high concentration however the largest storage occurs in skeletal muscles. The main route of elimination is by renal excretion in which almost all of the digoxin is eliminated in the form of urine whereas 20-28% is excreted by non- renal route. There is no or minimal hepatic metabolism of digoxin (Lehne 2010, pp. 522-527).
Pharmacodynamics
Digoxin works by increasing the force of myocardial contraction and cardiac output consequently regulating the rate and rhythm of heart. Digoxin causes accumulation of Ca++ in the cell of myocardium by inhibiting the enzyme called sodium potassium adenosine triphospate (Na+, K+ -ATPase) that is responsible for movement of sodium, potassium and calcium ions in and out of the cell thereby enhancing force of contraction. When digoxin inhibits the Na+, K+ -ATPase, it prevents pumping of K+ ions and bulging of Na+ ions as a result intracellular K+ level decreases and Na+ increases that ultimately gives rise to intracellular Ca++ ions by sodium potassium exchanger. Accumulated calcium ions increase the force of myocardial contraction by facilitating the myocardial contractile proteins (actin and myosin) (Lehne 2010, pp. 522-523). Furthermore, when the force of contraction and cardiac output is increased, atrial pressure increases as a result sympathetic neuron transmission to the heart and blood vessels is reduced to maintain the blood pressure level (baroreceptor reflex) thus maintaining the heart rates and reducing irregular heartbeats (Lehne 2010, p.524).
Dose
For rapid action in atrial fibrillation, digoxin 10-15 microgram per kg is taken as loading dose. The maintenance dose is 0.125-0.5mg per day which may increase per weeks as per the basis of clinical response of patient and the results of drug level in serum and its toxicity (Glover et al. 2016). Greta is taking digoxin 125 microgram daily which is appropriate for her maintenance dose.
Side Effects
The common side effects of digoxin are nausea, vomiting, headache and visual disturbances. Fatigue, GI upset, sinus bradycardia, psychosis and confusion may occur after the digoxin therapy (Lehne 2010). Greta has only nausea which is a common side effect of digoxin.

Indication
Digoxin is indicated in patient with problems in heart rate and rhythm. Patient of cardiac arrhythmias, atrial fibrillation can be treated with digoxin. Greta as she was diagnosed with AF, she has irregular heart rate and rhythm. Due to the inotropic properties of digoxin, her irregular heartbeats can be regulated.

To sum up, relating this assignment with case study of Greta, stroke is the sudden dysfunction of brain due to the inadequate blood supply. In her treatment, two anti- platelet drugs aspirin and clopidogrel was given for further stroke prevention and digoxin was ordered to treat atrial fibrillation. Regular rehabilitation therapy is helping to regain her lost physical disability. The medications should be taken life long with special consideration as they can cause various adverse effects.

REFERENCES
Ansara, A, Nisly, S, Arif, S, Koehler, J & Nordmeyer, S 2010, ‘Aspirin Dosing for the Prevention and Treatment of Ischemic Stroke: An Indication-Specific Review of the Literature’, Scholarship and Professional Work – COPHS, viewed 22 May 2018, <https://digitalcommons.butler.edu/cgi/viewcontent.cgi?referer=https://www.bing.com/&httpsredir=1&article=1040&context=cophs_papers>.

Almsherqi, Z, McLachlan, C & Sharef, S 2007, ‘Non-bleeding side effects of clopidogrel: Have large multi-center clinical trials underestimated their incidence’, International Journal Of Cardiology, volume 117, issue 3, Pages 415–417, viewed 16 April 2018, <https://doi.org/10.1016/j.ijcard.2006.05.058>.

Deb, P, Sharma, S & Hassan, K 2009, ‘Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis’, The Official Journal of the International Society for Pathophysiology , volume 17, Issue 3, page 197-218, <https://doi.org/10.1016/j.pathophys.2009.12.001>.

Dickerson, L, Carek, P, & Quattlebaum, R 2007, ‘Prevention of Recurrent Ischemic Stroke’, Trident Medical Center/Medical University of South Carolina Family Medicine Residency Program, Charleston, South Carolina, viewed 22 May 2018, <https://www.aafp.org/afp/2007/0801/p382.pdf>.

Glover, N, Mink, M, Yarema, M & Chuang, R 2016, ‘Digoxin toxicity Case for retiring its use in elderly patients?’, Canadian Family Physician, Volume 62, viewed 21 May 2018, <http://www.cfp.ca/content/cfp/62/3/223.full.pdf>.

Hall, R & Mazer, D 2011, ‘Antiplatelet Drugs: A Review of Their Pharmacology and Management in the Perioperative Period’, ANESTHESIA & ANALGESIA, Volume 112, Number 2, viewed 16 April,< https://ccme.osu.edu/RSSeriesBrochure/22851%20-%20Antiplatelet%20Drugs.pdf>.
Hankey, G & Eikelboom, J 2003, ‘Antiplatelet drugs’, The Medical Journal Of Australia, volume 178, Issue 11, viewed 16 april 2018, <https://www.mja.com.au/journal/2003/178/11/antiplatelet-drugs>.

Hung, J 2003, ‘Aspirin for cardiovascular disease prevention’, The medical Journal of Australia, volume 179, Issue 3, pp: 147-152, viewed 13 April 2018 <https://www.mja.com.au/journal/2003/179/3/aspirin-cardiovascular-disease-prevention>.

Kanyal, N 2015, ‘The Science of Ischemic Stroke: Pathophysiology ; Pharmacological Treatment’, International Journal of Pharma Research & Review, volume 4, issue 10, page 65-84, viewed 16 April 2018, <http://www.rroij.com/open-access/the-science-of-ischemic-stroke-pathophysiology–pharmacological-treatment-.pdf>.

Karlson, WK, Jensen, JS & Jakobsen, JC 2016, ‘Antiplatelet therapy for preventing stroke in people with atrial fibrillation’, Cochrane Database of Systemic Review, Issue 11, viewed 23 May 2018, <http://www.cochrane.org/CD012428/STROKE_antiplatelet-therapy-preventing-stroke-people-atrial-fibrillation>.

Lehne, RA 2010, Pharmacology for Nursing Care, 7th edition, Elsevier Health Science, St Louis, Missouri, USA. Reynolds, M 2014, ‘Outcomes with Digoxin in Atrial Fibrillation’, Journal Of American College of Cardiology, volume 64, Number 7, viewed on 17 April 2018, <http://www.onlinejacc.org/content/64/7/669>.

Sankar, R, Dachinamoorthi ,D & Shekar,K 2012, ‘A Comparative Pharmacokinetic study of Aspirin Suppositories and Aspirin Nanoparticles Loaded Suppositories’, Clinical Pharmacology & Biopharmaceutics, viewed 10 April 2018, <https://www.omicsonline.org/open-access/a-comparative-pharmacokinetic-study-of-aspirin-suppositories-and-aspirin-nanoparticles-loaded-suppositories-2167-065X.1000105.pdf>.

Ying, Z, Giachini, F, Tostes, R & Webb, R 2009, ‘Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation’, European Society of Cardiology, Cardiovascular Research, volume 83, viewed 23 May 2018, <https://www.researchgate.net/publication/24191299_Salicylates_dilate_blood_vessels_through_inhibiting_PYK2-mediated_RhoARho-kinase_activation>.