Module 4 Flashcards
(67 cards)
1
Q
WHAT IS A GENERAL OVERVIEW OF HYPERTENSION
A
- Chronically high blood pressure
- Prevealent in Cardiovascaulr idsease in NA
- Occurs in 24% of canadians
- Kidneys
○ Damage to blood vessels that supply the kidneys are increase the likelihood of kidney failure - Heart
○ Damag to blood vessels that supply heart lead to heart failure or angina or stroke - Brain
○ Damag to blood vessels to brain may lead to demention
Goal of these drugs is to decrease blood pressure
2
Q
WHAT IS NORMAL BLOOD PRESSURE
A
- Depends on age
- Young adult it is 120/80
- 120 during systole which is when the heart is contracting
And 80 mmHg during diastole which is between contractions
3
Q
HOW IS BLOOD PRESSURE REGLUATED
A
- Amount of blood pumped by the heart
- And the resistance of the peripherial artterioles (Peripheral vascular resistance or PVR)
- Cardiac output
○ CO = HR x SV
○ Volume of blood that is pumped by each ventricle per unit time
○ Same for left and right side of the heart - Heart rate
○ Heartbeats per unit time. Resting is between 60-100 - Stroke volume
○ Amount of blood pumped from ventricle per unit time
○ At rest should be 70/mL/beat - Arterial blood pressure is calculkated with
BP = CO * TPR (total periphgeral resistance) - Resistance of arterioles depends on the contriction or dillation of the blood vessles
- Depends on the autonomic nervous system
- Capacitance venules - How much blood is returned
- Heart - Sympathetic nervous system increases heart rate and Blood pressure. Decrease does the opposite
Volume of blood is controlled by kidneys - Increasing the volume increases pressure and the opposite
4
Q
WHAT IS THE CLASSIFICATION OF HYPERTENSION
A
- Usually silent and the person is not always aware
- Evelated blood pressure aabove 140/90
Influenced by age an co existing diseases
- Evelated blood pressure aabove 140/90
5
Q
WHAT ARE THE TYPES OF HYPERTENSION
A
- Primary - Essential hypertension
○ Most common with 90% of hypertensive patienst in this category, no identifiable cuase- Secondary hypertension
Underlying disease such as renal disorder (Renal stenosis which narrows the arteries of the kidney) or endocrine dusorder
- Secondary hypertension
6
Q
HOW CAN HYPERTENSION BE CONTROLLED
A
- Reduced weight
- Regular exercise
- Low salt diet
- Reduced alcohol consumption
- Stop smoking
Stress management
7
Q
WHAT ARE THE CLASSES OF HYPERTENSIVE AGENTS
A
- Drugs that alter sodium and water balance
- Drugs that decrease sympathetic nervous system activity
- Vasodillators - Ca channel blockers
Drugs modifying the renin angiotension system
8
Q
WHAT ISA BREIF OVERVIEW OF THE KIDNEY
A
- Inflyence the sodium and water rention in the kidney
- Each kidney made of millions of nephrons
- Each has a renal corpuscle and a renal tubule
- Renal corscule made of the glomerulus which has the bowmans capsule surrounds
- Fluid travels into the renal tubule where useful materials and water are readbsorbed
- Waste is left behind
- Divided into 3 Sections
- Proximal - 65% of reabsorption takes places
- Loop of henle - 25%
- Distal tubule - 7%
- Collecting ducts - 3%
From the collecting ducts the urine travels to the ureter which transfers the urine into the bladder
9
Q
WHAT ARE THE DRUGS THAT INFLUENCE SODIUM/WATER BALANCE
A
- Called diuretics
- They increase urine volume and decrease blood pressure
- Smaller doses of newer diuretics are more ffectibve than the ones that were used previously
- Held in high regard due ot the high safety
- Reduce incidence of stroke and other problems associatedw ith the cardiovascualr system
- 3 different duiretics
○ Loop diuretics
○ Thiazide diuretics
Potassium sparing diuretics
10
Q
WHAT ARE LOOP DIURETICS
A
- Act on the thick ascending limb of the loop of henlde where 25% of Na reabsorborption takes palce
- Most effective diuretic agents currently available
In rare cases ototoxicty can occur (Hearing loss) with the use of loop diuretics however they are reversible
- Most effective diuretic agents currently available
11
Q
WHAT ARE THIAZIDE DIURETICS
A
- Act on the distal convoluted tubule where 7% of the Na reabrotpion occurs
- They decrease NaCl Reabsorption in the distal and increase the water volume in urine
They provide gentle diuresis and reabsorption occurs at the distal and are safe for use in the elderly
- They decrease NaCl Reabsorption in the distal and increase the water volume in urine
12
Q
WHAT ARE POTASSIUM SPARING DIURETICS
A
- Areas where kidney and soidum is exchanged with potassium
- Increase excretion of urine
- 2 groups of them
- Aldosterone antagonists - aldosyerone is a steroid hromone actiovated by the renin-angiotensin system
- Causes an increase in reabsoprption of sodium and water
- And increases blood pressure
- Block aldoserone at receptor sites in the distal and collecting ducts
- Increased sodium and water excretion
- Potential adverse is hyperjalemua and androgen or estrogen like effects
Na channel blockers - Decrease the sodium reabsorption increasing the volume of water in the urine
13
Q
WHAT ARE THE DRUGS THAT DECREASE THE SYMPATHETIC NERVOUS SYSTEM ACTIVITY
A
- 2 classes of drigs b1 blockers and alpha blockers
- B1 blockers
○ Metoprolol decrease the atcivity of the sympathetic nervous system by producing a blockage of selective B1-adrenerguc receptors in the heart and other organs
○ Major portion of antihypertensives are these
○ Show a reduction in stroke and other serious cardio problems
○ Should be used with caution with people with astham or other obstructive lung diseases - Alpha blockers
○ Prozasin
○ Binds abd block to aloha in the peripheral arterioles
○ Reduces the vasoconstriction produced by the sympathetic neurotransmitter, norpeinephrien leads to a decrease in peripheral resistance
○ The adverse effecst have limited the clinical use of alpha blockers
Headache, orthostatic hypotension, dizziness, loss of sconscipoisness due to a dramatic loss in blood pressure
- B1 blockers
14
Q
WHAT ARE DRUGS THAT MODIFY THE RENIN ANGIOTENSIN SYSTEM
A
- RAS
- Regulated blood pressure and fluid balance in the body
- Renin is an enzyme released to the blood from the kidney
- It cobnverts angioteninogen to Angiotensin I
- Angiotensin converting Enzyme ACE
- Converts it to angiotensin II
- This has 2 effects
○ Vasoconstrictction of the renal blood vessels
○ Aldosterone secretion from the adrenal cortex
Which increases the NA and water retention in the kidney. Both of these effects lead * Angiotensin coverting enzyme ACE inhibitor
○ Prevents the conversion to angiotenin II which is the active form
○ Advanategs is that they do not cause sexual dysfuntion which is a problem seen in a lot of antihypertensives
○ They can be Used in pateints with asthama
○ They do not alter Carbohydate metabolism
○ They also reduce the incidence of heart rate in patients of high blood pressure
○ Adverse effects
§ 1.5-11% of patienst develop bothersome dry cough
§ This is the result of enzyme supression which causes a build up of substances in the lings
§ It can also cause fetal injurt and death when used in the second and third trimesters of pregancny
§ Benazeprill is a common ACE inhibitor in the treatment of Hypertension, Congestive heart failure and complications by diabetes
* Angiotensin receptor blocking drugs ○ Block the receptor for angiotensin II ○ Prevents the vasoconstrictive effects Produce less of a cough than ACE inhibtors
15
Q
WHAT IS THE BEST WAY TO DETERMINE THE CHOICE OF ANTIHYPERTENSIVES
A
- Most effective with least effects
- Use of a single is preffered
- Hypertension is only partially controlled with monotherapy
- Combination therapy may be needed
- Thiazide diuretics beta blockerfs Ace inhibitors or ARB are common
Alpha blockers and centrally acting agenst are only used if BP is still not controlled
16
Q
WHAT IS CORONORARY ARTERY DISEASE
A
- Common vascular disorder
- Narrowing of coronary arteries and reduced blood flow in the heart
Most common results from ischemia is angina pectoris which is advanced CHD
- Narrowing of coronary arteries and reduced blood flow in the heart
17
Q
WHAT IS ANGINA PECTORIS
A
- Usually due to atheroslerosis of the coronary arteries which is the buildip of lipid depoists causing narrowing
- Symptoms are sudden severe pressing pain in the chest
- Comes from dimihsed oxygen and blood flow
- Precipitated by the 4Es
Eating, exercise,excitement and exposure to cold - all of these demand oxygen
18
Q
WHAT ARE THE 2 TYPES OF ANGINA
A
- Typical (Exertional angina) - Characterized by chest pain with exertion due to a coronary obstruction
Variant(prinzmetal angina) - Chest pain experienced during rest variant thought to be due to coronary vasopasms without obstriuction it is the temporary sudden narrowing of one of the coronary arteries
19
Q
WHAT ARE THE CLASSES OF DRUGS TO TREAT ANGINA
A
- Organic nitrates
○ Include short acting nitroglycerin and long acting isorbide dinitrate- Beta drenergic antagonists
○ Beta blockers anatagonize Beta adrneergic receptprs, Propranolol is the prototypical drug - Ca channel blockers
○ Vasodillators
○ Nifedipine is the prototypical drug
- Beta drenergic antagonists
20
Q
WHAT IS THE ORGANIC NITRATE NITROGLYCERIN
A
- Organic nitrates relax smooth muscle of the blood vessels and exert therapeutic effects by 2 mechanisms
- Relaxation of large capacitance vessels leading to vasodillation
○ Decrease in venous blood returningto the heart, leading to decrease in cardiac output and blood pressure
○ Decrease in the workload and energy expenditure of the heart and thus decreae in the Oxygen requirements of the heart - Dillation of large coronary arteries
○ Cause the blood to be diverted to areas of the heart with low blood flow
○ Enhancing oxygen supply to areas of the heart deficient in oxygen - The neyzme nitric oxide synthase Nos cataluzes the conversion of arginine into citrulline and Nitric oxide NO
- Passes from endothalial cells into smooth muscle cells where it activates the nezyme guanul cyclase and relaxes the blood vessels
- No is an endogenous vasodillator
Nitroglycerin initates its mechanism by entering blood vessels and mobing into smooth vessels where it is converted to NO
- Relaxation of large capacitance vessels leading to vasodillation
21
Q
WHAT IS SUBLINGUAL NITROGLUCERIN GLYCERYL TRINITRATE GTN
A
- GTN
- More intensive when given in the sublingual route
- When placed under the tongue
- Achieved in 5 minutes gets to peak plasma concentration
Then drops off after 5 minites and is terminated within 20 to 30
22
Q
WHAT IS TRANSDERMAL GTN
A
- Approporate to abort ot control acute episodes of angina but limited value in prevnting episodes of angina
- Need to be administered every 30 minites
- Conviently administers GTN transdermally
Polymer bonded to membrane attached to adhevise which obatins a long lasting effect of 24 hour period
23
Q
DESCRIBE THE TOLERANCE OF GTN
A
- If GTN taken sublingually sveral times a day
- There is no development of tolerance
- It does develop to transdermal GTN after several hours
GTN patch is applied to the skin 12 hours then removed for 12 for the paztient to regain sensitivity
24
Q
WHAT ARE THE THERAPEUTIC USES OF GTN
A
- Terminal of individual attack
○ Given sublingually
○ Most used drug
○ Would be inactiveated as it passes through the liver and before it reaches thegenral circulator
○ It acs in 2 minutes to relieve pain and it is sudden and complete- Prevention of an individual attack
○ Sublingulally increases the exertion tolerance of a patient before the oxygen uin the heart musce drios to the level that pain is experienced
○ Taking GTn prior to exercise that normally would cause angina
○ The protective effect would last for 30 minutes - Chronic prophylaxis
○ If a patient has numerous attacks a day
○ And has to cdonsume many GTn tablets
○ Physician may prescrivbe a long acting organic nitrate
○ Isorbide dinitrate which is given orally 2-3 times a day
Will cut down the number of anginal attacks and the need to take GTN sublingually
- Prevention of an individual attack
25
WHAT ARE THE BETA ADRENERGIC BLOCKING AGENTS - PROPRANOLOL
* Angina is precipitated by an increase in sympathetic nervous system
* Stress and exercise
* Increase in myocardial oxugen requirement resulting in pain
Beta blocker decrease the atcivation of sympathetic nervous ystsem and can be used for long term prophylaxis of typical angina
26
WHAT IS CA BLOCKING DURGS - NIFEDIPINE
* Decrease amount of extracellular Ca reaching the sites inside the vascular smooth miscle leading to a relaxation of arterioles
* Decrease in resistance of the arterioles
* Reduce workload on the heart
* They reduce the force of myocardial contraction and in turn reduce the workload of oxygen demand on the heart Ca channel blockers are chosen over beta blockers for long term prophylaxis
* Common adverse effects are
* Flushing
* Ankle swelling
* Headache
Hypotension
27
WHAT IS THE DEVELOPMENT OF HEAART FAILURE
* Oter conditions like hypertension contribute to CHD
* Edema is often but not always present with heart failure
* Can involve both or 1 ventricle
* Decline ine cardiac performance and is reduced cardiac output and decreaed oxugen to the tissues
* Symptoms like shiortness of breath
* Fatigue, tachycardia
* Enlarged heart
* Fatugue is a consequence of decline in cardiac performance
* 2 main mechanisms the body compensates for a failing heart
Increases sympathetic nervous system - increasing the HR and the force of contraction and activiating the Ras - Increasing blood pressure
28
WHAT ARE THE GOALS OF HEART FAILURE TREATMENT
* Reduce symptoms and slow progression of heart failure
* Manage acute episodes of decompensated failure where a patients condition worsens, resulting in the need for urgent therapy hospitalization
* Heart failure can be managed with non and pharmacological treatments
* 2 main options are behavioural modificatiom like graudulaly increasing exercise
* In terms of surgery depending on the disease some people may be candidates for coronary revascularization like a coronary artery bypass or cardiac transplant
* Pharmacological treatments
○ Diuretics
○ Inhibitprs of RAS (ACE inhibitors, ARBs)
○ Vasodillators
○ Positive inotropic agents
29
CARDIAC GLYCOSIDES
* Diurectis inhibitors of RAS and vasodillators are the primary treatments for heart failure
* Cardiac glycosides may be used as a second line treatment
* Major glycopside used in Canada is Gigoxin
* Cardiac glycosides such as digoxin have a specific and powerful action on the myocardium
* Binds to specifically to the enzyme sodium potassium ATPase
* Extrusion of sodium form the cardiac cells
* Results in an increase in the intracellular concentration of Ca via the soduim-calcium exchanger
* Increased Intracellular concnetrtaion of calcium leads to an increase in myocardial contractiity
30
WHAT ARE THE THERAPUETIC USES OF DIGOXIN
* Patients with heart failure and atrial fibrillation
○ 50% of patients with normal sinus rhythm hasve rleief of heart failure of igoxin
○ Better results are seen with digoxin in patients who alos have atrial fibrillation
* Tretament of disordered electricla rhythyms of the heart arrthymias
○ Causes changes in the electrical properties of the heart
○ Important therapeutci action is to decrease number of electricla impulses
From the atria to the ventricles
31
WHAT ARE THE ADVERSE EFFECTS OF DIGOXIN
* Narrow therapuetic index of 2
* 25% of patients show toxocity
* disordered rhythms in the heart -arrthymia
○ Preparations are used to treat these disorders they can also cause the fatal disturbances
○ Disordered rhythym of the left venrtricle is the most common case
* Disturbance of vision
○ Vision is often blurred and white halos may appear on dark objects
○ Colour vision can also be disturbed
* Neurological effects
Headache, fatugue, muscle weakness and confusion
32
WHAT ARE THE DRUG INTERACTIONS OF DIGOXIN
* Changes in Intracellular potassium
○ Decrease in intracellular potassium occurs with most diuretics
○ Because digoxin and potassoim compete for the same spot on the sodium potassium ATPase
* Antibiotics such as erthyromyocin
○ Can interact with these anti biotics
Erthtomyocin interacts with the gut flora that function to break down and inactivate digoxin leading to an increase of digoxin in the blood
33
WHAT IS ATHEROSCLEROSIS AND CHD
* Coronary arteries in heart are responsible for supplying oxugen to the heart muscle
* In this disease a fatty sludge infiltrtaes the coronary arteries walls so they are narrowed and carry less blood
* The fat is made of accumulation of WBC cholesterol and triglycerides
* Eventually Ca will deposit and cause stiffness
* Then the heart will receive too little oxygen
* The heart can cope at rest but during exercise it is unable to and then causes angina pectoris
* Risk factors
○ Obesity - 20% or more overweight
○ Lack of exercise
○ Cigarette smoking
Hypertension
34
WHAT ARE LIPOPROTEINS
* Lipids including choelsterol, cholesterol esters and triglycerides are insoluble in water and are packaged for transport in the body
* Any group that transports fats are called lipoproteins
* They have a surface coat and a lipid core
Which is made of choelsterol and esters and tryglycerices
35
WHAT ARE THE TYPES OF TRIGLYCERICES
* Chylomicrons
○ Largest lipoproteins
○ Formed in the intestine
○ Carry triglycerides of the diet and some cholesterol and cholesterol esters for absorption
* Very low density lipoproteins - VLDL
○ Secreted in the liver and carry triglycerides to peripheral tissues for the utilization or storage
○ VLDL triglyceride at the least in part derived from Carbohydrates
* Low density lipoproteins LDL
○ "Bad" lipoprotein
○ Transports cholesteral away from the arteries to the liver
○ Where it is biotransformed into bile acids and excreted
This helps protect the against heart disease
36
WHAT ARE PRIMARY AND SECONDARY HYPERLIPORPITEINEMIAS
* Inability to break down lipids or fats in the body
* Specifdically cholesteral and triglycerides
* Primary
○ Arises from a gene defected inherited in a predictable mandelian fashion
* Secodnary
○ Complications of more generalized metabolic dusturbances
Such as diabetes mellitus, hypothyrdoidism or chronic ingestion of large amounts of alcohol
37
WHAT IS CHOLESTERAL AND THE HEART DISEASE LINK
* Studies show elevation of blood total cholesterol or LDL-cholesterol is a major risk factor for atherosclerotic events
* Individual with blood cholesteral greater than 220-250 tehre is a 3 fold greater risk of heart attack than in individuals with cholesteral less than 195
* Does lowering plasma concentration of LDL cholesteral diminish the risk of CHD?
○ Decreases of 50% in incidence rates
Elevated triglycerides are also associated with increased CHD
38
WHAT ARE THE THERAPUETIC MEASURES TO TREAT HYPERLIPOPROTEINEMIAS
* Behavioural changes like eliminating certain dietary intakes
* Drug therapy is instituted if this fails
* Sometimes both will be done in conjunction with each other
* Diet
○ Maintain a low in cholesteral and saturated fats
○ Saturated fats will raise choelsterol
○ Reducing fat intake is the best way to do it
○ Do not eclusively cut out cholesterol rich foods
○ Avoid fats from animal origin
Polyunsaturated fats assist in lowering blood cholesteral and improving the HDL/LDL ratio
39
WHAT ARE THE DRUG TERAPIES FOR HYPERLIPOPROTEINEMIAS
* First identify the nature of the lipid disorder
* Different lipids require different therapies
* Statins
○ Inhibit enzyme B-Hydroxyl B-methylglutaryl-CoA in the livers (HMG-coA)
○ This catalyzed the rate limiting step in cholesteral biosynthesis
○ Statins ensure more LDL is removed than being produced
○ Employed alone or clombination with other drugs
○ Most effective in the drug class when combined with exercise
○ Adverse effects
§ Myopathy and elevated liver enzymes
§ Elevated enzymes as liver damage
§ Commonly used are Lovastatin, simvastatin, fluvastatin
* Drugs that inhibit sterol absorption
○ Ezetimbe inhibitst he trnasporter in the GI tract responsible for the absorption of cholesterol and other sterols
○ Increasing the sterol level in the body
○ Blocks the reabsorption of bile salts which leads to the conversion of cholesteral to vile salts causing a net reduction
○ Usually used in combination with statins
* Bile binding resins
○ Bile acid sequestrants
a. In the liver cholesteral is metabolized to bile acids
b. Bile acids excreted in small intestine for digestion then reabsorbed
c. Bile acid binding resins are postively charged and bind to the negative bile salts and inhibit reabsorption and promote excreteion
d. Enhanced excretetion results in more cholesterol turning to vile
○ Administrations means there is a need for addition cholesteral in the liver to make new bile salts
○ Cholesteral is provided via the liver hencated uptake from LDL and lowering LDL by 20%
○ Cholestryamine - Suqyestrant binds in the GI tract to prevent reabsorption. Useful in hyperlipoproteinemias - relative safe drug may cause constipation or bloating
* Fibric acid derivatives
○ Decrease VLDL
○ Enhace breakdown of triglycerides
○ Decrease breakdown of fatty acids in adipose tissue
○ Decrease major therapeutic use of fibirc acid
○ Hypertriglyceridemia - Form where triglycerides predominate and VLDL is elevated
○ Adverse is rashes, GI upset, myopathy and hypojalemia
○ Gemfibrozil is used to treat the high levels for people in pancreatitis
* PCSK9 inhibitors
○ Drug in minoclonal antibody class
○ Target PCSK9 protein and act by increasing liver ability to remove LDL from the blood
○ Used when adequate control of hyperlipdemais has not been achieved with other classes of drugs
○ Gieven every 2 to 4 weeks and reduce LDL levels by 60-70%
○ Can substanially reduce cardiovascual events
○ Adverse effects are mild skin reactions at the site of injection and respiratory tract infections
○ They are very expensive
○ Alirocumab and evolocumab are the common ones
40
WHAT IS THE BLOOD COAGULATION CASCADE
* When indury to the vessels occury the following is the blood clotting process
* Vasocontriction
○ After vessel is injured it goes to spams and vasoconstricts restricting blood loss
* Formation of platetlets
○ They adhere to collagen fibrisl and help von wildebrand factor
○ They aggregate together and adhere to the site of injury forming a plug
* Blood coagulation
Results in the formation of fibrin strands that turn platlet plug into a more stable clot, cpmpleteing the coagulation process
41
WHAT ARE THE PATHWAYS OF THE COAGULAITON CASCADE
umber of cloting factors
* Extrinsic pathway
○ Activatedb y external trauma
○ Releases tissue factor TF which bidns to factor VIIa
○ Turns factor X into factor Xa combined with factor VA converts to factor II(prothrombin) to factor Iia(thrombin)
○ Then converts fibinogen to fibrin completeing the clot
* Intrinsic pathway
○ Activated by internal trauma
○ Involes factors XII and XI and IX\
○ Pathway is also activated by factor X
○ Which follows the same process as occurs in the extrinsic pathways forming fibrin completing the clot
42
WHAT IS FIBRINOLYSIS
* Enzymatic process that’s dissolves the firbin clot
* Occurs concimitantly with coagulation
* Controls size and spread of the fibrin clot
* Completely removes the cloth once the vessel has been repaired
* Tissue plasminogen activator t-PA activates plasminogen to plasmin which breaks down the fibrin clot
Plasmin is inhibited oncet he fibrin clot id dissolved
43
WHAT IS THE REGULATION OF THE COAGULATION CASCADE
* Happens in various phases by enzymatic inhibition or modulation cofactor activity
* This cascade involves Antithrombin III
* III is a relatively small protein that functions as an endogenous anticoagulant
* Neutralizes number of active cofactors in clotting (Thrombin, fibrin, Xa)
* Antithrombin III keeps balance between bleeding and formation of clots
Important for some anticoagluants
44
WHAT IS THROMBOEMBOLIC DISEASE
* Hypercoagulable states
* Manifest as deep vein thrombosis
* Pulmonary embolism or CHD
* Few conditions can result from this like genetic factors or acquired defects in the clotting mechanism
* Secondarily intravscular clot formation can occur as a result of infection, cancer or trauma
Some drugs predispose an individual to thrombosis
45
WHAT ARE THE PHARMACOLOGICAL TREATMENTS OF THEROMBEMBOLIC DISEASE
* Anticoagulants
○ Drugs that prveent or reduce coagulation within blood vessels by inhibiting coagulation cascade also called blood thinners
* Anti platelets
○ Drugs that decrease the aggregation of platlets
* Thrombolytics
○ Break down clots called clot busters
* Aim is to prevent formation of intravascular thrombi
* Minimize the tendency to bleed
* All anticoagulants have bleeding as a major adverse effect
* They do not later existing thrombi but ratehr prevent fyrther formation
46
THROMBIN INHIBITORS
* Heparin and low molecualar weight heparins
○ Natural substance occuring in mast cells of mammalian species
○ Extratced from pigs usually
○ Indirectly inhibit thrombin factor Iia
○ Binds to antithrombin III and ehnaces its ability
○ Inhibits clotting factors Xa and Iia
○ Case of fondaparinux only Xa is inhibited
○ Heparins accelrate the inhibition of Xa Iia by antithrombin III up to 1000 fold
○ Response is variable
○ Degree of antocoagulation must be monitored using a test that determines the time required
* Oral factor Xa inhibitors
○ Heparins must be given by injection
○ Which reduces compliance
○ These are oral
○ As effective as heparins and do not require to be monitored
○ Rivoxaban Is an orial factor Xa inhibitpr that is approved for the prevention of venous thrombeobolism
47
WHAT IS WARFARIN
* Widely perscribed drug
* Orally and effective
* Inhibits viatmin K dependint on clotting factors VII IX and X and II
* It is a vutamin K antagonist
* Decreases the rate of synthesis of these clotting factors
* Structures of warfarin and vitamin K are similar allowing it to bind and inhibit the enzyme
* Keeps vitamin K unactivated
* Onset response is delayed for 8 to 12 hours
* As time required for the existing clotting factors to be ulized
* Disadvantges
○ Cross placenta and cause feetus bleeding and also tetragenic
○ Degree of anticoagluation must be carefully monitored especially as the dose is titrated
48
WHAT ARE THE CLINICAL USES OF ANTICOAGULANTS
* Inherited disorders of coaglutions where natural anticoagulant sustem has some form of deficit
* Acquired disease - Number of disorders put the person at high risk for the formation of venous thrombi
* Long term use reduces the incidence of thrombotic evenys
* Also used in patients with artifical heart valves
* Prophylatic use during hip and knee replacement surgercies to prevent thrombotic complications - Usually low molecular weight heparin is administeres subcuctaneously
Treat overt thromboembolic disease - Venous thrombosis is treated initally with heparin or low molecular weight heparin for the first 5-7 days and therapy is switched ot the oral agent warafarin
49
WHAT ARE TRIGGERS FOR PLATELET AGGREGATION
* Initial step in vessel injury
* Prevntion of thrombi formation with drugs reduces the indicen of vascular events and improved orral survival
* The triggers for platelet drug action
○ Membrane receptors - on exterior of platelet that respons to norpineopherine, thrombin, and some prostoglandins
○ Platelet produces adeonoside diphosphates - Prostogalandis can interact with ADP and prostogalndin recepttors on the surface of the platelet
Platelet produces thromboxane A2 cyclic AMP and Ca ions that act inside the platelet to promote adherence
50
WHAT ARET HE ANTI PLATELET DRUGS
* COX 1 inhibitors
○ Major prostogalnding produced is thromboxane A2 TXA2
○ Inducer of platelet aggregation and potent vasoconstrictor
○ Aspirin reduces formation of TXA2 by irreverisbly inhibiting COX-1 (Cyclooxugenase-1) enzyme which forms protogalndins
○ Aspirin used as antithrobotic agent for person at risk of tsroke
○ Heart attacks and ischemic vascuyalr disease
○ Primary pevention of vascular events id the major use of it
○ Most people 50 years of age or older have 2 risk factors for vascular disease
* ADP receptor inhibitor
○ These compounds block platelet aggregation by inhibiting the ADP dependent activation of platelets
○ Drugs blockd the Adp receptors on the platelet
○ Some clinical uses of this drug include prevention of reoccuring stroke, reduction or prevention of myocardialc infarct, ischemic stroke, and following vascular surgies such as stent replacement
○ Clopidogerl sold has plan name plavix is an antiplatelet
* Platelet glycoprotein IIB/IIIA receptors
○ Block function of enzyme GPIIB/IIIa on exterior of platelet
○ Inhibiting aggregation
○ These are biologicals
○ Approved for coronary vessel occulusion ins patients undergoing bypass
○ Abximab is a glycoprotein IIB/IIA receptor inhibitor
○ Mainly used during and after coronary artery procedures like angioplasty to prevent platelets form sticking together and causing thrombus (blood clot)
51
WHAT ARE THE DRUGS USED IN BLEEDING DISORDERS
* Excessive bleeding occurs from thraumaus, surgeries, or conditions like hemophillia
* Common treatment is vitamin K
* Clotting factors VII, IX, X and II are vitamin K dependent
* It is used clinically in cases of vitamin K deficiency or in Warfarin overdose
* IN the case of hemophillias where specific coagulation factors are deficent
* Concentrated plasma fractions containing the mising factors are administered
Factor VII or IX may be used to stop bleeding
52
WHAT DEFINES ASTHMA
* Bronchoconstriction
○ Contraction of bronchia smooth muscles
* Muscoal edema
○ Swelling that occurs as a result of irritation and inflmmation of the bronchiolar epithelium
* Bronchiolar secretions
○ Increased mucous secretion due to inflammation
53
WHAT IS THE ALLERGEN INDUCED MODEL OF ASTHAM
* Allergens such as dustmites and pollens cause production of immune globin that binds to binds to mast cells and T lymphocytes - WBC
* Once produced Immune globulin (IgE) binds to mast cellsi n the airway mucosa
* Then on repxosure to the allergenc it triggers the mast cells to release mediators
* Cause synthesis and release of other mediaters they are histamine, tryptase, leukotrienes, and protogalndins
* Triggers contraction of muscle bronchioles narrowing the broncholar aurways and causing an asthma attack
* 3-6 hours allergen induced acute asthma attack second more sustanined phase of bronchoconstriction is termed
* Late asthmatic response
* Second phase of bronchoconstriction is termed the late asthmatic response
* May last for several weeks and is associated with inflammatory cell influx to the bronchia mucosa
* Clusteres in families
* This model does not represent all asthma attacks
* Some are trigger by non allergen stimuli like cold air an exercise
* Tendency to develop bronchospasms on encountersing non allergen is called nonspecific bronchiah yper-reactivity to distinguish from allergen induces asthma
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WHAT IS THE NONSPECIFIC BRONCHIAL HYPERREACTIVITY MODEL
* Not completely understood
* Inflammation of airway mucosa
* Combination of released mediators and an exagerated responsiveness to them
Treatment is aimed not only at preventing or reserving acute bronchospams using bronchodillators but reducing the overall amount of inflammtion
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HOW IS ASTHMA TREATED
* Control of precipitating factors like allergens or respitraory infections
* Use of anti astham agents like bronchodillators and anti inflammtory agents
* Short term relief from acute attack is most effective with bronchodillators
Long term is with both
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WHAT ARE THE 2 TYPES OF BRONCHODILLATORS
* Dillate or open airways
* Inhaled
* Sympathiomimetics - Drugs that mimic effects of endogenous agonists of sympathetic nervous system
* Antimuscarinics
Drugs that block the muscarinic receptor
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WHAT ARE SYMPATHOMIMETICS
* Selectively bind to B2 repcetors on bronchia smooth muscles
* B2 agonists are the ,ost effective and widely used
* Multiple types of B2 agonists exist
○ Short acting
§ Subutamol for acute asthma attacks
§ First line treatment
§ Inhaled
§ Minimal system toxicty
§ Reach maximal effect within 15-30 minutes
○ Long acting drugs
§ Salmeterol
§ Used in maintenace therapy of asthma
§ In combination with corticosteroids
Long acting are not recommended to be used alone
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WHAT ARE ANTI MUSCARINICS
* Drugs at the muscarinic receptor in the lungs
* Block the cholinergic mediated bronchoconstriction
* Administered from inhalation
* Not effective as the B2 agonists
* Used as adjunct therapy
* Ipratopium Is used to control and prevent symptoms caused by ongoing chronic obstrictive pulmonary disease like wheezing and shortness of breathe
* Often administered with salbutamol
For severe asthma
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WHAT ARE THE ANT INFLAMMATORY AGENTS
* Used in chronic management of asthma
* Corticosteroids
○ Steroid hrmones produced in adrenal cortex decrease production ofm acrophages, eosinophills and lymphocytes
* Leukotriene receptor antagonists
○ Selectively block action of leukotrienes on the respiratory tract
* Anto IgE antibodies
Targe the IgE protein respinsible for initiating allergic reaction
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WHAT ARE CORTICOSTEROIDS
* Block production of immune cells in the respiratory tract
* Reduce bronchia reactivity
* Imrpove all indices of asthma control
* Including symptoms of bronchial reactivity
* First line treatment for maintenace therapy asthma
* Adverse effects
○ Oropharyngeal candidiasis ( Fungal infection of the mouth)
○ Hoarseness (local effect on the vocal chords)
○ Increase risk of osteoporosis
○ And cataracts when used chronically
○ In children can slow growth rate by 1cm in first year of treatment
○ Overrall efect is minimal
○ Resvered for urgent or severe treatment
Example is fluticasone Inhaled synthetic corticosyertoid
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WHAT ARE LEUKOTRIENE RECEPTOR ANTAGONISTS
* Decreases mucous secretion and bronchoconstricttion
* Administered as tablets orally
* Improve control and frequency of astham attacks
* Main advanatage is taken orally
* Beneficial to children who comply horriobly with inhalers
Montelukast Sold as Singulair Used for maintenance treatment mainly seasonal
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WHAT ARE ANTI-IGE ANTIBODIES
* Inhibit binding of IgE to mast cells
* As a result mast cell degranulation does not occur
* Stops the cascade that leads to asthma
* After 10 weeks of administration IgE levels in blood are lowered to an undetectable level
* Repeated administration of anti-IgE antibodies reduce frequency and severity of asthma attack
* Disadvanatges
○ Expensive
Administered by injection
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HOW ARE ASTHMA TREATMENTS CHOSEN
* Clinical use of leukotriene pathway inhibitors and monoclonal anti IgE antibodies are used exclusively for pulmonary diseases
* For mild asthma occasional use of a bronchodillator (B2 agonist) may be all that is required
* For severe asthma long term control is required like anti inflammtory agents
* Like corticosteroids
* When monotherpay is not sufficient for reliving symptoms of asthma
* Other drugs may be combined
* Long acting B2 agonisys inhaled corticosteroids is effective
* Leukotriene pathway are less effective than corticosteroids and are used as adjuvants when symotoms are not adequately controlled with corticosteroids
* Severe asthma can be treated with Anti IgE antibody
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WHAT IS CHRONIC OBSTRUCTIVE PULMONARY DISEASE
* 2 co existing diseases
* Chronic bronchitis and emphysema
* Chronic bronchitis is the chronic inflammation of bronchi and is a persistent cough
* Smphysema is an abnormal permanent enlargement of air spaces in the peripheeral lung
* Results from tissue destruction due to chemical released during inflammation
* Emphysema is characterized by shortness of breathe
* COPD occurs in older patients as decreased airflow that is not fully reversible with bronchodillators and is poorly responsive to high dose corticosteroids
* COPD is a progressive diseases leading to loss of pulmonary function overtime
* Abnormal inflammtion from noxious particles or gases
* Cigarette smoking is the biggest risk factor
* Tar particles are easily deposited into the pheripheral airways
* Increases the receuitment of inflammtory cells
* Secrete number of different components like proteases and reactive oxygen species
* Agents will damage epithelial cells and break down CT
* Oxidants and other substances found in tar particles directly injure lung cells
COPD usually a consequence of smoking 15% occurs in non smokers usually from industrial inhalations from mining
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WHAT IS THE PATHOGENESIS OF COPD
* Many changes occur to the airways that inhibit the function of the lungs
* Changes occur in different locations
* Bronchi - medium sized airways of the lungs
○ Decreases ciliary clearance - Inhibition of activity and direct structural damage
○ Thickening of the wall - from edema, direct toxic effects, effects of inflammtory cells provoked from cigarette smoke, mucous gland hyperplasia
○ Excess mucous - due to hypersecretion, hyperplasia and decreased clearance
* Bronchioles - smaller airways
○ Decreased airway duameter due to increased wall thickness as a reuslt of inflammation, edema, and fibrosis
○ Increased mucous
Bronchospasms
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HOW IS COPD TREATED
* Similar pathogenesis of COPD and asthma
* COPD benefits less from treating asthma
* Beta 2 agonists and antimuscarinics
○ Relief of acute symtomps of COPD
○ Inhalation of short acting B2 agonist
○ Anti muscarunuc drug
○ 2 patients who have perissten symptoms of shortness of breath and limitation of activties will benefit from regular use of a bronchodillator
○ Longer acting selective anti muscarinic agent Tiotropium approved as treatment for COPD only
○ Taken daily with inhalation
○ Taken to imrpove functional capacity of the patients with COPD and reduce exacerbations
* Antibiotics
○ Major treatment difference between COPD and Asthma
○ Management of exacerbations
○ Antibiotics are routinely used
○ Sunce exacerbations commonly inmvolve bacterial infections
○ Bacterial infection to lower the airways does not commonly occur in asthma and therefore antibiotics are not often used to manage asthma axacerbations
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