Cardiovascular Hypertension Flashcards
Anatomical and locate terms of the CV
Left and Right Carotid Artery
Inferior Vena Cava
Superior Vena Cava
Renal Artery
Femoral Vein
Femoral Artery
Brachial Artery (Blood pressure)
Jugular vein
Aorta
General Blood Flow of Heart
Inferior/Superior Vena Cava
Right Atrium
Tricupsid Valve
Right Ventricle
Pulmonary Valve
Pulmonary Arteries (Deoxygenated Blood)
Lungs
Pulmonary Veins (Oxygenated Blood)
Left Atrium
Mitral valve
Left Ventricle
Aortic Valve
Aorta
Why is it more common to have left ventricular failure or dysfunction?
Left Ventricle more difficult (more force)
- Right ventricle less common as just pumping a short distance to the lungs
Role of the G.I. Tract
GI tract drains in to the liver –> Food or substance from outside world needs detoxification
All drugs that you take orally via tablet, they will be metabolized. Half of drug gone by time it hits systemic circulation
liver will destroy good portion of drug until released to normal circulation
Heart Valves
Tricupsid Valve
Mitral Valve
Aortic Valve
Pulmonary Valve
Mitral Valve
Left Atrium to Left Ventricle
Tricupsid Valve
Right atrium to right ventricle
Aortic Valve
left ventricle to aorta
Pulmonary Valve
Right ventricle to pulmonary arteries
Valvular disease is often associated with…
- Disease of a valve
- valvular disease in the left ventricle is often associated with reduced cardiac output
- If mitral valve did not close properly and blood flows backwards, cardiac output decreases –> less blood in aorta
Heart Sounds
Lub - 1st - closure of the tricupsid valve at the beginning of ventricular systole
Dub - 2nd - closure of the aortic and pulmonary valve at the end of ventricular systole
Systole
Occurs when the heart contracts, pumping blood out
Diastole
- Heart relaxing after contraction
Valve Prolapse Left Ventricle
- Mitral Valve Prolapse –> flaps of valve push back into atria –> blood leakage into atria–> reduced cardiac output
- Weak, tired, working hard –> require energy and oxygen to the muscles –> not nearly as much energy and oxygen delivered to muscles and brain
Why are valves important?
Prevent retrograde flow
What can valve dysfunction present as initially?
Valves can present as heart failure
Valve Replacement Surgery
Valve replacement surgery (or valve repair) are generally effective solutions to valvular dysfunction. Symptoms can be improved markedly.
Valves can be mechanical or biologic. If mechanical, long-term anticoagulant medications are needed to prevent clots from forming on the prosthetic surface.
Arteries, Arterioles and Capillaries
Deliver blood to tissues (always oxygenated except pulmonary artery)
High pressure (check yourself)
Two pressures (high and low)
Capillaries are leaky
Holes so substances can leak out e.g. sugar leak outs
Holes in capillaries vary in size
Glomerulus –> Filters blood to make urine
Veins do not work under high pressure state –> valves prevent backward flow –> slowly move
Where are capillaries located?
Endocrine tissues, small intestine, kidneys, skeletal muscle, cardiac muscle, brain (e.g. blood-brain barrier)
Endocrine Tissues, small intestine, kidneys capillaries
Free passage of substances up to 600nm in diameter
Skeletal Muscle, cardiac muscle, other tissues capillaries
Free passage up to 10nm in diameter
Brain Capillaries
Blood Brain Barrier
Tight junctions between endothelial cells
Little passive transport except water and C02
Implications for drug distribution (e.g., CNS infections)
Venules and Veins Characteristics
Lower pressure in venous system
Valves to prevent retrograde flow
Much more pliable than arteries
Contain 54% of blood volume at any given time
Venous tone influences venous return (i.e., return of blood to the heart)
Lymphatic System
Small endothelial “tubes” with contractile walls
“vacuum” fluid surrounding tissues
Drain into venous system
Also contain small clusters of immune cells (e.g., lymphocytes, macrophages) called “lymph nodes”
Lymphatic Dysfunction
Lymph Drainage –> removing fluid from any part of your body
Edema –> Fluid build up in tissues
Perfusion
- Cells are living in an “ocean” of ECF
- Arteriole –> Capillary –> Venule
- Capillaries leaks stuff out into the ECF which cells use, the capillaries also takes in waste –> venule
Blood Pressure
Pressure in the arterial wall
Feel it with your finger (pulse)
Can be measured (i.e., in mmHg)
Where is blood pressure often taken?
Brachial Artery
Principles of Measuring Blood Pressure
Blood flow through an open artery does not make sound
If you totally shut an artery, no sound when its closed
In between open and close, obstruct it, you will hear turbulent flow
How to measure blood pressure
Step 1
Pump up the cuff to ‘squish’ the brachial artery closed. Will hear no sound when closed.
Step 2
Slowly release the pressure, watch pressure in the gauge
Really slow releasing pressure, will start to hear turbulent flow
Point at which you hear sound, the pressure equals systolic blood pressure
Pressure in the cuff is now not strong enough to overcome systolic pressure, it is still strong enough that during diastole no blood is getting through
Step 3
Listen and watch the pressure gauge.
As soon as the noise disappears…..
THAT moment is the DIASTOLIC BLOOD PRESSURE
Systolic Blood Pressure
Pressure resulting from ventricular contraction (i.e., during systole)
Diastolic Blood Pressure
Pressure between contractions (i.e., during diastole)
Blood Pressure Normal ranges
<120 systolic
<80 diastolic
When blood pressure is being taken, the patient should be at…..
REST
Heart Rate Measurement
Count the number of beats in 60 seconds
OR count the number in 30 seconds and multiply by 2
When does blood pressure fluctuate?
Blood pressure fluctuates widely throughout the day and night
Intermittent high blood pressure has many BENEFITS
What are the benefits of intermittent high blood pressure?
↑ blood flow = ↑oxygen and glucose delivered to muscle.
Very useful –> Run faster, hit harder, yell louder, etc…
Regular activity (with rests!) will trigger cellular changes (e.g., ↑protein, ↑ mitochondria)
Parasympathetic homeostasis needs to occur in low pressure
Cardiovascular Disease Prevalence
2nd leading cause of death in Canada (after cancer)
Leading cause of death globally
CV drugs are used for many different CV conditions and risk factors
Risk factors for CV disease are highly prevalent in Canadians
Does hypertension work alone to produce CV disease?
NO
Many other risk factors (high cholesterol, diabtes, older age, etc.)
Why is sustained high blood pressure an issue?
BP should be lower when you sleep compared to when you fight.
↑ BP = ↑ energy to pump blood
Wastes energy for no added gain (i.e., during sleep)
Damages specific tissues/cells
Define hypertension
Consistent high blood pressure readings at rest (including during sleep!)
Exact cut off for diagnosing hypertension depends on other patient factors
What are the two causes of damage in regards to hypertension?
Damage typically is slow and results from two main consequences
↑ afterload
Arterial damage
Consequences of Sustained Hypertension on Heart
Left ventricular systolic dysfunction (LVSD) = poor contraction, ↓ CO
Left ventricular hypertrophy (LVH) – enlarged ventricle
Diastolic dysfunction - ↓ relaxation of ventricle, ↑ stiffness - ↓ CO
↑ myocardial oxygen demand due to muscle hypertrophy
Define Afterload
Afterload is the resistance against which blood is expelled.
Occurs at aortic valve and aorta
How can afterload be increased?
- High Blood Pressure
- Aortic Valve Stenosis, valve narrowed, more resistance
Describe the process of arterial wall damage
- Healthy blood vesssel walls are lined with with a blanket of endothelial cells
- High blood pressure damages the cells leading to beginning of:
Artherosclerosis, Suceptiblity to aneursym formation (weakened vessel wall)
Glomerular Nephritis –> Glomerlus filters blood, high pressure can damage glomerulus and cause proteins and blood cells to be filtered when they shouldn’t be
What causes hypertension?
Multifactorial problem
Where do anti-hypertensives target?
Natural Pathways
- Kidneys - fluid and electrolyte balance
- Hormones - sympathetic nervous system, RAAS
- Direct Targets (vasodilation, contractility)
Role of the Kidney in Blood Pressure
Can play a role in hypertension if it fails to eliminate enough fluid
Fluid builds up in vessels –> vessels are essentially “full” –> blood pressure is increased
Diuretics role
Diuretics INCREASE URINE PRODUCTION (excrete more fluid)
Their activity results from actions in the KIDNEY
Where do diuretics work?
Nephron
Different diuretics work at different segments of the nephron
Nephron and Salt Evolution
Very little salt in the natural environment –> no salt in vegetables
Body has programmed the body’s kidney to prevent the excretion of salt (sodium)
Channels dedicated in ascending loop of Henle and distal tubule Na+ reabsorbed
Huge evolutionary advantage
Na main electrolyte in blood
Salt Mainatains blood pressure, myocardium tissue contraction, nerves to conduct
Recalimaing fluid lost in urine is a huge thing
Normal Kidney Function
Filters 120ml/min into tubules
Makes urine at 1ml/min
Thus > 99% of filtered fluid is reabsorbed!
Reabsorption of sodium is the major driver of fluid retention!
Macula Densa Role
Sodium Handling
65% of all filtered sodium is reabsorbed at the proximal tubule
25% reabsorbed at the ascending loop of Henle
Afferent arteriole and ascending loop of Henle connected by specialized epithelial cells called macula densa
Macula densa senses Na concentrations in the nephron
Loop and TZD Diuretics inhibit… and work at….
Diuretics inhibit Na+ reabsorption
Inhibit channels that reabsorb channels
Make urine more concentrated with Na+
Diuretics are drugs that expel sodium
Ascending loop of henle distal tubule, no drugs for proximal tubule
Macula Densa Cells Role
↑ Na conc causes vasoconstriction of afferent arteriole, decrease glomerular pressure, decrease flitration, maintain fluid
Called tubuloglomerular feedback
In prehistoric times, Na likely meant dehydration
In other words, high sodium will decrease renal blood flow
Macula densa and patients with high sodium intake
- Macula densa sense high Sodium concentration, constrict afferent arteriole, less renal blood flow, less filtration, more fluid retained
- High sodium diet, maintain a lot of fluid, high blood pressure
Diuretics MOA
Diuretics increase urine production
Commonly used diuretics inhibit sodium reabsorption
More Na+ in the urine = more fluid excreted
High blood pressure often involves ↑ blood volume
Classes of Diuretics
Three major:
- Loop Diuretics (Na2-K+-2Cl- symport inhibitors)
Strong diuretics, not useful for hypertension unless CKD (a condition in which kidneys are damaged and cannot filter blood as they should) - Thiazide (Na-Cl- Symport Inhibitors)
Weaker diuretic effect than loop agents, best diuretic for hypertension in healthy people
Potassium Sparing Diuretics - Almost no diuretic effect
Used to prevent K+ loss
Loop Diuretics MOA simple
Inhibits Na+ reabsorption in the ascending loop of henle
Potent diuretics (25% of filtered Na+ is reabsorbed at this site)
Nephron segments distal to the loop have limited capacity to reabsorb Na+
More Na+ going past ascending loop, increase fluid uptake
Na+ K+ 2Cl- Symport Mechanism Normal
Na+ K+ 2Cl- Symport Transporter
Na+, K+ and 2 Cl- enter cell of ascending loop of henle by passing through apical membrane.
K+ leaves the cell through channels back to the renal tubule (apical)
3 Na+ leave to the ECF, 2K+ enter the cell through Na+K+ ATPase
into the ECF from renal tubule
Cl- leaves the cell across basolateral membrane. Cl- is negatively charged, so Mg2+ and Ca2+ passively flow
More NaCl in interstitial space, more fluid reabsorbed
Loop Diuretic MOA
- Inhibits Na+ K+ 2 Cl- symport transporter
- Blocks re absorption of Na and Cl (as well as K+)
Greater concentration of Na in the urine will keep fluid away from blood
- Fewer Cl- atoms in the interstitial space means less force to draw Ca2+ and Mg2+
Undesirable Actions of Loop Diuretics
Ca2+ and Mg2+ loss - decreased reabsorption by reducing the electrical gradient created by the symport pump (HOWEVER - often not enough to cause deficiency)
↑ K loss in urine because of reflex RAAS stimulation (increased renal pressure, juxtaglomerular cells release, renin, angiotensin II would release aldosterone, increased K+ excretion)
Uric acid retention in blood (uric acid is a contributor to an inflammatory condition called Gout). Mechanism not fully understood.
Loop Diuretic Drug
Furosemide
Why are loop diuretics not ideal for BP Control? What is the exception?
Fundamental disadvantage is short half-life (t½)
Potent stimulator of kidney activation
Renin-angiotensin-aldosterone system (RAAS) activation
Single doses can result in over-correction
Exception – patients with poor kidney function
Half-life is prolonged
Blood pressure effect is more stable
Thiazide Diuretics MOA
Inhibit NaCl transport in the distal tubule
Less NaCl in ECF, more fluid remains in distal tubule
Significantly weaker than loop agents because of location of action (90% of Na already reabsorbed)
Thiazide compared to loop diuretics
BETTER for BP control (longer/more gentle action)
Ca2+ can increase with long term use (mechanism not clear)
Mg2+ loss occurs but likely less than loop agents
Thiazide Diuretic Drug
Indapamide
Common uses of TZD and Loop Diuretics
Conditions with ↑ intravascular fluid
High Blood pressure - Thiazides (TZDs)*
High blood pressure in people with kidney disease – Loop agents* (ie. GFR <30ml/min)
Heart failure – Loop and TZD diuretics
Edema – fluid accumulation *****
Electrolyte problems with Na+ blocking diuretics
Hypokalemia (↓ K+), Hyponatremia (↓ Na+), Hypochloremia (↓ Cl), Hypomagnesemia (↓ Mg),
Calcium (↑ with TZDs, ↓ with Loops)
Hypokalemia Most Common (↓ K+ occurs in 9-13% of TZD users)
Impact on plasma metabolites/compounds
Hyperuricemia (↑ uric acid) - ↑ risk for gout
↓ Glucose tolerance = ↑ blood glucose (small effect)
Hemodynamic effects
Hypotension (one possible cause of dizziness)
Reduced renal perfusion (from ↓ blood volume)
↑ RAAS
Hypokalemia Na-Blocking Diuretics
Most common electrolyte imbalance with Na+-blocking diuretics
Can be quite common if:
Low K intake
Receiving other K-depleting drugs
Accelerated loss (vomiting / diarrhea illnesses)
↑ reabsorption of Na+ in distal tubule = ↑ K excretion
Stimulation of RAAS (from reduced volume/pressure)
Higher concentration of Na in the tubule
Situations that increase risk of hypokalemia
Elderly lady with poor appetite
Elderly man who uses laxatives every day
Middle aged man taking furosemide (loop) with the HCTZ
Man recovering from a violent “stomach flu” x 48 hours
K+ Sparing Diuretics MOA
As Na+ is pumped into the cell and ultimately out to the intercellular space, K+ will be ‘pushed’ away from the more positive side to the luminal side of the epithelial cell
Target late distal tubule and collecting duct
Inhibit Na+ channels in the luminal membrane of epithelial cells (Epithelial Na+ Channels or ENaCs)
↓ Na absorption exaggerates the polarization of the epithelial membrane
Discourages K+ excretion
K+ Sparing Diuretics Use
Very weak diuretics (little Na+ available by the distal tubule)
Mostly used to PREVENT K+ ↓ during diuretic therapy
Commonly combined with loop OR TZD-type diuretics
Carbonic Anhydrase Inhibitors
Not effective diuretics
Typically restricted to glaucoma (i.e.,↑ intra-ocular pressure)
Action Prevents reabsorption of NaHCO3
Carbonic Annhydrase Inhibitors MOA
In proximal tubule, Na+ is exchanged for H+ (Na+ in –> H+ out)
Luminal H+ reacts with filtered HCO3- to form H2CO3
Carbonic anhydrase converts H2CO3 –> CO2 + H2O
CO2 is reabsorbed easily into endothelial cell
In endothelial cell of proximal tubule:
Cytoplasmic carbonic anhydrase catalyzes the reaction backwards: CO2 + H2O –> H2CO3
H2CO3 ionizes to H+ + HCO3- because H+ conc’n is low
H+ continuously pumped into lumen (exchange for Na+)
Na+ HCO3- symporter moves HCO3- + Na+ to interstitial space
This is basically a mechanism to prevent a really important “buffer” from being lost in the urine.
However, because Na is involved, blocking the pathway results in a weak diuretic effect.
Main benefit of Carbonic Anhydrase Pathway
Enables re-absorption of HC03- which is a critical buffer in the blood
Acid base balance is closely regulated in the body.
Osmotic Diuretics
Freely filtered with little reabsorption (stay inside nephrons)
Create an osmotic effect to help keep water in urine
Typically in-hospital use only
Used much less frequently than other diuretics
What is RAAS
Renin-angiotensin-aldosterone system (RAAS)
RAAS is a system that increases blood pressure
RAAS over-activity occurs in MANY cardiovascular conditions
Major Hormone Products of RAAS
Angiotensin-II
Aldosterone
How is angiotensin-II produced?
- Two proteolytic steps:
Angiotensionogen converted to angiotensin I by renin
Angiotensin I coverted to angiotensin II by Angiotensin converting enzyme (ACE)
What are the three major actions of RAAs?
- Rapid pressor response - vasoconstriction
- Slow pressor response - kidney specific effects
- Vascular and cardiac hypertrophy and remodelling - heart tissue effects
Evolutionary Requirements of RAAS
- Dietary Na+ really low
- Rigorous lifestyle required adequate blood pressure
- Need quick increases in BP sometimes
- Need consistent/slow BP support (drought, etc.)
Angiotensi-II mediated vasconstriction in the Kidney
Fluid Depleted (Dehydration for example) –> Low blood volume –> low blood pressure –> low pressure in afferent arteriole –> low filtration pressure as not enough pressure to push through glomerulus –> low efferent arteriole
Consequence of low pressure to the kidneys
- Decreased filtration
- Decreased excretion of toxic substances
- Decreased tubular pressure –> collapse –> ACUTE RENAL FAILURE
How is RAAS activated?
LOW GLOMERULUS PRESSURE –> RENIN RELESE
- Low pressure detected in glomerulus triggers release of renin into blood
- Specialized cells in glomerulus monitor pressure at all times
What cell releases renin?
Juxtaglmoerular cells
How is renin release triggered?
- Intra-renal baroreceptors (low renal pressure)
- Macula Densa Cells (low Na+ in loop)
- b1 adrenergic receptors pathway (SNS activation)
- Juxtaglomerular cells
Renin’s pathway and role to Angiotensin II
Renin is an enzyme that is released into the bloodstrean and which has a binding site for angiotensinogen.
Angiotensionogen is an inert protein created by the liver that freely floats in the blood.
Renin activates angiotensinogen converting it to angiotensin I.
Angiotensin I is activated by ACE to angiotensin II. ACE is an enzyme connected to cells of tissues that respond to RAAS (heart cells, and kidney cells)
Angiotensin II in Kidney Role
Formation of angiotensin II causes preferential vasoconstriction of the EFFERENT arteriole
(efferent»_space;»afferent)
- Glomerular pressure increases without an increase in blood volume –> increase in filtration
CREATES INCREASED PRESSURE IN KIDNEY WITHOUT ALTERING BLOOD VOLUME
Angiotensin II also releases what hormone?
Aldosterone (steroid hormone)
- secreted by adrenal glands cortex on top of kidney following stimulation of angiotensin-type I receptor by angiotensin II
- Mimics corticosteroids
- slow pressor response
What is the main response of aldosterone? How does it achieve this?
Increased Na+ reabsorption and increased K+ excretion in distal nephron –> Increase fluid reabsoprtion, increase blood pressure
Increased synthesis and activity of ENaCs (epithelial Na+ channels)
Preference for Na+ over K+ –> Every Na+ reabsorped, one K+ excreted
Where does aldosterone bind along the kidneys?
- cells along the distal tubule/collecting tube
What class of steroids does aldosterone belong to? What is its role?
MINERALCORTICOSTEROIDS
- Main mineralcorticosteroid of the human body
- Saves minerals such as Na+
Glucocorticoids are anti-inflammatory agents that supress inflammation
What happens if aldosterone levels remain high for a long period of time?
- Increased Na+ reabsorption, increased fluid reabsorption (good if dehydrated but bad if you are not)
RAAS inhibition Medications
- ACE Inhibitors (ACEI)
- Angitensin Receptor Blockers (ARBS)
- Direct Renin Inhibitors
Why can ACE inhibitors cause an individual to develop a cough?
- A similar enzyme to ACE (angiotensin-converting enzyme) breaks down bradykinin into inactive peptides
- The accumulation of vasodilator peptides (e.g. bradykinin) can cause a cough
ACE Inhibtors
- Inhibit ACE activity
- ACE inhibition on endothelial cells throughout the body
- Many are prodrugs
ACEI Example
- Ramipril
What are the uses of ACEI and how do they work?
- High blood pressure –> Vasodilation and decreased aldosterone secretion
- Chronic Kindey (renal) disease –> decrease renal pressure (glomerular pressure) –> renal pressure already high, so want to decrease angiotensin II and aldosterone, to prevent further increase in glomerular pressure
- Heart failure and ischemic stroke (artherosclerosis) –> decrease adverse effects of angiotensin II and aldosterone on heart tissue and blood vessels
ACEI Cautions
- Reduced BP (used for many conditions; not just hypertension)
- Dry Cough
- Risk of hyperalkemia due to aldosterone inhibition - any drug that inhibits RAAS (K+ not excreted and stays in the blood)
- Decreased renal perfusion in vulnerable patients
- ## Teratogenic
How do angiotensin receptor blockers (ARBs) work?
- Inhibit the AT-1 receptor –> therefore blocks actions of angiotensin II
- Prevent binding to the receptor that
- Since angiotensin II cannot bind to receptor, prevent induced vasoconstriction and release of aldosterone
What are the effects of ARBS?
- Prevent induced vasoconstriction and aldosterone release
- Since have high blood pressure already, want to make sure blood vessels do not vasoconstrict further (rapid pressor response) or take on more fluid
ARBS and Cough
- Since ARBs do not inhibit the ACE enzyme, cough is less prevalent
ARB example
Valsartan
Why are ACEI’s and ARB’s appropriate tx for people with kidney disease?
- Indicated as first-line agents
- Long standing hypertension increases risk for chronic kidney disease
- Chronic kidney disease is when increased glomerular pressure damages the glomerulus and damages filtering function (protein and blood cells can escape)
- Decreasing vasoconstriction, decreases blood pressure, ultimately decreases glomerular pressure, decreasing damage
What are the effects of chronic kidney disease?
- Kidney function slowly decreases from damage
- Decreased rate of glomerular filtration
- Increased serum creatinine (easily excreted in healthy state)
- Difficulties excreting fluid and toxins
- Leakage of protein and larger molecules
How do ACEI’s and ARB’s work to protect the kidney?
- RAAS is high in people with cardiovascular disease and kidney disease
- If individual has normal BP and not dehydrated, RAAS is not useful
- If individual has normal BP and RAAS is active, glomerular pressure is high. If gomerulus already damaged, more damage
- By preventing angiotensin II creation (ACEI’s) or binding (ARB’s) can decrease glomerular pressure
Can ACEI’s and ARB’s cause kidney damage? If so, how?
YES
- If RAAS is activated, glomerular filtration pressure is increased
- If we block angiotensin II, filtration may decrease too much and can lead to acute renal failure
What individuals should not be taking ACEI’s and ARB’s?
- Vulnerable people
- People with low renal blood flow
- People who are dehydrated (reduce fluid volume even further)
- People with renal artery stenosis
What can happen if a person with low blood pressure intially takes an ACEI or ARB?
- Initially, RAAS will be active –> Attempts to increase blood pressure and glomerular filtration
- However, an ACEI or ARB will prevent RAAS from increasing blood pressure or increasing glomerular flitration
- Therefore, significantly lower blood pressure and decreased glomerular pressure
- Corrective measures by the body will occur. Renin and aldosterone levels will signifiantly increase in attempt to increase blood pressure and glomerular pressure
- If corrective measures are not enough, decreased glomerular pressure can cause acute renal failure
- Due to not enough pressure, renal tubules collapse and as a result decreased urine production and accumuation of toxins and fluids over time
Direct Renin Inhibitors MOA
- Binds to the active site of renin and blocks the conversion of angiotensinogen to angiotensin I
Mineralcoticoid-receptor antagonists (MRAS) Example
- Other name: aldosterone receptor antagonists
- Spironolactone
MRA’s MOA
- Inhibit aldosterone receptor
MRA’s Uses
- Resistant hypertension due to aldosterone excess
- Heart failure (block the negative effects of aldosterone on heart tissue)
Main cautions of MRA’s
- Increase K+
- Hormonal effects –> partially stimulates progesterone and androgen receptors (e.g. gynecomastia)
Sympathetic Nervous System
Fight or Flight System
SNS Receptors in Heart (targeted by BP meds)
Beta-1
SNS receptors Brain (targeted by BP meds)
Alpha-2
SNS receptors kidney (targeted by BP meds)
Beta-1 –> renin secreting cells
SNS receptors Blood vessels (targeted by BP meds)
Alpha- 1
Drug classes that interfere with SNS actions
- Beta-receptor antagonists (beta-blockers)
- Alpha-receptor antagonists (alpha-blockers)
- Alpha-receptor agonists (alpha-agonists)
Activation of (what receptors?) in the heart muscle causes?
Activation of B1 receptors in cardiac myocutes leads to increased intracellular Ca2+ that allows contractile proteins in the muscle to contract
Activation of (what receptors?) on arterial walls causes?
Activation of B2 receptors on some arterial wall cells cause a decrease inintracellular Ca2+ leading to relaxation/vasodilation
What receptors are important for beta-blockers for cardiovascular disorders? What are the receptors responsible for when activated?
1) Beta- 1 –> Increase heart rate and contractility (as well as renin release from pancreas)
2) Beta-2 receptors –> Vasodilation
3) Alpha-1 receptors –> Vasoconstriction
Beta-1 Selective Blockers and example
- Most common of all sub-types of beta-blockers
- Bisopropol
Common uses of Beta-1 selective blockers and mechanims
- High blood pressure (mechanism not clear; decrease CO vs decrease renin)
- High heart rate (tachycardia, tacharrythymia) –> Blocks Ca2+ channel
- Cardiac workload/cardiac ‘deman” (angina)
- cardiac damage (HF or heart attack) –> Adrenaline can make damage worse, so work as a shield
Non-selective Beta Blockers inhibit which receptors
- Beta-1 antagonist
- Beta-2 anatgonist
Non-selective Beta Blocker uses
- Additional effects related to tissues rich with B-2 receptors
-Smooth muscle –> inhibition of B2 receptors in blood vessels –> adrenaline will cause vasodilation - Lung - Inhibition of B2 receptors in airways –> drug interaction if taking salbutamol if asthmatic
- Rarely ever used due to tolerability
Non-selective Beta and Alpha Blocker receptors
Block B1, B2, and alpha-1 receptor antagonists
Non-selective Beta and Alpha Blocker receptors use
- Greater fall in BP compared to other beta-blockers
- Inhibit alpha 1 –> vasodilatory effect
What are the cautions with the use of beta-blockers?
- Decreased blood pressure
- Decreased cardiac output
- Bradycardia (decreased heart rate)
- Heart Block (AV node)
- Increased K+
- Exacerbate circulation problems via B2 cascade
- Theoretical interaction with respiratory medications
- Slight blood sugar increase
Blood Pressure Caution Beta-Blockers
- Not always using beta-blockers in individuals with high blood pressure
Heart Block: What drug and how does the drug make it worse/better?
- beta-blockers
- AV node slows down conduction so can hear the lub and dub sounds
- When an AV block, impulse is slowed down to much
- Complete AV block –> signal is completly blocked
What is the relationship between beta-blockers and K+?
- can lead to increased K+
- RAAS –> beta-receptors in the glomerulus
- When block these receptors, block ENAC channel. Na+ not reabsorped, less K+ excreted (Na+ moves through ENAC channel on apical membrane/renal tubule lumen in exchange for K+ in cell to renal lumen. 3 Na+ is transfered out of the cell by Na+/K+ ATPAse on basolateral membrane in exchange for 2 K+)
Can beta-blockers be used in asthmatic individuals?
- Blockade of B2 receptors in airway
- Typically not problematic in asthma
- Advise pts taking B2 agonists to watch for decreased response
Can beta-blockers be used in people with diabetes?
- Primary Issue - reduced recognition of hypoglycemia (SNS) trigger
- Secondary issue - slight increase in blood sugar from vasoconstriction (B2 blockade) and reduced insulin release (B-1 blockade)
Alpha-adrenergic receptor Antagonists Uses and MOA
- used to be use for BP control; now used for BPH (benign-prostatic hypertrophy)
- Inhibits vasoconstriction induced by SNS
- Often accompanied by increses in heart rate, CO and RAAS from baroreceptor activation
Alpha-2 Agonist Location of Action
- CNS
- “centrally-acting hypertensives)
- Lower BP by affecting the brain
Alpha-2 Agonists MOA
- alpha-2 receptor is located on the pre-synaptic terminal (auto-receptor)
- when stimulated, shuts down further release of messengers into the SNS nerve fiber
- reduce sympathetic outflow from the brain
- decrease circulating norepinephrine and decrease SNS nerve transmission
Alpha-2 Agonists Use, side effects and example
- Lowers blood pressure and heart rate
- Frequent side effects –> sedation, dry mouth
- Methyldopa
Endogenous peptide vasodilators examples
- Vasoactive intestinal peptide (VIP)
- Kinins (e.g. bradykinins)
- Atrial Natriuretic peptide (ANP)
- Brain natriuretic peptide
Drug and MOA for endogenous vasodilators
These vasodilator/diuretic peptides are broken down by an enzyme called neprilysin
Neprilysin inhibitor (sacubitril) inhibits this enzyme \
- Used exclusively for pts with heart failure
- No major effect on blood pressure at normal doses
- Only in combination with valsartan
Nitric Oxide MOA
- relaxes smooth muscle in blood vessel walls (vasodilation)
- a paracrine hormone synthesized by endothelial cells in response to increased pressure and NO signals smooth muscle cells next door to vasodilate
- cGMP in muscle cell reduces intracellular Ca2+
- Relaxation results from a decrease in cytoplasmic Ca2+
Nitrate Medication MOA and example
A family of prodrugs that are converted to nitric oxide in circulation
Nitroglycerin
Nitroglycerin MOA
- Conversion to Nitric Oxide
Spray and tablets cause vasodilation to VEINS as primary effect; little effect on BP (not used for hypertension)
Muscle Contraction Physiology
- Contraction initiated by an increase in cytoplasmic Ca2+
- Permits the interaction of contractile proteins (mysoin and actin)
- Contraction = Vasoconstriction
- Many triggers
Muscle relaxation Physiology
- Decrease in cytoplasmic Ca2+ due to cGMP
- cGMp is a intracellular messenger for relaxation via decreased Ca2+
- relaxation = vasodilation
Dihydropyridine Drugs (CCB) MOA and Example
AMLODIPINE
Arterial vasodilators
- Inhibits L-type Ca2+ channels
- A decrease in intracellular Ca2+ in vascular smooth muscle cells
- Promotes vasodilation in arteries ««_space;Veins
- Little impact on preload or heart rate –> Major advantage
How are CCB’s unique compared to other vasodilators? What is the MOA of vasodilators in “general?” What is the function of baroreceptors?
- Minimal effects on heart rate –> avoid reflex tachcardyia –> can be used as monotherapy
- In general, arterial vasodilators increase heart rate through SNS stimulation (reflex tachcardyia)
- reflex tachycardia is mediated by baroreceptors located in arteries
- Barorecptors sense the stretch/pressure and are linked to nerve endings signalling CNS
- Increased stretch causes reflex in vagal outflow (decreased heart rate)
- Decreased stretch, reflex increases in SNS outflow (increased heart rate, cardiac output and constriction)
- ## Reflex tachycardia is NOT DESIRABLE characteristic for CV drugs
Direct Acting Vasodilators
- directly relax arteriolar smooth muscle
- can cause reflex tachcardyia and fluid retention
- not first line –> adverese effects
PDE Physiology
- cGMp activates a specific enzyme in a muscle cell that decreases CA2+ causing vasodilation
- cells will degrade cGMP to maintain homeostasis
- ## degredation of cGMP occurs from phosphodiesterase (PDE) enzyme
PDE5 Inhibitors MOA
- Inhibit phosphodiesterase (PDE) enzyme leading to vasodilation by preventing the breakdow of cGMP
Can Nitroglycerin be taken with a PDE5 inhibitor?
NO –> DRUG INTERACTION
Nitroglycerin increases production of cGMP to promote vasodilation.
PDE5 Inhibitors prevent the breakdown of cGMP
- Abundance of cGMP
- When nitroglycerin is combined with PDE5, arterial blood vessels will be effected
- Severe hypotension can arise
- Wait atleast 24 hours after PDE5 inhibtor before using a nitrate
NON-DHP Calcium Channel Blockers (Non-DHP CCB) MOA
- NOn-DHP primarilarily effect is on cardiac smooth muscle
- Decrease contractility and decrease heart rate
Uses of NON-DHP Calcium Channel Blockers (Non-DHP CCB) and cautions
Effective at lowering blood pressure but commonly used for uncomplicate dhypertension
Useful for situations where heart rate is high (tachycardi) and myocardial demand is high
Dangerous if HR already low and severe systolic dysfunction
How much does hypertension medication lower blood pressure?
10 to 5 mmHG
General symptoms of blood pressure medications
Erectile dysfunction, diziness, unsteadiness, falls, fatigue, electrolyte changes (especially K+)
