McCauley: Basic Cardiovascular Pharmacology Flashcards
DIURETICS
Basic Pharmacological Effects:
All diuretics increase the loss of sodium into the forming urine, which results in increased urine flow and loss of water.
DIURETICS Drugs in this Class (6): Loop Diuretics (1): Thiazide and Thiazide-Like Diuretics: (3) Potassium Sparing Diuretics: (2)
Loop Diuretics
1. Furosemide
Thiazide and Thiazide-Like Diuretics:
- Hydrochlorothiazide
- Metolazone
- Chlorthalidone
Potassium Sparing Diuretics:
- Amiloride
- Spirinolactone
Proximal Tubule
Normal Physiology:
What is filtered in the proximal tubule?
How does tubular fluid maintain a constant osmolarity?
Basically all filtered organic metabolites are reabsorbed in the proximal tubule
Water is passively reabsorbed and tubular fluid maintains a constant osmolarity
What % of each is reabsorbed in proximal tubule?
NaHCO3
NaCl
Water
About 85% of the NaHCO3, 40% of the NaCl and 60% of the water that is filtered is reabsorbed in this segment.
Na reabsorption is catalyzed by three pivotal proteins in the lumenal cells, and water is reabsorbed along with the Na.
Proximal Tubule
Na Reabsorption
What is Na in the lumen exchanged for? Via what?
Once in the cell, Na pumped into interstitium/blood using:
Na in the lumen exchanged for intracellular H+ using the Na/H+ exchanger (NHE3)
Once in the cell, Na pumped into interstitium/blood using the Na/K ATPase.
Proximal Tubule
Bicarbonate Reabsorption
What does excreted H+ combine with? Form?
What is CA hydrolyzed by? Resulting in?
Excreted H+ combines with bicarbonate in the lumen to form carbonic acid
Carbonic acid is hydrolyzed by carbonic anhydrase found in the luminal membrane, resulting in the formation of water and CO2
Proximal Tubule
Bicarbonate Reabsorption
What happens when CO2 diffuses back into the cell?
What does intracellular carbonic acid dissociate into?
CO2 diffuses back into the cell where it combines again with water (using a different CA enzyme) to form carbonic acid
Intracellular carbonic acid dissociates into H+ (pumped back into lumen in exchange for Na) and bicarbonate (reabsorbed into the blood)
Proximal Tubule
Cl/Base Exchanger
What is the result of bicarb being reabsorbed faster than Na?
What happens to tubule fluid? What becomes activated?
What is exchanged forl Cl-?
Bicarbonate is reabsorbed faster/more extensively than Na, and as a result, H+ being pumped into the lumen in exchange for Na no longer buffered
Tubule fluid becomes acidic and activates this exchanger, which promotes the reabsorption of Cl- in exchange for base being pumped into lumen.
Proximal Tubule
Water Reabsorption
Volume of water that is reabsorbed vs permeability of the cell membrane:
What does water also pass through?
Volume of water that is reabsorbed exceeds the permeability of the cell membrane
- Water also passes through specialized water channels (aquaporin I)
Proximal Tubule
Drugs that Work Here (2):
Carbonic anhydrase inhibitors
Osmotic Diuretics
Proximal Tubule
Carbonic Anhydrase Inhibitors
MOA:
What is a topical CA inhibitor used locally?
Carbonic Anhydrase Inhibitors: reduce the activity of the Na/H exchanger, leading to loss of NaHCO3 and water; not often used in CV diseases
Dorzolamide: topical CA inhibitor used locally (ie. in the eye to reduce intraocular pressure)
Proximal Tubule
Osmotic Diuretics
Do not permeate:
Result of lack of permeation:
What is an osmotic diuretic given by IV to avoid osmotic diarrhea?
Osmotic Diuretics: do not permeate luminal membrane, increasing the osmolality of the forming urine and reducing the reabsorption of water; similar to glucose in diabetics.
Mannitol: osmotic diuretic given by IV to avoid osmotic diarrhea.
Loop of Henle:
Normal Physiology
Thin vs thick Ascending loop:
Thin Loop: more water passively reabsorbed into the hypertonic interstitium.
Thick Ascending Loop: impermeable to water.
Thick Ascending Loop
NaK2Cl Symporter (NKCC2): What does it transport from the lumen? Na pumped into interstitium/blood using what? What happens to intracellular K+? What is the result of this?
NaK2Cl Symporter: transports Na, K and 2 Cl into the cell from the lumen
Na pumped into interstitium/blood using Na/K ATPase
Intracellular K+ increases (coming in from lumen AND interstitium)
K+ diffuses back into lumen as a result (back diffusion of K+), resulting in a more positive luminal potential
Thick Ascending Loop
Positive Luminal Potential:
Positive Luminal Potential: driving force for NaK2Cl symporter, as well as the reabsorption of Ca++ and Mg++ from the tubular fluid.
Thick Ascending Loop
Drugs that Work Here (2):
Direct inhibitors of what transporter?
What is the diuretic effect primarily due to?
Loop (High Ceiling) Diuretics: direct inhibitors of the NaK2Cl transporter; diuretic effect can be severe and is primarily due to sodium loss (35% if filtered Na usually reabsorbed here)
- Furosemide
- Ethacrynic acid
What is the juxtaglomerular apparatus?
Where are juxtaglomerular cells located?
What do they do?
Juxtaglomerular Apparatus: microscopic structure in kidney located between the vascular pole of the renal corpuscle and the distal convoluted tubule of the same nephron
Juxtaglomerular Cells: located in the afferent arterioles of the glomerulus; act as intra-renal pressure sensory and secrete renin*.
What cells line the distal convoluted tubule sense changes in concentration of sodium chloride?
What do Extraglomerular Mesangial Cells do?
Macula Densa: cells lining the distal convoluted tubule who sense changes in concentration of sodium chloride.
Extraglomerular Mesangial Cells: communicate via gap junctions with structural mesangial cells that surround glomerular capillaries
What is renin secretion inversely proportional to?
Renin Secretion: inversely proportional to NaCl load delivered to macula densa (ie. if NaCl load is low, renin secretion increases).
Juxtaglomerular Apparatus Importance in Diuretic Use
Detection of NaCl load depends on action of:
What happens to NaCl if using a loop diuretic?
Detection of NaCl load depends on action of NaK2Cl transporter: if using a loop diuretic (and to a lesser extent, a thiazide diuretic), the NaCl will not be able to be transported into the cells of the macula densa due to the blockage of this receptor.
Juxtaglomerular Apparatus
How does the macula densa respond?
What are these drugs typically given along with?
Macula densa will perceive it as low NaCl load and stimulate renin release
As a result, these drugs are typically given along with an ACE inhibitor, to prevent the downstream effects of renin
Distal Convoluted Tubule
DCT and water:
What does the NaCC do?
What does Na/K ATPase do?
How does back diffusion of DCT compare to TAL?
DCT is impermeable to water
NaCC or NCC (Na/Cl- Symporter): electrically neutral pump that reabsorbs Na and Cl
Na+ pumped back into interstitium/blood using Na/K ATPase.
Unlike in the TAL, there is no back diffusion of K+ and therefore lumen is not positively charged (no driving force for reabsorption of cations).
Distal Convoluted Tubule
Ca++ Reabsorption: duel functions
Both are under the control of:
Ca++ Reabsorption:
Ca++ channel AND a Ca/Na exchanger
- Both of these under the control of PTH (receptors for it located on membrane of tubular cells).
Distal Convoluted Tubule
Drugs that Work Here (3):
Thiazide and Thiazide-Like Diuretics:
- Hydrochlorothiazide*
- Metolazone
- Chlorthalidone*
Distal Convoluted Tubule
Drugs that Work Here
What do they inhibit?
How does the diuresis compare to that of loop diuretics?
What if they are used with one?
Thiazide and Thiazide-Like Diuretics: inhibit the Na+/Cl- symporter (NaCC) of the distal convoluted tubule; diuresis not as profound as that cause by loop diuretics, and will have additive effects if used with one (can be used in combination)
Late Distal Tubule/Collecting Duct
What cell reabsorbs Na? Controlled by what?
What does the Late Distal Tubule/Collecting Duct contain that allows Na to enter? What is it driven by?
Na+ Reabsorption by Principal Cells: controlled by aldosterone*
Contain an epithelial Na channel (ENaC) that allows Na to enter the cell (driven by continuous expulsion of Na by Na/K ATPase on the basolateral side of the cell)
Late Distal Tubule/Collecting Duct
What is K+ loss controlled by?
What does Na reabsorption create?
K+ Loss via Prinicipal Cells: controlled by aldosterone (Na+ reabsorption)*.
Na reabsorption creates a negative lumen potential that promotes the reabsorption of Cl- and the secretion of K+.
Late Distal Tubule/Collecting Duct
What happens when Na reaches the distal tubule?
What is K+ worsened by? Why?
Therefore, the more Na+ that reaches the distal tubule, the more K+ lost (ie. loop and thiazide diuretics can cause hypokalemia).
K+ loss worsened if bicarbonate also present (ie. due to CA inhibitors) because it increases negative lumen potential but cannot be reabsorbed.
Late Distal Tubule/Collecting Duct
H+ Loss via:
What contributes to the expulsion of protons using ATP-dependent proton pump?
H+ Loss via Intercalated Cells: negative lumen potential contributes to expulsion of protons using ATP-dependent proton pump?
Late Distal Tubule/Collecting Duct
What does ADH stimulate to increase water reabsorption? Where?
The effect of lithium:
Water Reabsorption: ADH stimulates the expression AQP2 on apical membrane to increase water reabsorption (Lithium dramatically reduces this effect –> polyruria, polydipsia)
Late Distal Tubule/Collecting Duct
Drugs that Work Here:
Potassium sparing diuretics (all may cause HYPERkalemia)
Amiloride
Spironolactone
Amiloride is a specific inhibitor of:
What is it used more commonly for?
Amiloride: specific inhibitor of ENaC with mild diuretic action
Used more commonly to blunt hypokalemic side effects produced by diuretics (however, can also be managed by oral KCl supplements)
What is a competitive antagonist of aldosterone with mild diuretic action?
Spironolactone: competitive antagonists of aldosterone with mild diuretic action
Draw PCT schematic (pg 332)
Draw PCT schematic (pg 332)
Draw TAL schematic (pg 332)
Draw TAL schematic (pg 332)
Loop Diuretics (High Ceiling) Drugs in this Class: (4)
o Furosemide*
o Bumetanide
o Ethacyrnic Acid
o Torsemide
Loop Diuretics (High Ceiling) Clinical Use/Effects: (7)
Increases: Has direct effects that relieve: Ca: K: Elimination in toxic OD: What happens in acute renal failure?
Edema
Increases RBF
Appears to have direct effects that relieve pulmonary congestion and left ventricular pressure in heart failure (ie. these effects occur prior to diuresis)*
Acute hypercalcemia (in combination with saline)
Mild hyperkalemia
Elimination of bromide, fluoride, and iodine ions in toxic OD (halogens reabsorbed in ascending limb)
Acute renal failure (increase urine flow and K+ excretion, may help flush intratubular casts)
Loop Diuretics (High Ceiling)
Edema associated with: (3)
Heart failure
Liver disease (cirrhosis)
Renal disease (nephrotic syndrome, chronic and acute renal insufficiency)
Loop Diuretics (High Ceiling)
What can they potentially cause secondary to dehydration?
Can cause hypercalcemia secondary to dehydration
Loop Diuretics (High Ceiling) Pharmacokinetics
Oral absorption:
Eliminated by:
What does half-life depend on?
Why aren’t these good agents for HTN?
Well absorbed orally
Eliminated by tubular secretion and filtration (by the kidneys)
Half life depends on renal function (usually 1.5 hours)
Short half life is the reason why these agents are typically not good for tx of HTN
Loop Diuretics (High Ceiling) Adverse Effects: (7)
- Hypokalemia
- Alkalosis
- Hypomagnesia
- Dehydration (+/- hypercalcemia)
Hyperuricemia and gouty attacks (hypovolemia-enhanced reabsorption of uric acid in the proximal tubule)
Dose related hearing loss and allergic reactions (rare)
Loop Diuretics (High Ceiling)
Hypokalemia
What causes K+ secretion?
*Hypokalemia (increased Na+ to collecting duct causes K+ secretion)
Loop Diuretics (High Ceiling)
What causes alkalosis?
How is it managed?
- Alkalosis (increased Na+ to collecting duct causes H+ secretion)
- Both managed with administration of potassium sparing diuretics or KCl
Loop Diuretics (High Ceiling)
Hypomagnesia is controlled with:
*Hypomagnesia (controlled with Mg supplementation)
Loop Diuretics (High Ceiling)
Dehydration causes:
*Dehydration (+/- hypercalcemia)
Loop Diuretics (High Ceiling)
What causes Hyperuricemia and gouty attacks?
Hyperuricemia and gouty attacks (hypovolemia-enhanced reabsorption of uric acid in the proximal tubule)
Loop Diuretics (High Ceiling)
Drug Interactions:
Ex:
NSAIDs decrease diuretic effects> Due to interference with a number of prostaglandin mediated renal effects.
Ex: PGE2 supports ADH mediated water transport in the collecting duct
Thiazide and Thiazide-Like Diuretics
Drugs in this Class: (5)
o Hydrochlorothiazide* (Prototype) o Chlorthalidone* (Prototype) o Metolazone* o Quinethazone o Indapamide
Thiazide and Thiazide-Like Diuretics
What is edema associted with?
Edema associated with cardiac, hepatic and renal conditions
Thiazide and Thiazide-Like Diuretics
What is the most important CV application?
What dosing is recommended?
How does it affect the HR/CO?
Hypertension (most important CV application)
Use of low doses recommended (increasing can lead to unwanted SEs and extreme diuresis)
Lower peripheral resistance without significant effect on either HR or CO
Thiazide and Thiazide-Like Diuretics
How is there indirect action on smooth muscle cells?
What does this lead to?
Indirect action on smooth muscle cells by depletion of Na, which leads to reduction in intracellular Ca (Na/Ca exchanger brings in Na), making SMCs refractory to contractile stimuli
Thiazide and Thiazide-Like Diuretics
What happens to plasma volume and RBF?
How does it affected plasma renin activity?
How does race relate to sensitivity?
Marginally decrease plasma volume and RBF
Increase plasma renin activity
Equally effective in African and European-American populations (Asians may be more sensitive)
Thiazide and Thiazide-Like Diuretics
What is an important limitation?
What is the exception?
The majority (with the exception of metolazone) become practically ineffective when the GFR is <30 mL/min
Thiazide and Thiazide-Like Diuretics
What are they used in combination with for the treatment of CHF?
Chronic heart failure (often in combination with ACE inhibitors or loop diuretics)
Thiazide and Thiazide-Like Diuretics
Idiopathic hypercalcuria with kidney stones
MOA
What leads to the increase of basal Na/Ca exchanger? Where does this move Na and Ca?
What does this also lead to the reabsorption of?
Inhibit NCC and lower Na+ reabsorption in DCT, leading to increased activity of basal Na/Ca exchanger that moves Na into cells and Ca into interstitium
Also leads to reabsorption of Ca++ from tubule through apical channel
Thiazide and Thiazide-Like Diuretics
Treatment of Nephrogenic diabetes inisipidus (ie. caused by lithium)
MOA of decreased urine flow:
What happens to lithium clearance?
Results in paradoxical decreased urine flow that has not be explained (MOA unclear)
Need to monitor Li levels because it may reduce Li clearance
Thiazide and Thiazide-Like Diuretics
Oral absorption:
Excretion:
Half-life:
Well absorbed orally
Excreted in the urine via organic acid secretory system in the proximal tubule
Half life varies (majority of them are long enough for once daily dosing)
Thiazide and Thiazide-Like Diuretics
Adverse effects
On Calcium
SEs due to change in calcium (3)
Hypercalcemia (not by itself, but can unmask subclinical hypercalcemic conditions)
• Hyperparathyroidism
• Sarcoidosis
• Paraneoplastic syndromes
Thiazide and Thiazide-Like Diuretics
Adverse effects
On Potassium
On pH
What can reverse this effect?
Hypokalemia (same mechanism as loop diuretics)
Alkalosis (same mechanism as loop diuretics)
• Both reversed by potassium sparing diuretics or KCl supplements
Thiazide and Thiazide-Like Diuretics
How do they induce hyperuricemia?
Hyperuricemia (competes with uric acid for secretion by the organic acid secretory system in the proximal tubule)
Thiazide and Thiazide-Like Diuretics
Effect on glucose levels:
Impairs pancreatic release of what?
Effect on lipid profile:
Induce hyperglycemia (use with caution in patients with diabetes)
Impaired pancreatic release of insulin and reduced peripheral utilization of glucose
Alter lipid profile (use with caution in patients with dyslipidemia)
• 5-15% increase in total cholesterol and LDL
Thiazide and Thiazide-Like Diuretics
What severe but rare side effect effects sodium levels and only occurs in predisposed individuals
Hyponatremia (severe but rare side effect that only occurs in predisposed individuals; can be fatal)
Thiazide and Thiazide-Like Diuretics
DDI
NSAIDs reduce diuretic effects
Spironolactone
Effects in severe CHF.
Morbidity and mortality are reduced in patients who:
Spironolactone has beneficial effects in severe congestive heart failure (CHF). Both morbidity
and mortality are reduced in patients that are also taking an ACE inhibitor. This effect appears not
to be due to either diuresis or potassium sparing effects.
Spironolactone
What does spironolactone respond to aldosterone
Aldosterone is thought to facilitate
myocardial fibrosis, and spironolactone antagonizes this effect.
Spironolactone
What is it sometimes used in conjunction with? For what?
Effects on aldosterone:
Edema:
Spironolactone sometimes is used in conjunction with thiazide or loop diuretics to reduce K loss.
It is also used in both primary and secondary aldosteronism.
In addition, edema due to hepatic
cirrhosis is particularly responsive to spironolactone.
Spironolactone Adverse Effects (2)
Hyperkalemia (Most important)
Endocrine like effects (gynecomastia, impotence, peptic ulcers)
Spironolactone
What is Epleranone?
A more specific antagonist that causes fewer adverse effects
What can be used to limit diuretic induced hypokalemic alkalosis?
Amiloride can be used to limit diuretic induced hypokalemic alkalosis.
Amiloride
How is it used in Li-induced diabetes insipidus?
It is also used in Li induced diabetes insipidus to prevent entry of Li into the collecting duct cells and thereby limit Li’s ability to interfere with aquaporin 2 expression.
Agents That Interfere with Angiotensin II: (4)
enalapril
lisinopril
losartan
aliskiren
Agents That Interfere with Angiotensin II
How do these drugs reduce the effects of angiotensin II? (2)
These drugs reduce the effects of angiotensin II either by:
Interfering with its synthesis (aliskiren,
captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, ramipril and aliskiren)
or by
Antagonizing the binding of angiotensin II to its receptor (candesartan, losartan and valsartan).
Agents That Interfere with Angiotensin II
Structure and production:
Angiotensinogen → Angiotensin II:
Structure and Production: octapeptide produced by serial proteolytic cleavage of angiotensinogen
Angiotensinogen →(Renin)→ Angiotensin I →(ACE)→ Angiotensin II
Agents That Interfere with Angiotensin II
Renin
Cleaves:
Dependent on:
Where is angiotensinogen secreted?
Cleaves the amino terminal decapeptide from the plasma protein angiotensinogen to give angiotensin I (highly dependent on the concentration of angiotensinogen, which is produced in and secreted by the liver)
Agents That Interfere with Angiotensin II
Angiotensin Converting Enzyme (ACE)
Cleaves what from angiotensin I?
Catalyzes the degradation of:
Angiotensin Converting Enzyme (ACE): cleaves two C-terminal residues from angiotensin I to produce angiotensin II (located in the vascular endothelium of most organs- esp. lungs and kidney)
Also catalyzes the degradation of bradykinin
Agents That Interfere with Angiotensin II
Control of Secretion of Renin
Where is the NaCl load delivered?
Relationship between renin and NaCl:
How is NaCl detected in TAL?
In DCT?
NaCl Load (Macula Densa): release of renin INVERSELY proportional to NaCl load that is detected by the macula densa
NaCl is transported into the macula densa to be detected using NaK2Cl symporter (TAL) and the NaCC symporter (DCT)
Agents That Interfere with Angiotensin II
What cells detect changes in renal blood pressure? Where are these cells located?
What happens when there is increased BP?
How do NSAIDs affect renin secretion?
Changes in Renal BP (Juxtaglomerular Cells): changes in renal BP detected by these cells in the afferent arterioles of the glomeruli
Increased pressure inhibits the release of PGs and stimulates renin secretion
NSAIDs and other inhibitors of PG synthesis DECREASE renin secretion
Agents That Interfere with Angiotensin II
What are Beta-1 Adrenergic Receptors activated by?
How do they affect renin secretion?
Activation of Beta-1 Adrenergic Receptors: by SS postganglionic stimuli (powerful force for renin secretion)
Factors Affecting Production/Secretion of Angiotensinogen: (3)
Corticosteroids
Estrogens (oral contraceptives)
Thyroid hormones
Effects of Angiotensin II
What mediates it?
Effect on arterial pressure:
Effect on Na and fluid:
Effect on vasculature:
General Effects: all mediated by AT1 receptor and involve many mechanisms of signal transduction
Increased arterial pressure
Na and fluid retention (directly and indirectly- induce release of aldosterone)
Vascular and cardiac remodeling
Effects of Angiotensin II
Effects on Peripheral Resistance
What are the direct effects?
Where is it most and least pronounced?
Direct Effects: acts directly on arteriolar smooth muscle cells to cause constriction and increase in vascular resistance (more potent than NE)
Most pronounced in kidney
Least pronounced in skeletal muscle beds
Effects of Angiotensin II
Effects on Peripheral Resistance
Indirect effects:
Enhances release of: (2)
Effect on NE uptake:
Indirect Effects: also act to increase BP
Enhances release of NE from SS nerves and EPI from the adrenal glands
Reduces neuronal NE uptake
Effects of Angiotensin II
Effects on Peripheral Resistance
Effect on vascular sensitivity to NE:
CNS effect:
Increases vascular sensitivity to NE
Acts on areas of CNS that are not protected by BBB to increase sympathetic tone (ie. area postrema)
Effects of Angiotensin II
Effects on Renal Function
Effects on Na retention:
Stimulates what in proximal tubule?
Effect on aldosterone secretion:
What decreases renal blood flow?
Increased Na retention:
Stimulated Na/H exchange in proximal tubule
Enhances aldosterone secretion
Decreased renal blood flow due to AT1 mediated contraction of renal smooth muscle and enhance SS tone
Effects of Angiotensin II
Effects on Renal Function
Effect on GFR:
Effect on mesangial cells:
Effect on afferent and efferent arterioles of glomerulus:
Decreased GFR
Constricts mesangial cells in glomerulus
Constricts both afferent and efferent arterioles of glomerulus (exert opposing effects on GFR)
Effects of Angiotensin II
Effects on Cardiovascular Structure
Direct effect on heart:
Effect on smooth muscle cells in heart:
Effect on cardiac myocytes:
Effect on ECM synthesis:
Direct Effects: contribute to increased wall-to-lumen ratio in vessels and the concentric cardiac hypertrophy seen in HTN
Increases migration, proliferation and hypertrophy of smooth muscle cells
Hypertrophy of cardiac myocytes
Increases ECM synthesis by both cardiac and vascular fibroblasts
Effects of Angiotensin II
Effects on Cardiovascular Structure
Indirect Effects on heart:
Effect on cardiac preload:
Effect on afterload:
Effect of aldosterone:
Indirect Effects: involved in cardiac hypertrophy and remodeling
Increased cardiac preload (volume expansion)
Increased afterload (greater peripheral resistance)
Increased aldosterone causes myocardial fibrosis
Angiotensin Converting Enzyme (ACE) Inhibitors
General Pharmacological Effects
Effect on peripheral resistance:
Effect on heart rate:
Decrease peripheral resistance without increasing HR
Angiotensin Converting Enzyme (ACE) Inhibitors
General Pharmacological Effects
Effect on cardiac and vascular remodeling:
Effect on sodium:
Reduce cardiac and vascular remodeling
Promote naturiesis
Angiotensin Converting Enzyme (ACE) Inhibitors
Drugs in this Class:
o Enalapril* o Lisinopril* o Captopril o Fosinopril o Peridopril o Quinapril o Ramipril
Angiotensin Converting Enzyme (ACE) Inhibitors
Hypertension
Effect in high vs low renin HTN:
What types of HTN can be controlled by ACE-Is?
How are diuretics included?
Effective in both high and low renin HTNs
Most mild to moderate HTNs (independent of plasma renin levels) can be controlled with ACE inhibitors +/- diuretic
Angiotensin Converting Enzyme (ACE) Inhibitors Heart failure (all stages)
Effect on preload:
Afterload:
Effect on CO and SV:
cardiac and vascular remodeling:
Reduced preload (venodilation and improved renal hemodynamics)
Reduced afterload (decreased peripheral resistance and increased arterial compliance)
Both of these effects lead to increased CO and SV
Reduced cardiac and vascular remodeling
Angiotensin Converting Enzyme (ACE) Inhibitors
What is the effect of loop diuretics on renin? How do ACE-Is counteract these effects?
Decrease effects of high renin levels caused by loop (and possibly thiazide) diuretics
Angiotensin Converting Enzyme (ACE) Inhibitors
Useful against what conditions? (4)
They are useful against: Hypertension Heart failure Ventricular dysfunction after infarction Diabetic nephropathy
Angiotensin Converting Enzyme (ACE) Inhibitors Diabetic nephropathy (and other chronic renal diseases)
What is the effect to the glomerular efferent arteriole?
Intraglomerular pressure?
What does this lead to?
Decrease resistance in glomerular efferent arteriole and reduced intraglomerular pressure (with decreased GFR)
Above effects + improved renal blood flow leads to reduced proteinuria and improve renal function (naturiesis)
Angiotensin Converting Enzyme (ACE) Inhibitors
Pharmacokinetics
What are Enalapril and lisinopril:
What activates them?
Half-lives:
Most ACE inhibitors are subject to:
Enalapril and lisinopril are PRODRUGs that are activated by cleavage of an ester bond in the liver
Half lives around 12 hours
Most ACE inhibitors are subject to first pass metabolism
Angiotensin Converting Enzyme (ACE) Inhibitors
Adverse Effects
Blood pressure:
Most common adverse effect:
Hypotension possibly causing loss of consciousness (after first dose in patients with high plasma renin activity)
Persistent dry cough (most common; due to increased bradykinin and lung PGs; most severe in African Americans)
Angiotensin Converting Enzyme (ACE) Inhibitors
Adverse Effects
Potassium levels:
In what patients?
How are ACE-I K sparing?
Used clinically to:
Often combined with:
May be less effective in what population?
Hyperkalemia (in patients with renal insufficiency or those treated with potassium sparing diuretics, K supplements or beta-blockers)
- ACE inhibitors are K sparing themselves due to reduction in aldosterone secretion
- Used clinically to minimize the ability of diuretics to cause hypokalemia (often combined with thiazide diuretics in one formulaton)
May be less effective in African-Americans and elderly patients
Angiotensin Converting Enzyme (ACE) Inhibitors
NSAIDs
Effect on Na excretion:
When used with ACE-I:
Decrease Na excretion and may cause hyperkalemia
Antagonize antihypertensive effect of ACE inhibitors
Angiotensin Converting Enzyme (ACE) Inhibitors
Contraindications: (2)
Pregnancy: teratogenic
Bilateral renal artery stenosis: acute renal failure may occur in these patients since renal perfusion is maintained by angiotensin II
Renin Inhibitor (Aliskiren)
MOA:
Formulations:
Adverse Effects:
MOA: inhibits renin competitively and consequently reduces angiotensin II synthesis
Formulations: first drug of this class approved in the US; also formulated in combination with HCZ
Adverse Effects: cough and GI disturbances
Renin Inhibitor (Aliskiren)
DDIs:
Contraindications:
Drug Interactions:
- Decreases serum concentration of fureosemide
- Cyclosporine increases aliskiren blood levels dramatically
Contraindications: pregnancy (teratogen)
AT1 Antagonists (Angiotensin Receptor Blockers/ARBs)
Similar effects to:
Useful in which patients?
General Pharmacological Effects: similar effects to ACE inhibitors with similar pharmacological efficacy
Especially useful in patients who develop ACE-inhibitor-mediated cough
AT1 Antagonists (Angiotensin Receptor Blockers/ARBs)
Drugs in this Class: (4)
Losartan*
Valsartan*
Candesartan
Irbesartan
AT1 Antagonists (Angiotensin Receptor Blockers/ARBs)
Adverse Effects:
DDIs:
Contraindications:
Adverse Effects: same as ACE inhibitors (except for the cough); also reports of hepatic dysfunction
- Also possibly less effective in African Americans
Drug Interactions:
o NSAIDs: decrease antihypertensive effects
Contraindications: pregnancy (teratogen)
What type of agents are beta blockers?
SYMPATHOLYTIC AGENTS
Beta Blockers
General Uses in CV Medicine: (5)
HTN Cardiac arrhythmias Angina Acute MI Heart failure
Effects of Beta Blockade
Reduced heart rate:
Important to minimize myocardial O2 consumption in patients with angina and heart failure
Effects of Beta Blockade
Conduction velocity through the AV node and refractory period:
Reentry:
Propagation of atrial arrhythmias:
Decreased conduction velocity through the AV node and increased refractory period
Reduce reentry (involved in pathogenesis of different arrhythmias)
Prevent the propagation of atrial arrhythmias to the ventricles
Effects of Beta Blockade
Ventricular ectopic beats:
important when?
Suppresses ventricular ectopic beats
- Especially important in the acute phase of MI
Effects of Beta Blockade
cardiac contractility:
cardiac work during exertion:
Prevents:
improves:
Reduction of cardiac contractility (decreased work and reduced O2 consumption)
Reduction of cardiac work during exertion (also due to decreased HR) prevents occurrence of angina episodes and improves exercise tolerance
Effects of Beta Blockade
peripheral resistance:
SV:
Decreased peripheral resistance and slowing of ventricular ejection
Improves SV in obstructive cardiomyopathy
Effects of Beta Blockade
Rate of development of systolic pressure:
Beneficial in:
Decreased rate of development of systolic pressure
Beneficial in dissecting aortic aneurism
Effects of Beta Blockade
Produces what after MI?
Produces a slower, regular, more efficient heart beat with decreased peripheral resistance (after MI)
Effects of Beta Blockade
NE mediated cardiac hypertrophy:
Reduce NE mediated cardiac hypertrophy in heart failure
Effects of Beta Blockade
thyrotoxicosis:
chronotropism:
inotropism:
Control cardiac effects of thyrotoxicosis (decrease chronotropism and inotropism)
Effects of Beta Blockade
Suppression of renin release due to sympathetic stimulation of the juxtaglomerular apparatus
Major role in:
Suppression of renin release due to sympathetic stimulation of the juxtaglomerular apparatus
Major role in the control HTN (inhibit B1 receptors)
Effects of Beta Blockade
Suppression of renin release due to sympathetic stimulation of the juxtaglomerular apparatus
K sparing due to:
Secondary to:
Potassium sparing (like ACE inhibitors) due to the reduction in aldosterone secretion (secondary to decreased renin)
Effects of Beta Blockade
Suppression of renin release due to sympathetic stimulation of the juxtaglomerular apparatus
Combined with:
Usually combined with a diuretic (often a thiazide) to control HTN, although they are effective alone
Beta Blockers
Adverse Effects
Due to excessive beta blockade: (4)
Bradycardia
Heart failure
Hypotesion
Bronchospasm (B2 block in bronchioles)
Beta Blockers
Adverse Effects
CNS Effects: (5)
Depression Fatigue Insomnia Hallucinations Impotence
Beta Blockers
Adverse Effects
Hypoglycemia:
Hypoglycemia: can occur in diabetics due to block of beta2 receptors which are normally stimulated to enhance glycogenolysis; can also mask hypoglycemia sensations (hunger, palpitations, tremor- NOT sweating)
Beta Blockers
Adverse Effects
Negative effects on lipid profiles:
Beta blockers with intrinsic sympathomimetic effects:
Negative effects on lipid profiles: raise triglycerides, lower HDL and HDL/LDL ratio
Beta blockers with intrinsic sympathomimetic effects may have less of these effects (ie. pindolol and labetalol)
Beta Blockers
Adverse Effects
Hypertensive crisis and acute coronary events upon withdrawal:
Hypertensive crisis and acute coronary events upon withdrawal: due to up-regulation of post synaptic receptors induced by long-term beta blocker treatment
Beta Blockers
Adverse Effects
Racial differences:
Racial differences: may be less effective in African Americans
Beta Blockers
Contraindications: (2)
Asthmatics
Caution with diabetics (hypoglycemia)
Beta Blockers
Drug Interactions:
NSAIDs: reduce antihypertensive effects
Various Beta Blockers
Propanolol:
hepatic metabolism:
Blood levels:
Propanolol: non-selective
Extensive first pass hepatic metabolism
Blood levels show remarkable variation
Various Beta Blockers
Metoprolol:
hepatic metabolism:
COPD:
Sustained release form:
Metoprolol: beta1 selective (prototype)
Extensive first pass hepatic metabolism
Can be used with caution in some forms of COPD (ie. emphysema), but still contraindicated in asthmatics because their specificity is not absolute
Sustained release form used against chronic heart failure (reduces mortality and hospitalization)
Various Beta Blockers
Atenolol:
Atenolol: beta1 selective
Does NOT undergo first pass metabolism
Specificity not good enough to allow use in asthmatics
Various Beta Blockers
Pindolol:
cardiodepressant effects:
effects on serum lipids:
Pindolol: non-selective with some beta1 agonist activity
Less cardiodepressant effects
Less effects on serum lipids
Various Beta Blockers
Labetalol:
peripheral resistance: serum lipid: effective in African-Americans? orthostatic hypotension: pregnant patients:
Labetalol: alpha1 and non-selective beta blockers PLUS some beta sympathomimetic activity
Reduces peripheral resistance with less effect on HR and CO
Does not affect serum lipids
May be EQUALLY as effective in African-Americans as in other groups
May cause orthostatic hypotension
Used to manage hypertension in pregnant patients
Various Beta Blockers
Carvediol:
inhibits:
vascular smooth muscle mitogenesis:
Metabolized by:
Carvediol: alpha1 and beta non-selective blocker (beta effects more prominent)
Also inhibits oxygen radical mediated lipid peroxidation
Reduces vascular smooth muscle mitogenesis
Both of the above properties contribute to use in heart failure
Metabolized by CYP2D6 (quinidine and fluoxetine compete)
Various Beta Blockers
Esmolol:
Half life:
Administered by:
Esmolol: ultra-short acting beta1 selective blocker
Half life of only 10 minutes
Administered by IV to control supraventricular arrhythmias, HTN and MI in acutely ill individuals
Various Beta Blockers
Sotalol:
Sotalol: non-selective PLUS a K+ channel blocker
Various Beta Blockers
Nebivolol:
Acts on:
Type:
Nebivolol: beta1 selective antagonist metabolized to a beta2 agonist
Acts on peripheral beta2 receptors to increase NO and lower peripheral resistance
3rd generation beta blocker (secondary antihypotensive effects)
Other 3rd Generation Beta Blockers:
Other 3rd Generation Beta Blockers: celiprolol and betaxolol
- Also Nebivolol
Methyldopa
MOA:
MOA: overall, dampens central adrenergics to reduce vasomotor tone (does NT suppress peripheral adrenergic activity
Methyldopa
Brain:
Especially in:
Results in:
Brain: Actively transported into the brain and metabolized in neurons to form methylNE, which is released and acts on presynaptic alpha2 receptors
Especially in nucleus of tractus solitarius of the medulla oblongata
Results in INHIBITION of further NE release
Methyldopa
Periphery:
Periphery: stored in secretory vesicles in place of NE and causes same potent vasoconstrictor effects as NE
Methyldopa
Effects:
Effects: lowers peripheral resistance without significant effects on HR, CO, RBF, plasma volume or renin secretion
Methyldopa
Adverse Effects: (3)
- CNS Effects
- Hepatotoxicity (rare)
- Hemolytic anemia (~20% develop + Coombs test due to presence of anti-Rh Abs; 1-% develops actual hemolytic anemia)
Methyldopa
CNS Effects: (5)
CNS Effects:
- Sedation
- Dry mouth
- Reduced libido
- Parkinsonian signs
- Hyperprolactinemia (may lead to galactorrhea)
Methyldopa
Use:
Effective antihypertensive (especially when combined with a diuretic; SEs limit use)
Tx of HTN in pregnancy
Clonidine
MOA:
At high concentrations:
Some hypotensive effects also mediated by:
MOA: selective alpha2 receptor agonist that inhibits central release of NE, causing reduction of adrenergic outflow from solitary tract in medulla oblongata
At high concentrations, may also act as an agonist at alpha2 R on vascular smooth muscle cells and cause vasoconstriction
Some hypotensive effects also mediated by activation of imidazoline R in rostroventrolateral medulla
Clonidine
Effects:
Use:
Effects: same as methyldopa
Use:
- Antihypertensive (effects potentiated by diuretic)
- Transdermal patch can blunt reflex sympathetic activity caused by vasodilators
Clonidine
Adverse Effects: (6)
Sedation
Dry mouth
Postural hypotension
Impotence
Symptomatic bradycardia (or even sinus arrest) in patients with dysfunction of sinus node
AV block in patients with AV node dysfunction (or taking drugs that depress AV conduction)
Clonidine
Contraindications:
Do not give to depressed patients (withdraw if depression develops)
Clonidine
Withdrawal:
poorly compliant patients:
Associated with increased SS tone (headache, tremors, tachycardia and rebound HTN)
For this reason, patches should not be given to poorly compliant patients
Clonidine
Drug Interactions:
TCAs may reduce antihypertensive effects (surprisingly, this is NOT seen with methyldopa)*
Guanethidine
MOA:
CNS action:
MOA: taken up by postganglionic SS fibers and accumulates in synaptic vesicles, where it replaces NE (gradual depletion of NE stores); also stabilizes the neuronal membrane (acts like a LA) and inhibits NE release
NO action in the CNS (too polar to pass BBB)
Guanethidine
Effects:
Effects: reduction in peripheral resistance (antihypertensive effects)
Guanethidine-Induced Sympathectomy:
Effects (4):
Guanethidine-Induced Sympathectomy: results in relative PS predominance and reduces clinical use
- Reduction of HR and CO
- Orthostatic hypotension
- Diarrhea
- Impaired ejaculation
Reserpine
MOA:
MOA: blocks the ability of neuronal vesicles to take up and store SS amines (NE, DA, 5HT) in both the CNS and PNS (postganglionic adrenergic neurons and adrenal medulla)
Reserpine
Effects:
Effects: antihypertensive effects due to reduced peripheral resistance AND reduced CO
Reserpine
Adverse Effects
At effective doses:
What can cause sedation?
At effective doses, sympathetic reflexes are basically intact and postural hypotension is mild
Depletion of central amine stores can cause sedation, depression and Parkinson sx
Reserpine
Use:
Cost:
Mild to moderate HTN (in combination with a diuretic)
Above effects and introduction of new drugs has lowered use
Low cost still makes it a sensible option (esp. in the elderly and in poor countries)
Phentolamine and Phenoxybenzamine
MOA:
MOA: nonselective alpha receptor blockers
Phentolamine and Phenoxybenzamine
Use:
Use: clinical treatment and diagnosis of pheochromocytoma and impotence
Prazosin
MOA:
MOA: selective alpha1 receptor antagonists
Prazosin
Effects:
Effects: antihypertensive action due to decreased arteriolar resistance and increased venous capacitance
Prazosin
Adverse Effects:
most common:
Initially in the course of treatment, patients experience a sudden drop in peripheral resistance, increased HR and CO, and increased renin secretion (over long term, these effects normalize)
Orthostatic hypotension is the most common (depends on plasma volume; hypervolemia reduces incidence)
Prazosin
Use: (2)
Tx of HTN (not for monotherapy; combined with diuretics or beta blockers)
Tx of urinary symptoms associated with BPH (inhibit contraction of prostate smooth muscle)
Other alpha1 receptor antagonists: (3)
Doxazosin (associated with increased risk of developing heart failure)
Tamsulosin (tx of urinary symptoms associated with BPH)
Terazosin
Calcium Channel Blockers
Voltage-Gated Calcium Channels:
Mediates entry of Ca++ into:
Also carries Ca++ currents to:
Voltage-Gated Calcium Channels: multi-subunit proteins involved in excitation-contraction coupling; principle type in cardiac and vascular tissues is L-type (slow channel)
Mediates entry of Ca++ into smooth muscle cells and cardiomyocytes of atria/ventricles
Also carries Ca++ currents to cells forming SA and AV nodes
Calcium Channel Blockers
MOA:
MOA: binding of drug reduces the frequency of VGCC opening and subsequently markedly reduces the transmembrane Ca++ current
Calcium Channel Blockers
Smooth Muscle:
Very prominent with:
Effect on venous beds:
Smooth Muscle: roughly half Ca required for maximal contraction comes from SER and other half from extracellular space (through VGCCs); inhibition of these channels results in reduction of arteriolar smooth muscle tone and peripheral resistance
Very prominent with nifedipine (and other DHPs), less with non-DHPs (verapamil>diltiazem)
No CCBs have significant effects on venous beds (ie. no effect on cardiac preload)
Calcium Channel Blockers
Cardiac Contraction:
Effect for nifedipine and other DHPs:
Diltiazem and verapamil:
Cardiac Contraction: Ca influx through VGCC necessary for cardiac contraction; inhibition results in reduced cardiac inotropism
Effect minimal for nifedipine and other DHPs (trigger sudden peripheral vasodilation that causes baroreflex-mediated SS tone–> overcomes any negative inotropic effect)
Significant for diltiazem and marked for verapamil (non-DHPs)
Calcium Channel Blockers
SA Node Automatism and AV Node Conduction depend on:
Nifedipine and other DHPs:
Diltiazem and verapamil (non-DHPs):
SA Node Automatism and AV Node Conduction: depend on both Ca currents and the rate of recovery of slow Ca channels
Nifedipine and other DHPs slow inward current of Ca without affecting recovery of channels, resulting in minimal effects on SA node automatism and no effect on AV conduction
Diltiazem and verapamil (non-DHPs) reduce both Ca influx and rate of channel recovery, resulting in marked effects on SA node automatism and AV conduction (reduce HR and AV conduction velocity)
Dihydropyridines
Drugs in this Class (2 important):
9 Total:
Nifedipine*
Amlodipine*
Clevidipine
Nicardipine
Felodopine
Israpine
Nitrendipine
Nimodipine
Nisoldipine
Dihydropyridines
What is for emergency HTN?
What affects cerebral vessels more prominently than other DHPs?
Clevidipine (management of emergency HTN; much shorter half live than nicardipine)
Nicardipine (management of emergency HTN)
Nimodipine (affects cerebral vessels more prominently than other DHPs; reduction of morbidity in patients with subarachnoid hemorrhagic stroke)
Nifedipine
Nifedipine* (short half life of 3 hours, but also available in time released formulation)
Amlodipine
Amlodipine* (half life of 40 hours allowing for once daily dosing with minimal cardiac effects; can be safely administered in patients with heart failure- only DHP that reduces mortality in patients with LV dysfunction)
Dihydropyridines
Effects:
Effects: all DHPs tend to effect vascular VGCCs more than cardiac VGCCs (use as antihypertensives)
Dihydropyridines
Pharmacokinetics
Oral Administration:
Metabolism:
Plasma Protein Binding:
Oral Administration: but bioavailabilty reduced by first pass hepatic metabolism
Metabolism: extensively in the liver
Plasma Protein Binding: extensive
Dihydropyridines
Adverse Effects: (4)
Short-acting agents (ie. nifedipine) cause:
Short-acting agents (ie. nifedipine) cause sudden vasodilation leading to powerful baroreceptor mediated reflex (increased HR and inotropism, leading to possible development of heart attacks due to increased oxygen demand)
Flushing
Peripheral edema (pitting in the ankles)
Dizziness
Dihydropyridines
Drug Interactions
NSAIDs:
Increased metabolism:
Decreased metabolism:
NSAIDs: do NOT mitigate antihypertensive effects of CCBs
Increased metabolism: rifampin, phenytoin
Decreased metabolism: azole antifungals
Non-Dihydropyridines
Drugs in this Class: (2)
Diltiazem
Verapamil
Non-Dihydropyridines
MOA:
Verapamil:
MOA: act at different sites in the VGCC than DHPs (more cardioselective)
Verapamil: also has alpha1 blocking properties that contribute to anti-hypertensive effects
Non-Dihydropyridines
Use
Treatment of:
Prevention of:
Treatment of supraventricular tachycardias
Prevention of ventricular arrhythmias in patients with atrial fibrillation
Non-Dihydropyridines
Adverse Effects (3):
Bradycardia and heart failure (due to depression of cardiac contractility)
Cardiac block (due to depression of AV conduction)
Hypotension
Non-Dihydropyridines
Contraindications: (3)
Patients with cardiac block or systolic dysfunction
Patients being treated with beta blockers (similar pharmacological actions)
Flushing, pitting edema, dizziness (more common with DHPs)
Non-Dihydropyridines
Verapamil Drug Interactions: (2)
Severe hypotension may occur if used with quinidine (also an alpha blocker)
Decreases renal clearance of digoxin (need to lower dose)
Nitroglycerin and Isosorbide Dinitrate
MOA:
Increase NO in SMCs –>?
Sensitivity:
MOA: powerful smooth muscle relaxants
Increase NO in SMCs –> activations guanlyl cyclase to catalyze synthesis of cGMP –> dephosphorylation of MLCs and smooth muscle relaxation
Sensitivity is veins>arteries>arterioles>precapillary sphincters
Nitroglycerin and Isosorbide Dinitrate
Effects
Increased venous capacitance leads to:
Peripheral resistance:
Also cause:
Increased venous capacitance leads to decreased venous return and resulting decrease in ventricular filling pressure
Reduce peripheral resistance (action on arteries) leading to reduction in afterload AND redistribultion of coronary flow from epicardium to endocardium (dilation of coronary vessels)
Also cause relaxation of intestinal, hepatic and renal SMCs (transitory and not used clinically)
Nitroglycerin and Isosorbide Dinitrate
Uses: (4)
Classic Angina
Variant Angina
Unstable Angina
Heart Failure
Nitroglycerin and Isosorbide Dinitrate
Classic Angina: Benefit: Venous dilation results in: end diastolic ventricular pressure: peripheral resistance:
Classic Angina: atheromatous obstruction of larger coronary vessels
Benefit: reduction of myocardial oxygen consumption
Venous dilation results in decreased venous return to the heart and reduction of intraventricular pressure and ventricle radius
Reduction in end diastolic ventricular pressure results in reduction in coronary flow resistance (improves cardiac perfusion)
Reduction in peripheral resistance results in decreased afterload (less O2 consumption)
Nitroglycerin and Isosorbide Dinitrate
Variant Angina:
Benefit:
Coronary flow:
Prevention of:
Variant Angina: transient spasm of coronary vessels
Benefit: mainly due to dilation of epidural arteries
Redistribution of coronary flow from epicardium to endocardium
Prevention of arterial spasm
Nitroglycerin and Isosorbide Dinitrate
Unstable Angina:
Benefits: (2)
Unstable Angina: increased coronary artery tone or non-occlusive platelet clots near AS plaques
Benefit:
- Decreased O2 demand and coronary artery dilation
- NO decreases platelet aggregation (important in pathogenesis)
Nitroglycerin and Isosorbide Dinitrate
Heart Failure
Benefit:
Improves?
Decreases?
Benefit: decrease in preload and afterload
Improves CO and decreases pulmonary congestion (preload)
Nitroglycerin and Isosorbide Dinitrate
Adverse Effects: (3)
o Orthostatic hypotension (tends to subside)
o Reflex tachycardia (can be treated with beta blockers)
o Throbbing headache (meningeal artery pulsations; tends to subside)
Nitroglycerin and Isosorbide Dinitrate
Administration
Acute Angina:
Prevention of Angina:
Acute Angina: sublingually (avoid first pass metabolism)
Prevention of Angina: orally (increase dose)
Nitroglycerin and Isosorbide Dinitrate
Pharmacokinetics
Half Lives:
Formulations:
Tachyphylaxis:
Half Lives: isosorbide has a longer half life AND two active mononitro catabolites (longer duration of action)
Formulations: nitroglycerin also available as a transdermal patch or ointment
Tachyphylaxis: some patients develop a certain degree of tolerance to nitrates (mechanism unclear)
Nitroglycerin and Isosorbide Dinitrate
Contraindications:
PDE-5 Inhibitors (Viagra): potentiate actions of nitrates and can cause profound hypotension or MI
Nitrates
Newly Approved Agents for Angina
General:
General: approved for the treatment of classic angina in patients who are still symptomatic after tx with a combination of more conventional agents
Nitrate
Newly Approved Agents for Angina
MOA:
MOA: metabolic modulators that partially inhibit enzyme required for oxidation of free fatty acids in the myocardium (results in a switch of myocardial metabolism from FFA to glucose oxidation, with reduction of myocardial O2 consumption- FFA oxidation requires more O2 per ATP produced)
Ranolazine
Additional MOA:
Use:
Additional MOA: thought to inhibit a late Na current that normally facilitates inward Ca current (results in reduction of intracellular Ca)
Use: recommended for use in association with nitrates, beta blockers and/or CCBs (only modestly increases exercise duration alone)
Ranolazine
Adverse Effects:
Metabolism:
Adverse Effects: most serious is prolonged QT interval
Metabolism: CYP3A4 in the liver (watch DDIs)
Ranolazine
Contraindications:
Drug Interactions:
Contraindications: quinidine, sotalol and ziprasidone (all prolong QT interval)
Drug Interactions: potential interaction with digoxin (increased effect of digoxin)
Vasodilators
MOA:
MOA: act directly on arteriolar smooth muscle to produce vasodilation and reduce peripheral resistance
Vasodilators
Use:
Use: not used alone (cause reflex mediated increase in HR, CO, renin secretion and plasma volume); usually administered with a beta blocker to reduce these effects
Vasodilators
Classic Angina:
Classic Angina: not great against this because it is an ARTERIOLAR dilator (no effects on coronary arteries)
Vasodilators
Coronary Steal:
Coronary Steal: arterioles below AS plaque of obstructed vessel are already maximally dilated and therefore only mildly responsive to arterial vasodilators while other arterioles downstream from normal coronary vessels are powerfully dilated (result is diversion of blood from ischemic areas –> angina attacks or MI)
Vasodilators
Hydralazine
MOA:
MOA: unknown (but relaxes smooth muscle)
Vasodilators
Hydralazine
Use:
Complicated HTN:
Heart failure:
Complicated HTN (triple combination of hydralazine + beta blocker + diuretic) - Rare due to development of lupus-like syndrome or other immune related diseases that are reversible upon withdrawal
Vasodilators
Hydralazine
Use:
Heart failure:
Heart failure (combined with nitrates)
- Combination reduces mortality in patients intolerant to ACE inhibitors or ARBs
- Beneficial effects due to reduction of afterload (improve CO)
Vasodilators
Minoxidil
MOA:
Leads to:
When coadministered with beta-blockers and diuretics?
MOA: induces the activation of ATP-modulated K channel of smooth muscle resulting in K influx, hyperpolarization and relaxation of arteriolar smooth muscle cells
Leads to enhanced flow from arterial to venous bed and increases venous return (no direct effects on venous system), leading to improved CO
This occurs EVEN when coadministered with beta-blockers and diuretics
Vasodilators
Minoxidil
Use:
Severe hypertension response
Use: always in triple combination with beta-blockers and diuretics
Severe hypertension that is poorly responsive to other agents (esp. those associated with renal insufficiency secondary to hypertension- usually improves renal function, due to dilation of renal arteries)
Minoxidil
Contraindications:
Contraindications: hypertensive patients with left ventricular hypertrophy (increased venous return and poor ventricular compliance can cause increased filling pressure, pulmonary hypotension and possibly heart failure)
Minoxidil
Adverse Effects:
Hypertrichosis (if on the drug for extended periods of time)- exploited for the topical treatment of male baldness (Rogaine)
Vasodilators
Diazoxide
Use
Management of HTN:
Management of hypertensive crises:
- Administered:
- Combine with:
No longer used for routine management of HTN (long-term uses causes hyperglycemia due to inhibition of insulin secretion)
Management of hypertensive crises (rarely)
- Needs to be administered by IV bolus or continuous IV infusion
- Recommended to combine with a beta blocker (enhances hypotensive action and minimizes reflex tachycardia and increased CO)
Vasodilators
Sodium Nitroprusside
MOA:
MOA: generates NO via both enzymatic and nonenzymatic pathways (activation GC, increase cGMP, dilation of arterioles and venules)
Sodium Nitroprusside
Effects
peripheral resistance:
preload:
CO Effects: (3)
Reduction of peripheral resistance and afterload (arterioles)
Reduction of preload (venules)
CO Effects
Sodium Nitroprusside
CO Effects: (3)
- Reduction of cardiac output in patients with HTN but preserved cardiac function
- Enhanced CO in patients with severe LV dysfunction
- Associated with modest increase in HR and overall reduction in myocardial O2 consumption rate
Sodium Nitroprusside
Uses: (4)
o Hypertensive emergencies (sometimes)
o Acute aortic dissection (with a beta-blocker to prevent increase in HR)
o Cardiogenic shock secondary to massive acute MI or rupture of papillary muscle
o Induction of controlled hyptension in normotensive patients under surgical anesthesia
Sodium Nitroprusside
PK
Decomposes in:
effects disappear within:
High doses/long term treatment can result in:
Decomposes in light (cover solutions with opaque wrapping)
Fast acting (effects disappear within 3 minutes)
High doses/long term treatment can result in cyanide or thiocyanate poisoning (metabolism by SMC)
Sodium Nitroprusside
Cyanide Accumulation: (4)
In liver:
more likely to occur in people:
Can cause:
Can be prevented with administration of:
CN –> Thiocynate in the liver, which is eliminated by the urine
CN accumulation more likely to occur in people with impaired renal function
Can cause severe lactic acidosis
Can be prevented with administration of sodium thiosulfate
Digoxin
MOA:
Na removed by the Na/Ca exchanger, causing:
Increase in release of Ca from SER results in:
Also directly affects:
Duration of ventricular AP:
MOA: inhibitor of the Na/K ATPase, causing the accumulation of Na in the cytoplasm
Na removed by the Na/Ca exchanger, causing an increase in cytoplasmic Ca which enters the SER
Increase in release of Ca from SER results in improved efficiency of contractions of the heart without increasing cardiac work or O2 consumption (positive inotropic effect)
Also directly affects electrical activity of the heart
- Duration of ventricular AP shortens (increased K conductance in response to higher Ca++ levels in the cytoplasm)
Digoxin
Effects: (3)
Increase in CO, reducing stimulus for increased SS tone (reduced HR and vascular tone)
Decreased filling pressure and increased systolic ejection fraction decrease heart size and O2 demand
Improved RBF and GFR reduces edema
Digoxin
Use:
Reduces hospitalization, symptoms and death from progressive heart failure in patients that can be treated with 1ng or less of digoxin per mL of plasma (higher levels toxic)
Agents that Increase Cardiac Contractility: (3)
Digoxin
Bipyridines
Adrenergic Agonists
Digoxin
Toxicity
Fairly selective for:
first sign of toxicity:
What may also occur?
Fairly selective for cardiac Na/K ATPase (4 isoforms of alpha subunit, which it binds), but first sign of toxicity is the result of inhibition of Na/K ATPase in GI tract and CTZ (N/V/D, anorexia)
CNS effects may also occur (ie. aberrations in color vision)
Digoxin
Toxicity
High doses of digoxin cause membrane potential to: Caused by: DADs initiate: Can eventually initiate: Tx:
High doses of digoxin cause membrane potential to become more positive, resulting in the appearance of DADs (delayed after potentials)
- Caused by very high Ca load in SER and oscillating Ca levels in the cytoplasm
- DADs initiate a second contraction (bigeminy)
- Can eventually initiate after-potentials that cause ventricular fibrillation
- Treated by reducing the level of digoxin using anti-digoxin Fab fragment
Digoxin
Toxicity
Electrolyte levels determine digoxins effects
Potassium
Hyperkalemia:
Hypokalemia:
Calcium:
Magnesium:
Electrolyte levels determine digoxins effects:
Potassium (esp. important)
- Hyperkalemia reduces effects (K inhibits binding to Na/K ATPase)
- Hypokalemia increases cardiac pacemaker rate, AP duration and arrhythmogenesis
o Especially pronounced in ECTOPIC pacemakers
o Can occur secondary to diuresis, vomiting, diarrhea
Calcium (hypercalcemia increases risk of arrhythmias)
Magnesium (hypomagnesium increases risk of arrhythmias)
Digoxin
PK
Safety:
Absorption:
Safety: very narrow therapeutic window and prone to PK interactions
Absorption: well absorbed orally; some patients require higher doses due to reduced bioavailability as a result of their GI flora (toxicity may result in these patients if they take Abx- reduce flora)
Digoxin
PK
Distribution:
Excretion:
- What reduces renal elimination?
Half Life:
o Distribution: well distributed (including to CNS)
o Excretion: largely unchanged in the urine
- Quinidine reduces renal elimination (causes toxicity)
o Half Life: ~40 hours
Bipyridines
Drugs in this Class:
Inamrinone
Milrinone
Bipyridines
MOA:
Intracellular cAMP:
Results in:
MOA: inhibitors of the isoform of cAMP phosphodiesterase that is found in cardiac and smooth muscles
Increases intracellular cAMP which amplifies cardiac and vascular effects of catecholamines (normally stimulate activation of AC cAMP)
Results in increased myocardial contraction and vasodilation
Bipyridines
Toxicity:
Use:
Toxicity: serious toxicities include arrhythmias, marrow and hepatic toxicities
Use: only available as IV agents used exclusively for acute heart failure and temporary management of severe chronic heart failure
Adrenergic Agonists:
Dobutamine
Dopamine
Isoproterenol
Dobutamine
MOA:
Isomer action:
MOA: racemic mixture with the predominant effect as an agonist at beta1 and 2 R (mostly beta1)
- Isomer action at alpa1 receptors are opposing
Dobutamine
Effects
most important pharmacological effect:
HR:
Systolic/diastolic pressure:
Effects: most important pharmacological effect is enhancement of CO (systolic pressure) with little increase in HR and diastolic pressure (therefore, overall O2 consumption is only moderately increased)
Only induces a moderate increase in HR (unclear why) with important increase in cardiac contractility –> improved CO
Systolic pressure is increased but diastolic pressure is unchanged (no effect on peripheral resistance)
Dobutamine
Use: (3)
Short-term treatment of acute cardiac decompensation after heart surgery
Acute heart failure or MI
Diagnosis of the presence of coronary obstruction (infusion during ECG useful to induce segmental alterations of cardiac contraction in people with CAD)
Dobutamine
Cautions: (2)
Use in MI may increase size of infarct (increase myocardial O2 demand)
Patients with atrial fibrillation (infusion may increase the ventricular response rate- facilitates AV conduction)
Dopamine
Effects:
Effects: synthesized in epithelium of proximal tubule and seems to exert local diuretic and natriuretic effects
Dopamine
Low Doses:
Low Doses: interacts mainly with vascular D1 receptors resulting in smooth muscle vasodilation of renal, mesenteric and coronary beds
Improves renal function (enhances GFR, RBF, and sodium excretion)
Dopamine
Medium Doses:
Medium Doses: interacts with Beta1 receptors (increase HR, contractility and systolic pressure with no effect on diastolic pressure- no change in peripheral resistance)
Dopamine
High Doses:
High Doses: interacts with alpha1 receptors, causing substantial increase in peripheral resistance
Dopamine
Use:
Low doses for short-term treatment of severe congestive heart failure associated with compromised renal function
Medium or high doses for the treatment of cardiogenic or septic shock
Isoproterenol
MOA:
MOA: potent non-selective beta R agonist with low affinity for alpha receptors
Isoproterenol
Use: (3)
- HR and AV conduction
- Chronotropic effects
- asthma and shock
Promptly enhances HR and AV conduction in patients with bradycardia or AV blocks while they are prepared to be implanted with an artificial pacemaker
Chronotropic effects also useful in patients with torsades de pointes (facilitate restoration of sinus rhythm)
No longer used for the treatment of asthma and shock (replaced by other sympathomimetic drugs)
SA node:
AP typical of:
Depolarization caused by:
SA node: electrical impulses originate here
AP typical of automatic tissue (same for AV node):
Depolarization (phase 0) caused by inward Ca current
SA node
Repolarization due to:
Diastolic potential:
Diastolic depolarization eventually:
Repolarization (phase 3) due to outward K current (delayed rectifier)
Diastolic potential (phase 4) is unstable resulting in gradual diastolic depolarization (inward Na current partially mitigated by outward rectifying K current)
Diastolic depolarization eventually reaches threshold and accounts for automaticity of SA node
Ventricular muscle/Atrial muscle/Purkinje Fibers:
Depolarization caused by:
Plateau phase maintained by:
Ventricular muscle/Atrial muscle/Purkinje Fibers: AP is not automatic (usually- note that all cardiac tissue has the potential to become automatic)
Depolarization (phase 0) caused by inward Na current which inactivate rapidly and depolarizing current is limited by rectifying K channels
Plateau phase maintained by inward Ca current (L-type and some T-type) and outward K current)
Ventricular muscle/Atrial muscle/Purkinje Fibers
Repolarization due to:
Diastole:
Repolarization (phase 3) due to outward K current
Diastole (phase 4) is more stable than nodal tissue (balance of inward Na and Ca against outward K; effects of Na/K ATPase and Na/Ca exchanger also present)
Cardiac Action Potentials
EKG
P Wave:
QRS Complex:
T Wave:
P Wave: atrial depolarization
QRS Complex: ventricular depolarization (also masks atrial repolarization)
T Wave: ventricular repolarization
Cardiac Action Potentials
EKG
PR Interval:
ST Segment:
QT Period:
PR Interval: time period between atrial and ventricular depolarizations (AV conduction time)
ST Segment: reflects the plateau of the ventricular AP
QT Period: period from ventricular depolarization until repolarization
Mechanisms of Cardiac Arrhythmia
Altered automaticity
Abnormal electrical activity can occur if:
Ectopic rhythms develop when:
Abnormal electrical activity can occur if SA nodal rate is pathologically low (ie. after MI) and a latent pacemaker generates escape rhythm
Ectopic rhythms develop when latent pacemakers arise that have faster intrinsic rates than the SA node (due to ischemia, electrolyte imbalance or high SS activity)
Mechanisms of Cardiac Arrhythmia
Triggered activity
General:
Normal action potentials trigger afterdepolarizations
Mechanisms of Cardiac Arrhythmia
Triggered activity
Early After Depolarizations:
Can lead to:
Early After Depolarizations: occur when QT interval (ventricular depolarization) is prolonged and exceeds the refractor period, so that an AP can occur before ventricular repolarization
Can lead to torsades de pointes (very dangerous arrhythmia)
Mechanisms of Cardiac Arrhythmia
Triggered activity
Delayed Afterdepolarizations (DADs): In the case of cardiac glycoside toxicity (digoxin), related to: Reflected in the EKG as:
Delayed Afterdepolarizations (DADs): occur after ventricular depolarizations (mechanism not well understood)
In the case of cardiac glycoside toxicity (digoxin), related to increased intracellular Ca++
Reflected in the EKG as bigeminy
Mechanisms of Cardiac Arrhythmia
Defects in conduction
Re-entry:
Must be:
Conduction flow:
Re-entry: pathological self-sustaining electrical circuit that stimulates a region of the myocardium repeatedly and rapidly
Must be a barrier to conduction (a region of damaged tissue that will not support normal conduction but will allow retrograde conduction at a slower than normal velocity)
Conduction will flow around the damaged area, and if retrograde flow is slow enough (ie. that the refractory period of normal tissue is past), the returing current can depolarize the tissue (“circus rhythm)
Mechanisms of Cardiac Arrhythmia
Conduction block
Action potential fails to propagate because:
Tissue beyond the block:
Action potential fails to propagate because of unexcitable myocardium (drugs, trauma, scarring, ischemia)
Tissue beyond the block is then able to generate escape rhythms
Mechanisms of Cardiac Arrhythmia
Accessory pathways
Bypass:
Wolf-White-Parkinson Syndrome:
- Predisposes the individual to:
Bypass the AV node
Wolf-White-Parkinson Syndrome: Bundle of Kent (short circuit between atria and ventricles that competes with normal pathway)
- Predisposes the individual to re-entry and tachyarrhythmias
Antiarrhythmic Drugs
Class I Agents:
Na Channel Blockers
Antiarrhythmic Drugs
Class I Agents (Na Channel Blockers)
MOA:
Decreases automaticity by:
Increases threshold in the myocardium by:
MOA: blockage of Na channels (not highly selective for Na channels- affect others)
Decreases automaticity by reducing the phase 4 slope in the SA node
Increases threshold in the myocardium by decreasing the phase 0 upstroke
Antiarrhythmic Drugs
Class I Agents (Na Channel Blockers)
State Dependent:
State Dependent: most channel blockers bind to the open and/or inactivated states (dissociate from resting channels)
Therefore, the blockers bind better when firing rate is high (ie. more open and inactivated channels)
Also dissociate more slowly from ischemic tissues (longer depolarization)
Antiarrhythmic Drugs
Class I Agents (Na Channel Blockers)
Class IA Agents: (3)
Procainamide
Quinidine
Disopyramide
Procainamide
MOA:
threshold of myocardium:
conduction velocity in myocardium:
AP:
MOA: blocks Na channels (in open state)
Increases threshold of myocardium
Decreases conduction velocity in myocardium
Prolongs AP (non-specific blockade of K channels) and therefore prolongs QRS duration
Procainamide
Use:
Use: usually drug of 2nd choice; should be started in the hospital (as should all class I drugs)
o Atrial and ventricular arrhythmias
o Sustained ventricular arrhythmias after MI
Procainamide
Cardiac Toxicity: (3)
o Excessive slowing of conduction
o Excessive AP prolongation
o Prolonged QT interval and induction of torsades de pointes
Procainamide
Other Toxicity:
Long term therapy can cause lupus like disease with anti-nuclear Abs
Class IB Agents: (2)
Lidocaine
Mexiletine
Class IC Agents: (3)
Flecainide
Propafenone
Moricizine
Antiarrhythmic Drugs
Class I! Agents:
Beta Blockers
Class II Agents (Beta Blockers)
Effects: (3)
Reduce HR
Increase AV conduction time and PR interval
Inhibit after-depolarization-mediated automaticity
Class II Agents (Beta Blockers)
Use: (2)
Prevent ventricular tachycardia due to atrial flutter or fibrillation
Prevent recurrences of paroxysmal supraventricular tachycardias
Class II Agents (Beta Blockers)
Agents Used: (2)
Esmolol
Sotalol
Esmolol:
Esmolol: short half life and can be used by IV for immediate control of atrial tachycardia
Sotalol:
Use:
Sotalol: nonspecific beta blocker that also has K channel blocking properties
Use: for both atrial and ventricular tachyarrhythmias
Sotalol
SE:
Contraindications:
SE: torsades de pointes (due to increased QT interval)
Contraindications: Wolf-White-Parkinson Syndrome
Class III Agents
MOA:
AP :
EADs:
MOA: inhibit repolarization of the myocardium by blocking outward K channels
Prolongation of AP (longer QT interval) increases refractoriness and decreases reentry
However, also increases EADs and possibly torsades de pointes
Note: Treatment should be initiated in the hospital
Class III Agents
Drugs in this Class: (4)
Dofetilide (specific K channel inhibitor)
Ibutilide (specific K channel inhibitor)
Sotalol (also a class II agent)
Amiodarone
Amiodarone
MOA:
MOA: inhibits Na (inactivate state), K and Ca channels; also a powerful alpha and beta blocker (considered class III but has powerful class I and significant class II and class IV properties)
Amiodarone
Effects: (3)
o Prolongs refractoriness
o Increases AV conduction time
o Causes bradycardia
Amiodarone
Uses: (2)
Restoring sinus rhythm in atrial tachycardia (oral)
Treating recurrent ventricular tachycardias and fibrillation (oral)
Amiodarone
Effects on EKG:
PR, QRS and QT intervals are all prolonged (however, torsades de pointes is uncommon)
Amiodarone
Adverse Effects
Cardiac:
Cardiac: bradycardia, decreased contraction and heart block
Amiodarone
Adverse Effects
Non-Cardiac: (3)
Pneumonitis leading to pulmonary fibrosis
Hyper and hypothyroidism (analog of thyroxin)
CNS symptoms
Amiodarone
Metabolism:
Metabolism: in the liver by CYP3A4
Amiodarone
Drug Interactions: (3)
Drug Interactions:
o Inhibits the metabolism of digoxin, warfarin, benzos and other drugs
o Levels decreased by rifampin (and other inducers of CYP)
o Levels increased by cimetidine (and other inhibitors of CYP)
Class IV Agents:
Calcium Channel Blockers
Verapamil and Diltiazem block:
Verapamil and Diltiazem: block L-type channels in cardiac cells more readily than DHPs
Verapamil blocks:
Effects: (2)
Verapamil: blocks both open and inactivated channels (favors actively firing tissues)
Effects:
o Reduces phase 0 of SA and AV nodal APs causing bradycardia and prolonged AV node conduction velocity and refractoriness
o Also suppresses EADs and DADs
Verapamil
Uses: (2)
Reentrant supraventricular tachycardias
Reduce the risk of ventricular tachycardia due to atrial flutter or fibrillation
Diltiazem:
Diltiazem: has similar effects to Verapamil
Verapamil and Diltiazem
Contraindications of Both:
Wolf-White-Parkinson syndrome
Verapamil and Diltiazem
Adverse Effects: (3)
Bradycardia
Hypotension
Decreased contraction
Verapamil and Diltiazem
Drug Interactions:
Drug Interactions: common
Beta blockers
Raise drug levels of digoxin
Adenosine
MOA:
Administration:
MOA: binds to P1 purinergic receptors that open G-protein regulated K channels
Administration: given rapidly as a bolus (half life of 6 seconds)
Adenosine
Effects:
Use:
Effects: inhibits SA nodal, atrial and AV nodal conduction
Use: terminate many supraventricular arrhythmias
Magnesium Sulfate
Administration:
Uses: (3)
Administration: given by IV
Uses:
Treat digoxin related arrhythmias (mechanism unclear)
Drug induced torsades de pointes (mechanism unclear)
Arrhythmias due to hypomagnesia
