Agents that Alter Vascular Tone and Control Plasma Volume
I.
Review on Function and Significance of Kidneys
A.
Why Kidneys?
Fun facts
Receive 20% of Cardiac Ouput
Account for 7% of oxygen consumption in the body
Filter 120 ml/min of plasma into nephron (measured by determining creatinine)
Only 1% actually ends up in urine
** Something important must be going on !
Three primary roles for kidneys
1. Excrete metabolic end products and toxins
2. Control concentrations of body fluid constituents
(Na, K, Ca, Mg, Glc, H, HC03, Uric acid, etc)
3. Control volume of body fluids
Success in performing these roles is dependent upon kidneys'
capacity to form urine of an appropriate volume and composition.
B.
Formation and Composition of Urine (3 primary factors)
1. Cellular regulation of osmolarity (figure 29-2,29-3 G & G)
a. Transport of small ions
Review general sites and mechanisms for ion transport.
b. Transport of organic acids and bases
Active, competitive, bidirectional transporters with significance for
drug action, drug interactions and treatment of Gout.
Acids
Para-amino hippuric acid (PAH)
Penicillin
Sulfinpyrazone
Probenecid
Uric Acid
Aspirin
Loop diuretics
Thiazide diuretics
Glucuronide conjugates
Sulfate Conjugates
c. Water transport is always passive
Bases
Tetra ethylammonium (TEA)
Quinine
Thiamine
Morphine
Epinephrine
2. Glomerular Filtration
Estimated by creatinine clearance or plasma creatinine levels.
Normal is 120 ml/min of 180 L/day **small changes are significant*"
Function of:
a. Permiability (glomerular ultrafiltration coefficient, Kf) (size, charge)
Altered by disease - loss of charge
b. Starling forces (C = capillary; I = interstitial)
Hydrostatic (Cp, Ip)
(p = pressure)
Colloid Osmotic (Con, Ion) (on = oncotic = colloid osmotic)
c. Renal Blood Flow (RBF or RPF - renal plasma flow)
Controlled by autoregulatory, neuronal, humoral factors
3. Integrated Hormonal Control
Hormones that allow for adaptation with direct actions on kidney or vasculature.
Understanding interrelationships of hormone is critical.
Quick summary of several hormones
Angiotensin
Water and Na+ conservation
Aldosterone
Na+ conservation, regulate plasma K+
Anti-diuretic Hormone (ADH)
Water conservation
Atrial natriuretic peptide (ANP)
Diuresis, naturesis
Prostaglandins
Vasodilation, diuresis
Nitric oxide
Vasodilation, diuresis
Bradykinin
Vasodilation, diuresis
Endothelin
Vasoconstriction
II.
Hormonal Interrelationships in Renal Physiology:
Pathology and Opportunities for Drug Interventions
A.
Renin - Angiotensin System
1. Physiologic Function
- conserve water
- conserve Na
- maintain GFR
2. Source and Synthesis
3. Control of Angio I1 synthesis or release
a. Control of synthesis: Renin
b. Increased release
1)  Renal perfusion
2) Sympathetic stimulation
3)  Na/Cl load at macula densa
4) PG's
c. Decreased release
1) Neg. feedback
2) ANF
4. Mechanism of Action of Angio I1
a. Cellular Actions
1) Receptor mediated
2) Transduction AT1
* Adenyl cyclase - (Gi) inhibition
*Gq /PLC  IP3 -  Ca++
*Gq /PLC and PLD -- DAG -  gene transcription
*PLA2 - stimulated production of AA products
b. Physiologic Actions (Fig. 31-4)
1) Pressure response
a) General vasculature
- Direct Ca++ dependent vasoconstriction (40x NE)
- Facilitation of actions of NE peripherally
-  CNS sympathetic outflow
-  Adrenal (medulla) NE release
b) Renal vasculature
- Constrict afferent  GFR
- Constrict mesangial  filtration  surface area
- Constrict efferent  GFR
2) Regulation of Na+ (conservation)
-  Aldosterone syn./ release
-  Na+ reabsorp at PCT
3) Regulation of H20 (conservation)
-  Na+ reabsorption
-  drinking
-  ADH release (vasopressin)
4) Effects on heart
- Stimulate hypertrophy of cardiac muscle
(direct and indirect)
5) Other
-  PG's
5.
Manipulating Renin-Angiotensin System
a. Mimic Angiotensin II (agonists) (?)
b. Prevent Angiotensin - mediated effects
1) Therapeutic Value (Indications)
 Hypertension - & TPR
 CHF
 Early stabilization of MI
 Nephropathy
c. Specific Agents
1) ACE inhibitor
(Prototype - Captopril)
MOA - Inhibition of rate-limiting enzyme for Angio II syn
Indications - see above
Potential Adverse Rxn
 Dramatic  BP with first dose
 Renal failure
 Hyperkalemia
 Category D 2nd/3rd trimester
 Miscellaneous hassles: Cough, Rash, Loss of taste
 Rare: Neutropenia, Proteinuria, Anaphylactoid
2) Angio II R blockade
(Prototype - Losartan)
MOA - Competitive Antagonist A1 receptor
Indications - Should be about the same
Potential Adverse rxns
At least the first four should be similar
3) Renin Antagonists
B. Eicosanoids
1.
Synthesis:
In kidney we seem to be primarily concerned with prostaglandins.
Sites of action include:
Afferent: PGI2, PGE
Glomerulus: PGI2, PGE2, PGF2, TXA2
Interstitium: PGE2
2.
Physiologic Actions - 2 primary renal actions (generally oppose Angio 11)
a. Regulation of RBF
b. Solute Reabsorption
3. Therapeutic Implications
a. Interactions of NSAIDs with diuretics
b. Significance in Regulating RBF during pathology
C. Aldosterone
1.
Physiologic Function
Regulates Kp
Coincident conservation of Na
2.
Source + Synthesis (See physiol)
3.
Regulation of Synthesis or Release
a.  Release
-  Kp
- Ang II
-  Nap
- ACTH (permissive role)
b.  Release
- ANF
4.
Mechanism of Action
a. Cellular actions
1) Control of cellular osmolarity
2) Cellular actions of Specific to Aldosterone
a) Receptor mediated
b) Selectivity
c) MOA
b. Physiologic Actions
5. Pathologic consequences of Altered Aldosterone
a. Excessive Aldosterone
b. Inadequate Aldosterone - Addison's Disease
D. Antidiuretic Hormone (ADH, Vasopressin)
1.
Physiologic Function
- Conserves H20
(allows land dwellers to conserve H20)
2.
Source + Synthesis
3.
Control of Synthesis and Release
a. Increase
- osmolarity (osmoreceptors near hypothal)
-  volume (atrial baroreceptors)
- Ang II
- Stressors (temp, emotional)
b. Decrease if:
- ANF
4.
MOA
a. Cellular actions
b. Physiologic Actions
1) Vascular
2) Renal
5.
Consequences of altered ADH activity
a. Increased ADH - Syndrome of inappropriate ADH secretion
b. Decreased ADH  Diabetes Insipidus
1) Nephrogenic (ADH resistant)
2) Neurogenic (ADH sensitive, central DI)
ADH agonists
Lypressin (8-lysine vasopressin)
Desmopressin (1 -deamino - 8-D-argenine vasopressen)
E.
Atrial Naturetic Peptide (ANP, ANF)
1.
Physiologic function
2.
Source + synthesis
3.
Control of synthesis + release
4.
MOA
a. Cellular Actions
b. Physiologic Actions
1) Diuresis
Inhibit ADH release
Vasodilation
Increased RFP
2) Naturesis
 Aldosterone syn. (basal + stimulated)
 Renin
Direct  Na+ reabsorption in collecting duct (counter ADH)
3) Other:  stim. drinking
5.
Manipulating ANP
a. Pathophysiology
b. Potential value of  ANF
1) Receptor agonists
2) Inhibition of neutral endopeptidase 24.1 1
(also referred to as vasopeptidase inhibitors)
III.
Diuretics
A.
General Mechanisms
B.
Osmotic Diuretics
Prototype:
Mannitol (inert, freely filtered, not reabsorbed)
Primary Site of Action:
Mechanism of action:
Loop of henle (thin segments), Proximal tubule
Artificially elevate osmolarity
Limit passive sodium reabsorption in TAL
Other actions:
Increased RPF, decreased medullary osmolarity
Increased excretion Na, K, Ca, Mg, C1, HC03,
Phosphate
Indications:
Maintain GFR
Maintain plasma osmolarity
Dehydrate specialized compartments
Facilitate excretion of toxins (?)
Contraindications:
Established renal disease
Pulmonary edema, heart disease
Severe dehydration
C.
Carbonic Anhydrase Inhibitors
Prototype
Primary Site of Action:
Mechanism of action:
Acetazolamide
Proximal tubule
Irreversible inhibition of carbonic anhydrase,
limiting sodium reabsorption
Other actions:
Facilitates HC03 excretion, decreases Cl excretion
Increases phosphate excretion
Decreases aqueous humor
Tendency to decrease RBF
Indications:
Diuresis (not common)
Open angle glaucoma
Mountain sickness
Adjunct in epilepsy
Alkalinize urine
Warnings, S.E.:
Caution with preexisting electrolyte imbalance
May induce hyperchloremic acidosis
Caution if predisposition to kidney stones
Decreases RBF
Sulfonamide sensitivity
Contraindications:
Acidosis
Renal or hepatic dysfunction
D.
Loop Diuretics
Prototype:
Furosemide
Primary Site of Action:
Thick Ascending Limb of Loop of Henle
Mechanism of action:
Inhibition of Na/K/2C1 luminal transporter:
Decreased sodium reabsorption
Decreased medullary concentration gradient
Other actions:
Tendency to increase RBF
Persistent decrease in blood pressure
Increased excretion Na, K, Ca, Mg, C1, H
Indications:
Edema (diuresis)- especially refractory edema
Hypertension
Hypercalcemia
Acute renal failure
Warnings, S.E., CI:
CI: Severe electrolyte imbalance
CI: Established anuria
Caution with preexisting electrolyte imbalance
Possible hypochloremic alkalosis (loss of C1, K, H)
Hyperuricemia
Aggravate preexisting diabetes
Increased plasma lipids
May aggravate renal / hepatic insufficiency
Sulfonamide sensitivity
Ototoxicity (usually reversible)
GI upset (ethacrynic acid)
DI:
Synergistic with other diuretics
Synergistic with other antihypertensives
Decreases Li excretion
Low K sensitizes heart muscle to digitalis
NSAID's decrease efficacy
Other organic acids may decrease efficacy
Avoid other ototoxic agents (amnoglycosides.. .)
E.
Thiazide (thiazide-like) Diuretics
Prototype:
Hydrochlorothiazide
Primary Site of Action:
Early distal Convuluted Tubule
Late cortical sections of Loop of Henle
Mechanism of action:
Inhibition of NaIC1 luminal transporter:
Decreased sodium reabsorption
Other actions:
Tendency to decrease RBF
Persistent decrease in blood pressure
Increased excretion Na, K, Mg, C1, H
Increased reabsorption of calcium
Indications:
Edema (diuresis)
Hypertension (often DOC)
Congestive heart failure
Hypercalciuria
Diabetes Insipidus
(Meniere's disease)
Warnings, S.E., CI:
CI: Severe electrolyte imbalance
CI: Established anuria
Caution with preexisting electrolyte imbalance
Possible hypochloremic alkalosis (loss of C1, K, H)
Hyperuricemia
Aggravate preexisting diabetes
Increased plasma lipids
May aggravate renal / hepatic insufficiency
Sulfonamide sensitivity
DI:
Synergistic with other diuretics
Synergistic with other antihypertensives
Decreases Li excretion
Low K sensitizes heart muscle to digitalis
NSAID's decrease efficacy
Other organic acids may decrease efficacy
CaC03
F.
Potassium-Sparing Diuretics
1.
Na Channel Inhibitors
Prototypes:
Triarnterene and Amiloride
Primary Site of Action:
Late distal Convuluted Tubule
Collecting Duct
Mechanism of action:
Inhibition of apical Na channel
Decreased sodium reabsorption
Other actions:
Retention of potassium and hydrogen ion
Modest decrease in blood pressure
Increased excretion Na, Cl
Indications:
Edema (rarely)
Hypertension (in combination)
Hypokalemia
Warnings, S.E., CI:
CI: Anuria
CI: Severe renal disease
CI: Hyperkalemia
May induce hyperkalemia and metabolic acidosis
DI:
Synergistic with other diuretics
Synergistic with other antihypertensives
Decreases Li excretion
High K desensitizes heart muscle to digitalis
NSAID's decrease efficacy
Inhibition of RenidAngiotensin system may
aggravate hyperkalemia
K supplements should not be used
2.
Aldosterone antagonist
Prototype:
Spironolactone (canrenone)
Primary Site of Action:
Late distal Convuluted Tubule
Collecting Duct
Mechanism of action:
Competitive inhibition of aldosterone receptor
Decreased sodium reabsorption
Other actions:
Retention of potassium and hydrogen ion
Modest decrease in blood pressure
Increased excretion Na, Cl
Indications:
Edema (rarely)
Hypertension (in combination)
Hypokalemia
Congestive Heart Failure
Aldosteronism
Warnings, S.E., CI:
CI: Anuria
CI: Severe renal disease
CI: Hyperkalemia
May induce hyperkalemia and metabolic acidosis
Gynecomastia
Impotence (men); Ammenorhea (women)
DI:
Synergistic with other diuretics
Synergistic with other antihypertensives
Decreases Li excretion
High K desensitizes heart muscle to digitalis
NSAID's decrease efficacy
Inhibition of RenidAngiotensin system may
aggravate hyperkalemia
K supplements should not be used
G.
Complications of Diuretic Therapy
1. Hypokalemia
When to treat:
How to treat:
10 - 40% of patients develop hypokalemia
Patients with renal or hepatic failure at greatest risk
K supplement
Add K-sparing drug
Don't do both K supplement and K-sparing drug
2. Vascular depletion
3. Hyperkalemia
Treat with kayexelate (Na polystyrene sulfonate)