Digoxin

Digitoxin

Ouabain

Strophanus

Classification:

Cardiac glycoside

Mechanism of Action:

1. Inhibition of Na⁺/K⁺ ATPase pump →

2. Results in small increase of [Na⁺]_in →

3. ↑ [Na⁺]_in results in decreased activity of Na⁺/Ca²⁺ exchanger →

4. Results in increased [Ca²⁺]_in →

5. ↑ [Ca⁺]_in is stored in SR and released with AP →

6. Net effect: ↑ force of contraction (inotropy) & SV

*Also*

1. Decreased sympathetic tone & increased vagal tone →

2. Slowing of impulse conduction through AV node →

3. Increase AV block

*Toxic doses results in increased SNS activity

Clinical Use:

1. Congestive Heart Failure

2. Atrial fibrillation

Pharmokinetics:

1. Secreted unmetabolized in urine (long half life)

Toxicity:

1. Arrhythmias: AV block & atrial tachycardias

2. CNS (dig-delirium) = yellow green hallucinations

3. GI symptoms (nausea, vomiting, etc.)

4. Oscillatory after-potentials due to increase in RMP → elicit AP in Purkinje cells → bigeminy

Antidote:

1. Digibind = digoxin immune Fab

2. K⁺ supplementation, antiarrhythmics, cardiac pacer

Contraindications: electrolyte imbalances

1. Hypokalemia: K⁺ and digoxin compete for binding Na⁺/K⁺ ATPase, thus hypokalemia potentiates digoxin effects. Similarly, hyperkalemia reduces efficacy.

2. Hypercalcemia enhances digitoxin-induced increases in intracellular Ca²⁺ and thus also potentiates effects/toxicity. Consequently, hypocalcemia nullifies effects of digoxin for the same reason.

Captopril

Ramipril

Benzepril

Enalapril

Lisinopril

Classification:

ACE inhibitors

Mechanism of Action:

1. Inhibition of Angiotensin Converting Enzyme (ACE) →

2a. Blocks conversion of antiotensin I to angiotensin II →

3a. Reduction of angiotensin II in blood →

4a. Inhibition of angiotensin II effects:

- ↓ vasoconstriction (↓ TPR)

- ↓ release of aldosterone from adrenal glands

- ↓ release of vasopressin (ADH) from posterior pituitary

2b. Blocks degradation of bradykinin and other vasodilators of kinin family →

3b. Increase of endogenous vasodilators (kinin family) →

4b. Results in cough and angioedema

(*ACE also breaks down bradykinin)

Clinical Use:

1. CHF

2. Hypertension

3. Protection of diabetic kidney

Pharmakokinetics:

1. Poor bioavailability → solution is esterified prodrug, which is metabolized by endogenous esterases to active molecule.

Toxicity:

1. Cough is major side effect (30%)

2. Hypotension

3. Hyperkalemia (from impaired aldosterone action)

4. Teratogen

5. Renal damage (if preexisting disease or fetus)

Losartan

Valsartan

Irbesaratn

Candesartan

Classification:

1. Angiotensin II receptor blockers

Mechanism of action:

1. Competitively inhibits Angitensin II receptor (AT-II₁ receptor site) →

2. Inhibition of angiotensin II effects:

- ↓ vasoconstriction

- ↓ release of aldosterone from adrenal glands

- ↓ release of vasopressin (ADH) from posterior pituitary

*No inhibition of ACE, thus no increase in endogenous vasodilators of kinin family → no cough or angioedema

*There are two AT-II receptors:

- AT-II₁: G_q → vasoconstrictor, aldosterone & ADH secretion

- AT-II₂: G_i → vasodilator

Clinical Use:

1. CHF

2. Hypertension

Toxicity:

1. No cough!

2. Hypotension

3. Hyperkalemia (from impaired aldosterone action)

4. Teratogen (fetal renal toxicity)

Classification:

1. Renin inhibitor

Mechanism of action:

1. Inhibits renin's action on substrate (angiotensinogen) →

2. Results in decreased angiotensin I formation →

3. Results in decreased angiotensin II formation →

4. Inhibition of angiotensin II effects:

- ↓ vasoconstriction

- ↓ release of aldosterone from adrenal glands

- ↓ release of vasopressin (ADH) from posterior pituitary

*No inhibition of ACE, thus no increase in endogenous vasodilators of kinin family → no cough or angioedema

Clinical uses:

1. Hypertension

Toxicities:

1. Headache & diarrhea

2. Teratogen???

3. Hyperkalemia (from impaired aldosterone action)

4. Hypotension (especially in Na⁺-depleted patients)

Isosorbide dinitrate

Nitroglycerin

Isosorbide mononitrate

Classification:

VENOdilator (Higgy has a small weiner too)

Mechanism of Action:

1. Mitochondrial aldehyde dehydrogenases metabolize into free nitrate ions (NO_2^-) →

2. Free nitrate is reduced to NO →

3. NO stimulates guanylyl cyclase to produce cGMP →

4. ↑ [cGMP] results in smooth muscle relaxation →

5. Venodilation results in reduced preload →

- ↓ myocardial wall tension

- ↓ O₂ demand

*Can cause vasodilation of both arteries and veins, but aldehyde dehydrogenase is enriched in mitochondria of venous smooth muscle cells → predominately venous action

Clinical uses:

1. Acute congestive heart failure

2. Angina pectoris

3. Hypertension of patients with CAD

Toxicities:

1. Hypotension

2. Reflex tachycardia

3. Throbbing headaches (dilation of meningeal arteries)

*Tolerance frequently develops

Classification:

Recombinant Natriuretic peptide

Mechanism of action:

1. Normally synthesized by ventricular myocytes in response to ventricular wall stretch →

2. Binds guanylate cyclase-coupled natriuretic peptide receptors →

3. Stimulates increase of [cGMP] →

4. Relaxation of smooth muscle of vasculature →

5. Vasodilation, both arteriolar and venous:

- ↓ preload

- ↓ afterload

- may ↑ natriuresis and improve response to diuretics

Pharmacokinetics:

1. Short duration 1-2 min; IV

Clinical use:

1. Short term decompensated congestive heart failure

Toxicities:

1. Hypotension

2. Tachycardia (reflex)

Milrinone

Inamrinone

Cilostazol

Classification:

Type III PDE inhibitor

Mechanism of action:

1. Inhibits type III cAMP phosphodiesterase in cardiac and SM cells →

2. Decreased degradation of cAMP →

3. ↑ Action of PKA:

In myocardium:

1. Increased cAMP, PKA phsophorylates VGCC →

2. Increased Ca²⁺ influx →

3. Increased contractility

In vascular smooth muscle:

1. Increased cAMP results in PKA activation →

2. PKA phosphorylates MLCK (kinase) = inactivation →

3. MLCP (dephosphorylation) dominates →

4. Smooth muscle relaxation →

5. Arteriolar and venous dilation

*Like albuterol's cAMP mediated effects on bronchiolar smooth muscle

Clinical use:

1. Acute congestive heart failure

Toxicities:

1. Hypotension

2. Ventricular arrhythmias

3. Hepatotoxicity

4. Thrombocytopenia

Chlorothiazide

Hydrochlorothiazide

Benzothiadiazine

Classification:

Diuretic (thiazide)

Mechanism of action:

1. Inhibits the Na⁺/Cl^- co-transporter in distal tubule →

- ↑ excretion of Na⁺, Cl^-, Mg²⁺ and K⁺

- ↓ Ca²⁺ excretion

*Ca²⁺ is actively transported from lumen into DCT epithelium. In cell, Ca²⁺ is transported back into circulation via Na⁺/Ca²⁺ antiporter.

**Inhibition of Na⁺/Cl^- transporter creates and inward Na⁺ gradient potential, which drives Na⁺/Ca²⁺ antiporter reclaiming all Ca^+.

Clinical use:

1. Hypertension

2. Edema

3. Congestive Heart Failure

Toxicities:

1. Hyponatremia

Furosemide

Bumetamide

Torsemide

Ethacrynic Acid

Classification:

Diuretic (loop)

Mechanism of action:

1. Inhibits the Na⁺/K⁺/2Cl^- transporter in ascending LOH →

2. More Na⁺ reaches the CCD →

- ↑ excretion of H⁺, Na⁺, K⁺, Mg²⁺ and Ca²⁺

*Normally, most of the K⁺ leaks back into lumen creating an electropositivity which drives Ca²⁺ and Mg²⁺ reabsorption via paracellular transport in LOH.

**Also disrupts the osmotic gradient of countercurrent exchange system. This results in less osmotic drive for H₂O in response to ADH secretion.

***Also have a potent pulmonary vasodilating effect!!!

Clinical use:

1. Hypertension

2. Congestive Heart Failure

3. Edema

Toxicities:

1. Hypokalemia

2. Ototoxicity

Triamterene

Amiloride

Classification:

Diuretic K⁺-sparing

Mechanism of action:

1. Inhibition of ENaC channel in CCD →

2. Less Na⁺ reabsorbed in response to aldosterone secretion

- ↓ the Na⁺/K⁺ ATPase action & Na⁺/K⁺ exchange

- ↑ Na⁺/H₂O excretion

- ↓ K⁺ excretion

Clinical use:

1. Hypertension

2. Congestive Heart failure

Toxicities:

1. Hyperkalemia

Spironolactone

Epleronone

Classification:

Diuretic (K⁺-sparing)

Mechanism of action:

1. Binds and competitively inhibits aldosterone steroid receptor -->

2. Inhibition of aldosterone effects:

- ↓ Na⁺ pump expression, hence ↓ reabsorption of Na⁺

- ↓ K⁺ secretion

- ↑ Na⁺/H₂O excretion

Clinical use:

1. Hypertension

2. Congestive Heart Failure

3. Hyperaldosteronism

Toxicities:

1. Hyperkalemia

2. Gynecomastia

3. Ototoxicity

4. Metabolic alkalosis

Satavaptan

Lixivaptan

Mozavaptan

Classification:

1. Diuretic

Mechanism of action:

1. Inhibition of vasopressin (ADH) receptor (AVPR-2) in distal tubule and CCD →

2. Decreased reabsorption of H₂O →

- ↓ Aquaporin 2 insertion

- ↑ H₂O excretion (dilute urine)

- ↓ Na⁺ excretion

Clinical use:

1. Hyponatremia

2. Ascites (cirrhosis)

3. CHF

4. SIADH

Toxicities:

1. Hyperkalemia?

1. ACh released on SA and AV nodes →

2. Binds M₂ (muscarinic) GPCR on pacemaker cells  →

3. G_i leads to ↓ in cAMP and, thus PKA activity →

- ↑ K⁺ channel activation → K⁺ efflux

- ↓ Ca²⁺ channel activity → ↓ spontaneous action potential

- ↓ AV conduction velocity

- ↓ HR

1. NE synthesized and released on nerves throughout heart →

2. Binds to β-adrenergic GPCR →

3. G_s results in ↑ cAMP and, thus PKA action →

- ↑ Na⁺ and Ca²⁺ channel opening

- ↑ spontaneous action potential

- ↑ conduction velocity through AV node

- ↑ HR

Baroreceptors (stretch) in aortic arch and carotid sinus tonically fire:

1. Increase in firing due to increase in BP → ↑ PSNS activity and ↓ CO

2. Decrease in firing due to decrease in BP → ↑ SNS activity and ↑ CO

1. Renin release is stimulated from juxtaglomerular (JG) cells in kidney by three mechanisms:

  1) A ↓ in BP detected by baroreceptors

  2) Macula densas detects a decrease of NaCl in filtrate

  3) SNS activity on β₁ adrenergic receptors on JG cells

2. Renin is secreted from JG cells and cleaves circulating angiotensinogen to form angiotensin I →

3. Angiotensin Converting Enzyme (ACE) converts angiotensin I to angiotensin II →

4. Angiotensin II activates various GPCRs →

- ↑ vasoconstriction

- ↑ aldosterone secretion (Na⁺/H₂O retention)

- ↑ release of ADH from posterior pituitary

- ↑ stimulation of thirst relex in hypothalamus

1. Competitively inhibits B-adrenergic GPCR on heart and kidney cells:

- ↓ HR → ↓ CO

- ↓ Renin → ↓ BP

- ↓ arrhythmias

- ↓ cardiac remodeling

2. Classification:

Non-selective → propanolol

β₁-selective → bisoprolol, metaprolol

Mixed α/β → carvedilol, labetolol

[image]

Classification:

Combined ateriodilator and venodilator

Mechanism of action:

1. Continuous IV infusion →

2. NP breaks down in circulation releasing NO →

3. Diffuses into cell and stiumlates guanylyl cyclase →

4. ↑ cGMP results in activation of PKG →

5. PKG activates MLC-Phosphatase →

6. Results in vasodilation

Clinical uses:

1. Malignant hypertension emergencies

2. Acute decompensated heart failure

Pharmacokinetics:

1. SHORT duration of few minutes

2. Breaks down in light to release cyanide ions

*Co-administer with a sulfure donor like thiosulfate (mitochondrial rhodanese enzyme detoxifies CN to thiocyanate)

Toxicities:

1. Hypotension

2. Reflex tachycardia

3. Throbbing headaches (dilation of meningeal arteries)

Classification:

ARTERIOdilator

Mechanism of action:

1. Activates endothelial nitric oxide synthase (eNOS) →

2. NO Diffuses into muscle cell and stimulates GC →

3. ↑ cGMP results in activation of PKG →

4a. PKG activates MLC-Phosphatase &

4b. PKG phosphorylates K⁺ channels (hyperpolarization) →

5. Results in SM relaxation and vasodilation

Clinical Uses:

1. Chronic therapy

Toxicities:

1. Tachycardia

2. Salt & H₂O retention

3. Reversible Lupus erythematosus

1. Release of nitric oxide from endothelium (hydralazine) or from drug (nitroprusside, nitrates)

2. Hyperpolarization of vascular smooth muscle through K⁺ channel opening (minoxidil sulfate, diazoxide)

3. Reduction of Ca²⁺ influx via L-type channels (verapamil, diltiazem, nifedipine)

4. Activation of dopamine receptors (fenoldopam)

Example: dobutamine

1. Acts as agonist of β-adrenergic GPCR →

*Used for acute decompensated heart failure

1. GPCR activation via M1/3 muscarinic, histamine, bradykin, ATP, etc.  →

2. ↑ Ca²⁺/Calmodulin →

3. ↑ eNOS activity producing NO →

4. NO diffuses into muscle cell →

5. PKG mediated vasodilation...

Sildenafil

Vardenafil

Tadalafil

Classification:

Phosphodiesterase V inhibitor

Mechanism of Action:

1. Selectively inhibits PDE5 →

2. Impedes breakdown of cGMP in SM cells →

3. ↑ cGMP results in PKG activation →

4. SM relaxation...

Clinical use:

1. Erectile dysfunction

2. Pulmonary hypertension

3. BPH

4. Angina

Toxicities:

1. Vision problems/headache

2. Dizziness/flushing

3. Excessive vasodilation

4. 4-hour erection...is this a bad thing?

Smooth Muscle:

1. Activates adenylyl cyclase (Gs) →

2. Increase in cAMP activates PKA →

3. PKA phosphorylates MLCK and inactivates →

4. MLCP dominates activity →

5. SM relaxation...

Cardiac cell:

1. Activates adenylyl cyclase (Gs) →

2. Increase in cAMP activates PKA →

3. PKA phosphorylates phospholamaban →

4. Phospholamban cannot inhibit release of Ca²⁺ from SR →

5. ↑ Ca²⁺ influx →

6. Increase force of contraction (inotropy)

Heart:

1. ↓ Ca²⁺ influx during cardiac action potential →

2. ↓ conduction velocity →

3. ↓ HR and cardiac output (CO)

4. ↓ myocardial O₂ demand

Smooth muscle:

1. ↓ Ca²⁺ influx following GPCR activation →

2. ↓ Ca²⁺/calmodulin, hence ↓ MLCK activity →

3. Smooth muslce relaxation (vasodilation)

Heart and vasculature: diltiazem & verapamil

Vasculature only: DHP's (nifedipine)