CARDIAC GLYCOSIDES

Cardiac glycosides (Digitalis)

Digoxin

Digitoxin

Sympathomimetics

Dobutamine

Dopamine

Vasodilators

α-blockers (prazosin)

Nitroprusside

ACE-inhibitors (captopril)

Pharmacology of Cardiac Glycosides

1. Positive inotropic effect (as a result of increase  C.O., the symptoms of CHF subside).

2. Effects on other cardiac parameters

1) Excitability

2) Conduction Velocity; slightly increased in atria & ventricle/significantly

reduced in conducting tissue esp. A-V node and His-Purkinje System

3) Refractory Period; slightly ^ in atria & nodal tissue/slightly v in ventricles

4) Automaticity; can be greatly augmented - of particular concern in ventricle

3. Heart Rate

-Decrease due to 1) vagal stimulation and 2) in the situation of CHF, due to improved hemodynamics

4 Blood Pressure

-In CHF, not of much consequence. Changes are generally secondary to improved cardiac performance.

-In the absence of CHF, some evidence for a direct increase  in PVR due to vasoconstriction.

5. Diuresis

-Due primarily to increase in  renal blood flow as a consequence of positive inotropic effect (increase CO etc.) Possibly some slight direct diuretic effect.

 Mechanism of Action of Cardiac Glycosides

Associated with an interaction with membrane-bound Na+-K+ ATPase (Na-K pump).

Clinical ramifications of an interaction of cardiac glycosides with the Na⁺ K pump.

I. Increase levels of Ca⁺⁺, Increase therapeutic and toxic effects of cardiac glycosides

II. Decrease levels of K⁺ , Increase toxic effects of cardiac glycosides

Therapeutic Uses of Cardiac Glycosides

• CHF
• CHF accompanied by atrial fibrillation
• Supraventricular arrhythmias

Mixed Narcotic Agonists/Antagonists

These drugs all produce analgesia, but have a lower potential for abuse and do not produce as much respiratory depression.

A. Pentazocine

• Has a combination of opiate analgesic and antagonist activity.
• Orally, it has about the same analgesic potency as codeine.
• In contrast to morphine, cardiac workload tends to increase due to an increase in pulmonary arterial and cerebrovascular pressure. Blood pressure and heart rate both also tend to increase.
• Adverse reactions to Pentazocine

• Nausea, vomiting, dizziness.

• Psychotomimetic effects, such as dysphoria, nightmares and visual hallucinations.

• Constipation is less marked than with morphine.

B. Nalbuphine

• Has both analgesic and antagonist properties.
• Resembles pentazocine pharmacologically.
• Analgesic potency approximately the same as morphine.
• Appears to be less hypotensive than morphine.
• Respiratory depression similar to morphine, but appears to peak-out at higher doses and to reach a ceiling.
• Like morphine, nalbuphine reduces myocardial oxygen demand. May be of value following acute myocardial infarction due to both its analgesic properties and reduced myocardial oxygen demand.
• Most frequent side effect is sedation.

C. Butorphanol

• Has both opiate agonist and antagonist properties.Resembles pentazocine , pharmacologically., 3.5 to 7 times more potent than morphine., Produces respiratory depression, but this effect peaks out with higher doses. The respiratory depression that does occur lasts longer than that seen following morphine administration.
• Butorphanol, like pentazocine, increases pulmonary arterial pressure and possibly the workload on the heart.
• Adverse reactions include sedation, nausea and sweating.

D. Buprenorphine

• A derivative of eto`rphine. Has both agonist and antagonist activity. 20 to 30 times more potent than morphine.Duration of action only slightly longer than morphine, but respiratory depression and miosis persist well after analgesia has disappeared.
• Respiratory depression reaches a ceiling at relatively low doses.
• Approximately 96% of the circulating drug is bound to plasma proteins.
• Side effects are similar to other opiates:
  • sedation, nausea, vomiting,
  • dizziness, sweating and headache.

Nitrous Oxide (N2O)

MAC 100%, blood/gas solubility ratio 0.47
- An inorganic gas., low solubility in blood, but greater solubility than N2
- Inflammable, but does support combustion.
- Excreted primarily unchanged through the lungs.
- It provides amnesia and analgesia when administered alone.
- Does not produce muscular relaxation.
- Less depressant to both the cardiovascular system and respiratory system than most of the other inhalational anesthetics.
- Lack of potency and tendency to produce anoxia are its primary limitations.
- The major benefit of nitrous oxide is its ability to reduce the amount of the secondary anesthetic agent that is necessary to reach a specified level of anesthesia.

Paracetamol

Paracetamol or acetaminophen is analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains.

paracetamol acts by reducing production of prostaglandins, which are involved in the pain and fever processes, by inhibiting the cyclooxygenase (COX)  enzyme.

Metabolism Paracetamol is metabolized primarily in the liver. At usual doses, it is quickly detoxified by combining irreversibly with the sulfhydryl group of glutathione to produce a non-toxic conjugate that is eventually excreted by the kidneys.

Thrombolytic Agents:

Tissue Plasminogen Activator (t-PA, Activase)

t-PA is a serine protease. It is a poor plasminogen activator in the absence of fibrin. t-PA binds to fibrin and activates bound plasminogen several hundred-fold more rapidly than it activates plasminogen in the circulation.

Streptokinase (Streptase)

Streptokinase is a protein produced by β-hemolytic streptococci. It has no intrinsic enzymatic activity, but forms a stable noncovalent 1:1 complex with plasminogen. This produces a conformational change that exposes the active site on plasminogen that cleaves a peptide bond on free plasminogen molecules to form free plasmin.

Urokinase (Abbokinase)

Urokinase is isolated from cultured human cells.Like streptokinase, it lacks fibrin specificity and therefore readily induces a systemic lytic state. Like t-PA, Urokinase is very expensive.

Contraindications to Thrombolytic Therapy:

• Surgery within 10 days, including organ biopsy, puncture of noncompressible vessels, serious trauma, cardiopulmonary resuscitation.

• Serious gastrointestinal bleeding within 3 months.

• History of hypertension (diastolic pressure >110 mm Hg).

• Active bleeding or hemorrhagic disorder.

• Previous cerebrovascular accident or active intracranial bleeding.

Aminocaproic acid:

Aminocaproic acid prevents the binding or plasminogen and plasmin to fibrin. It is a potent inhibitor for fibrinolysis and can reverse states that are associated with excessive fibrinolysis.

Loop (High Ceiling) Diuretics

Loop diuretics are diuretics that act at the ascending limb of the loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

Agent: Furosemide

Mechanism(s) of Action

1.    Diuretic effect is produced by inhibit of active 1 Na⁺, 1 K⁺, 2 Cl^-  co-transport (ascending limb - Loop of Henle). 
o    This produces potent diuresis as this is a relatively important Na re-absorption site.

2.    Potassium wasting effect 

a.    Blood volume reduction leads to increased production of aldosterone 
b.    Increased distal Na load secondary to diuretic effect 
c.    a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting (same as thiazides but more likely)

3.    Increased calcium clearance/decreased plasma calcium 

o    secondary to passive decreases in loop Ca++ reabsorption.
o    This is linked to inhibition of Cl^- reabsorption.
o    This is an important clinical effect in patients with ABNORMAL High Ca⁺⁺