Lecture 11b Clinical uses of adrenergic agonists

Clinical Uses of Adrenergic Agonists Cardiovascular:  Cardiogenic Shock, Cardiac arrest: β agonist: Adrenaline, dobutamine or dopamine Dopamine is clinically more useful in the treatment of shock, in which significant increase in sympathetic activity might compromise renal function and worsens the peripheral circulation  Malignant hypertension: α2 agonist: Clonidine  HYPOTENSION: α1 agonist phenylephrine  Heart block : β agonist: isoprenaline  It’s only used now to reverse the block which is produced by overdoses of β – blockers

N.B. cardiac arrest means : complete cessation of heart’s activity. While heart block means : partial or complete inhibition of the spread of conduction of the electrical impulse from the atria to the ventricles Anaphylactic reactions: Ad is the first line of treatment for bronchoconstriction & CV collapse Both β and α agonist required. We use EP with steroid and antihistamine to cause Bronchodilation, Increase BP

Clinical Uses of Adrenergic Agonists (cont.) Respiratory:  Asthma and premature labor contractions: For treatment » Isoprenaline (β agonist), Salbutamol, Terbutalin & Salmeterol (selective β2 is preferred) For prophylaxis » Salmeterol & Formoterol Norepinephrine is NOT used in treatment of asthma  Nasal Decongestion: Ephedrine  Haemostatic in epistaxis: Adrenaline & Ephedrine Miscellaneous:  Mydriatic: Ephedrine  Glaucoma: Adrenaline decrease IOP in open angel glaucoma, decrease aqueous humor production by VC of ciliary body BV.  Depression: Amphetamine ritordine

With local anesthetics: Adrenaline & NA These drugs are used in dentistry because of their vasoconstrictive actions on blood vessels. They are added to local anesthetics because they prolong the action of the local anesthetic, reduce the risk for systemic toxicity, and help to create a dry field.

Central Nervous System Stimulation These medications are used for the treatment of attention deficit hyperactivity disorder, narcolepsy, and as diet aids.

Adverse Effects –CNS disturbance: anxiety, fear, tension, headache & tremors –Cerebral hemorrhage –Tachycardia & Cardiac arrhythmias –Tachyphylaxis occurs with indirectly acting drugs

Contraindications to use of adrenergics Cardiac dysrhythmias, angina pectoris Hypertension Hyperthyroidism Cerebrovascular disease Distal areas with a single blood supply such as fingers, toes, nose and ears Renal impairment use caution

Toxicity of adrenergics in critically ill patients Affects renal perfusion Can induce cardiac dysrhythmias Increases myocardial oxygen consumption May decrease perfusion of liver Tissue necrosis with extravasation

Epinephrine Actions: 1- Cardiovascular: strengthens the contractility of the myocardium (positive inotropic) and increases its rate of contraction (positive chronotropic). Cardiac output therefore increases. With these effects comes increased oxygen demands on the myocardium. Epinephrine constricts arterioles in the skin, mucous membranes, and viscera (α effects), and it dilates vessels going to the liver and skeletal muscle.

Therefore, the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure. 2- Respiratory: Epinephrine causes powerful bronchodilation by acting directly on bronchial smooth muscle. This action relieves all known allergic- or histamine-induced bronchoconstriction. In the case of anaphylactic shock, this can be lifesaving. 3- hyperglycemia 4- lipolysis

Pharmacokinetics: Epinephrine has a rapid onset but a brief duration of action (due to rapid degradation). In emergency situations, epinephrine is given intravenously for the most rapid onset of action. It may also be given subcutaneously, by endotracheal tube, by inhalation, or topically to the eye. Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes. Only metabolites are excreted in the urine.

Biotransformation: Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO, and COMT. Therapeutic uses: 1.bronchospasm 2.Glaucoma 3.Anaphylactic shock 4.Cardiac arrest 5.With anasethtics

Adverse effects: 1.CNS disturbances: 2.Hemorrhage: The drug may induce cerebral hemorrhage as a result of a marked elevation of blood pressure. 3.Cardiac arrhythmias: Epinephrine can trigger cardiac arrhythmias, particularly if the patient is receiving. 4.Pulmonary edema: Epinephrine can induce pulmonary edema

Interactions: 1.Hyperthyroidism: Epinephrine may have enhanced cardio-vascular actions in patients with hyperthyroidism. involve increased production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response. 2. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions. This is due to the ability of cocaine to prevent reuptake of catecholamines into the adrenergic neuron; thus, like norepinephrine, epinephrine remains at the receptor site for longer periods of time. 3. Inhalation anesthetics: Inhalational anesthetics sensitizethe heart to the effects of epinephrine, which may lead to tachycardia.

4. Diabetes: Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased. 5. β-Blockers: These agents prevent epinephrine's effects on β receptors, leaving α receptor stimulation unopposed. This may lead to an increase in peripheral resistance and an increase in blood pressure.

Nor epinephrine Actions 1- Cardiovascular actions: Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to intense vasoconstriction of most vascular beds, including the kidney (α1 effect). Both systolic and diastolic blood pressures increase. [Note: Norepinephrine causes greater vasoconstriction than does epinephrine, because it does not induce compensatory vasodilation via β2 receptors on blood vessels supplying skeletal muscles, etc. The weak β2 activity of norepinephrine also explains why it is not useful in the treatment of asthma.]

Uses: Shock; because it increases vascular resistance and, therefore, increases blood pressure. However, dopamine and metaraminol is favored, because it does not reduce blood flow to the kidney, as does norepinephrine When norepinephrine is used as a drug, it is sometimes called levarterenol

Pharmacokinetics: Norepinephrine may be given IV for rapid onset of action. The duration of action is 1 to 2 minutes following the end of the infusion period. It is poorly absorbed after subcutaneous injection. destroyed in the gut if administered orally. Metabolism is similar to that of epinephrine. Adverse effects: These are similar to those of epinephrine.