Lecture 13 to 14: Adrenergic drugs Flashcards
1
Q
Catecholamines: chemical structure
A
- β-phenylethylamine can be viewed as the parent compound of the sympathomimetic amines;
- Norepinephrine, epinephrine, dopamine, isoproterenol and a few other agents have –OH groups substituted at positions 3 and 4 of the benzene ring.
2
Q
EPINEPHRINE
A
When a large dose is given IV
- There is increase in blood pressure. Due to:
- Increased ventricular contraction (Beta1 effect).
- Increased heart rate (Beta1 effect) This may be opposed by the baroreceptor reflex.
- Vasoconstriction (alpha1 effect).
When a low dose is given IV
- Peripheral resistance decreases, because beta2 receptors are more sensitive to epinephrine than alpha1 receptors. Diastolic pressure falls.
- Systolic pressure increases due to increased cardiac contractile force (Beta1 effect).
- Heart rate increases (Beta1 effect).
- There is no increase in mean blood pressure, so the baroreceptor reflex does not kick in.
3
Q
EFFECTS OF EPINEPHRINE ON THE RESPIRATORY SYSTEM
A
Bronchodilation (Beta2 action)
4
Q
METABOLIC EFFECTS OF EPINEPHRINE
A
- incr glycogenolysisinliver(Beta2 effect)
- incr Lipolysis (Beta3 effect)
5
Q
Effects of Epinepherine on smooth muscles and renal
A
- Increases renin release (β1 effect).
- Constricts arterioles in skin, mucous membranes and viscera (α1 effect).
- At low doses dilates blood vessels going to the skeletal muscle and liver (β2 effect).
- Epinephrine relaxes GI smooth muscle (α1, α2, and β2 effects). Intestinal tone and frequency and amplitude of spontaneous contractions are reduced. Sphincters are contracted (α1effect).
- The detrusor muscle of the bladder relaxes (β2 effect), the trigone and sphincter contract (α1 effect). This may lead to urinary retention. Contraction of smooth muscle in the prostate (α1 effect) promotes urinary retention.
6
Q
EPINEPHRINE: USES
A
- Anaphylactic Shock: drug of choice.
- Used to treat acute asthmatic attacks; epinephrine and isoproterenol are potent bronchodilators.
- Cardiac arrest: can restore cardiac rhythm in patients with cardiac arrest.
- In Local Anesthetics: Epinephrine increases duration of local anesthesia by producing vasoconstriction at the site of injection.
7
Q
Epinepherine: Adverse Effects & Interactions
A
ADVERSE EFFECTS
- CNS disturbances: anxiety, fear, tension, headache, tremor.
- Hemorrhage: may induce cerebral hemorrhage due to incr in blood pressure.
- Cardiac arrhytmias: particularly if the patient is receiving digitalis.
- Pulmonary edema.
INTERACTIONS
- Hyperthyroidism: Epinephrine may have enhanced CV actions in patients with hyperthyroidism. The mechanism appears to involve an increase in production of adrenergic receptors on the vasculature of the hyperthyroid individual, leading to a hypersensitive response.
- Cocaine: in the presence of cocaine, epinephrine produces exaggerated CV actions, due to the ability of cocaine to prevent re-uptake of catecholamines into the adrenergic neuron. Thus, like norepinephrine, epinephrine remains at the receptor for longer.
- β-blockers: β-blockers prevent epinephrine’s activation of β receptors, leaving α receptor activation unopposed. This may lead to an increase in peripheral resistance and blood pressure.
8
Q
NOREPINEPHRINE
A
- Potent agonist at alpha1, alpha2, and Beta1 receptors; **In practice, when given in therapeutic doses to humans, the α-adrenergic receptor is the most affected. **
- Little action on Beta2 receptors therefore it has relatively little capacity to increase bronchial air flow
- Vasoconstriction: alpha1 effect; Both systolic and diastolic blood pressures increase.
- Cardiac output is unchanged or decreased;** reflex bradycardia counteracts local actions of norepinephrine on the heart. **
- Effect of atropine pre-treatment: if atropine is given before norepinephrine, norepinephrine causes tachycardia.
9
Q
Norepinepherine & Baroreceptors
A
- Baroreceptor reflex: in isolated cardiac tissue norepinephrine increases cardiac contractility (β1 effect). In vivo, little stimulation is observed.
- This is due to the increase in blood pressure that induces a reflex rise in vagal activity by stimulation of baroreceptors. The reflex bradycardia counteracts local actions of norepinephrine on the heart.
- decr PR: alpha1
10
Q
NOREPINEPHRINE: USES
A
- has only limited therapeutic value. It can be used to treat shock because it increases vascular resistance and therefore increases blood pressure.
- However, dopamine is better because it doesn’t decrease blood flow to the kidney as does norepinephrine.
11
Q
Dopamine
A
- Activates dopamine receptors and alpha and Beta receptors.
- Substrate for both MAO and COMT -> ineffective when given orally.
- Drug of choice for shock: primary interaction of dopamine is with vascular D1 receptors, especially in the renal, mesenteric, and coronary beds. By activating adenylyl cyclase and raising cAMP, D1 receptor stimulation leads to vasodilation. Infusion of low doses of dopamine causes increase in glomerular filtration rate, renal blood flow and Na+ excretion. As a consequence, dopamine is especially useful in management of states of low cardiac output associated with compromised renal function, such as cardiogenic and hypovolemic shock.
- incr systolic blood pressure by stimulating heart rate (Beta1 effect).
- incr perfusion to the kidney (D1 effect).
- Superior to norepinephrine that may cause kidney shutdown.
- **Dopamine also causes release of norepinephrine from nerve terminals, which contributes to its effects on the heart. **
- **At high concentrations, dopamine activates vascular α1 receptors, leading to vasoconstriction. **
12
Q
FENOLDOPAM
A
- D1-receptor selective agonist, which selectively leads to peripheral vasodilation in some vascular beds. Indicated for in-hospital, short-term management of severe hypertension.
- should be administered by continuous intravenous infusion. A bolus dose should not be used.
13
Q
ISOPROTERENOL
A
- NON-SELECTIVE Beta-ADRENERGIC AGONISTS
- Stimulates Beta1 and Beta2 adrenergic receptors.
- Action on alpha receptors is insignificant.
CVS
- Increases heart rate and force of contraction (Beta1 effect).
- Dilates arterioles of skeletal muscle (Beta2effect): decreases peripheral resistance.
- Decr diastolic BP
- Useful in treatment of atrioventricular block or cardiac arrest.
- increase systolic blood pressure slightly, but it greatly decreases mean arterial and diastolic blood pressure.
Pulmonary: Bronchodilation (Beta2 action).
OTHER EFFECTS
- GI smooth muscle is relaxed.
- causes less hyperglycemia than epinephrine, in part because insulin secretion is stimulated by the strong β-adrenergic activation of pancreatic islet cells.
- Isoproterenol and epinephrine are equally effective in stimulating the release of free fatty acids and in energy production.
PHARMACOKINETICS
- Absorbed systemically by sublingual mucosa.
- More reliably absorbed when given parenterally or as inhaled aerosol.
- Marginal substrate for COMT, and stable to MAO action.
ADVERSE EFFECTS
Similar to epinephrine.
14
Q
DOBUTAMINE
A
- Beta1-SELECTIVE ADRENERGIC AGONISTS
- The (-)-isomer is an alpha1 agonist and a weak Beta1 agonist.
- The (+)-isomer is an alpha1 antagonist and a potent Beta1 agonist.
- Clinical result: alpha effects cancel out leaving only beta1 effects
- Acute management of CHF: Increases cardiac output with little change in heart rate.
- Doesn’t significantly elevate O2 demands of the myocardium: major advantage over other sympathetic drugs.
15
Q
Terbutaline & Albuterol
A
- Beta2-ADRENERGIC AGONISTS
- Short acting
- Used in asthma.
16
Q
Salmeterol & formoterol
A
- Beta2-ADRENERGIC AGONISTS
- LONG-ACTING
- always used with a corticosteroid
- **Prolonged duration of action: 12hours as a result of high lipid solubility **
- Slow onset of action: **not suitable for prompt relief of breakthrough attacks of bronchospasm. **
26
Q
EPINEPHRINE REVERSAL
A
- All alpha-adrenergic blockers reverse the alpha-agonist effects of epinephrine.
- The vasoconstrictive alpha1 action of epinephrine is blocked, but vasodilation caused by activation of alpha2-receptors is not blocked.
- Therefore, the systemic blood pressure decreases in response to epinephrine given in the presence of phenoxybenzamine.
- NOTE: The actions of norepinephrine are not reversed but diminished, since norepinephrine lacks significant β-agonist action on the vasculature.
