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. **
17
Q
Beta2-ADRENERGIC AGONISTS: ADVERSE EFFECTS
A
- Tremor, restlessness, apprehension, anxiety, tachycardia.
- Adverse effects are less likely with inhalation therapy than with parenteral or oral therapy.
18
Q
PHENYLEPHRINE
A
- alpha1 selective agonist
- Vasoconstrictor
- **It has no direct effect on the heart, but induces reflex bradycardia when given parenterally. **
Uses
- Used to increasing blood pressure in hypotension resulting from vasodilation in septic shock or anesthesia.
- Used to increase blood pressure and terminate episodes of supraventricular tachycardia.
- Nasal decongestant. Given orally or topically.
- Mydriatic w/o cycloplegia and with ability to accommodate
19
Q
CLONIDINE
A
- alpha2-SELECTIVE ADRENERGIC AGONISTS
- **Partial alpha2 agonist. Centrally acting antihypertensive agent. **
- Activates central alpha2-adrenoceptors.
- Reduces sympathetic outflow. This reduces blood pressure.
- Adverse effects: lethargy, sedation, xerostomia.
- NOTE: **IV infusion of clonidine causes an acute rise in blood pressure, apparently because of activation of postsynaptic α2 adrenoceptors in vascular smooth muscle. The hypertensive response that follows IV administration is not seen when the drug is given orally. **
20
Q
METHYLDOPA
A
- alpha2-SELECTIVE ADRENERGIC AGONISTS
- Centrally acting antihypertensive agent.
- Taken up by noradrenergic neurons.
- Converted to alpha-methylnorepinephrine which activates central alpha2-adrenoceptors (similar to clonidine)
- This decreases blood pressure.
- Drug of choice for treatment of hypertension during pregnancy.
- Adverse effects: sedation, impaired mental concentration, xerostomia.
21
Q
BRIMONIDINE
A
- Highly selective alpha2 agonist.
- alpha2-SELECTIVE ADRENERGIC AGONISTS
- Given ocularly to lower intraocular pressure in glaucoma.
- Reduces aqueous humor production and increases uveoscleral outflow (not Canal of Schlemm).
22
Q
EPHEDRINE
A
- MIXED-ACTING ADRENERGIC AGONISTS
- Induce release of norepinephrine
- Activate adrenergic receptors.
- Stimulates alpha and Beta receptors and releases norepinephrine from nerve endings.
- Not a catecholamine -> poor substrate for COMT and MAO -> long duration.
- Excellent absorption orally and penetrates the CNS.
ACTIONS
- Increases systolic and diastolic blood pressures.
- Causes bronchodilation.
- Concomitant use of ephedrine with an anticholinesterase may have a synergistic effect in myasthenia gravis (the exact mechanism by which ephedrine affects skeletal muscle contraction is unknown).
- Mild stimulation of CNS: incr alertness, decr fatigue and prevents sleep.
- Improves athletic performance.
- Ephedrine-containing herbal supplements were banned by the FDA because of life-threatening CV reactions.
USES
- Used as a pressor agent, particularly during spinal anesthesia when hypotension frequently occurs.
- Used in myasthenia gravis.
- Used in allergic disorders, such as bronchial asthma. Now used infrequently to treat asthma.
23
Q
PSEUDOEPHEDRINE
A
- MIXED-ACTING ADRENERGIC AGONISTS
- One of four ephedrine enantiomers.
- Available over the counter as a component of many decongestant mixtures.
24
Q
PHENOXYBENZAMINE
A
- Irreversible alpha-antagonist via alkylation
- Also blocks H1, muscarinic and serotonin receptors and inhibits reuptake of norepinephrine by presynaptic adrenergic nerve terminals.
- Unsuccessful for hypertension.
Uses
- Used in Pheochromocytoma
- Prior to surgical removal of the tumor.
- For chronic management of inoperable tumors.
- Note: **β-blockers should not be given before establishing effective α blockade, since unopposed β blockade could cause blood pressure elevation due to increased vasoconstriction. **
Adverse Effects
- Postural hypotension, nasal stuffiness, nausea and vomiting.
- It can inhibit ejaculation.
- May induce tachycardia, mediated by the baroreceptor reflex, and is contraindicated in patients with decreased coronary perfusion.
25
PHENTOLAMINE
* Reversibly blocks alpha1 and alpha2 receptors.
* blocks serotonin receptors, and is an agonist at muscarinic, H1 and H2 receptors.
Uses
* Pheochromocytoma: short-term control of hypertension.
* Causes postural hypotension.
* Diagnosis of pheochromocytoma by the phentolamine blocking test.
* Hypertensive crisis associated with stimulant drug overdose.
* Hypertensive crisis due to sudden withdrawal of sympatholytic antihypertensive drugs (eg, clonidine).
* Indicated for the prevention of dermal necrosis after the inadvertent extravasation of norepinephrine.
Adverse Effects
* The drug can also trigger arrhythmias and anginal pain.
* Contraindicated in patients with decreased coronary perfusion.
26
EPINEPHRINE REVERSAL
* 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.**
27
alpha1-SELECTIVE ADRENERGIC BLOCKERS
* PRAZOSIN TERAZOSIN DOXAZOSIN TAMSULOSIN
* Selective blockers of the alpha1-receptor.
Uses
* Useful in the treatment of hypertension. Not DOC
* BPH
* Tamsulosin is Drug of Choice (DOC) for symptom relief; little effect on BP
* the first dose produces an exaggerated hypotensive response that can result in
syncope (fainting) 30 – 90 minutes after the dose is taken. This action, termed a 'first dose' effect may be minimized by adjusting the first dose to 1/3 or 1/4 of normal dose, and by giving the drug at bed time.
* Relax smooth muscle in the bladder neck, prostate capsule and prostatic urethra improving urinary flow.
28
alpha1-BLOCKERS: CV EFFECTS
* Lower arterial blood pressure by relaxing both arterial and venous smooth muscle.
* First dose produces an exaggerated hypotensive response that can result in syncope (fainting).
* The first dose must be 1/3 or 1/4 of normal dose.
29
YOHIMBINE
* alpha2-SELECTIVE ADRENERGIC BLOCKERS
* Used in the past to treat erectile dysfunction.
* Phosphodiesterase type 5 inhibitors have replaced it.
* **Yohimbine can reverse the antihypertensive effects of an α2-adrenoceptor agonist such as clonidine. **
30
PROPRANOLOL
* The prototype Nonselective beta-blocker
* Beta-adrenergic antagonists slow heart rate and decrease myocardial contractility (primarily block β1)
* α1 and β-blockers
* Partial agonists
* Blocking Beta2 receptors in the lungs can precipitate a respiratory crisis in patients with COPD or asthma; **contraindicated **in patients with **asthma. **
CVS
* β-blockers attenuate the expected rise in heart rate.
* Also peripheral resistance increases due to blockade of vascular β2 receptors and compensatory sympathetic reflexes that activate vascular α-adrenergic receptors.
* Patients with hypertension (though not normotensive subjects) show a gradual reduction of both systolic and diastolic blood pressures that takes several days to develop fully.
* The mechanism is complex, and involves the following:
* Reduction in cardiac output
* Reduction of renin release from the juxtaglomerular cells of the kidney
* A central action, reducing sympathetic activity
Metabolic effects
* decr glycogenolysis
* decr glucagon secretion.
Uses
* lower blood pressure in hypertension by decreasing cardiac output.
* Beta-blockers, particularly timolol, are effective in diminishing intraocular pressure in **glaucoma**.
* effective for prophylaxis of **migraine. **
* blunt sympathetic stimulation that occurs in **hyperthyroidism. **
* decrease O2 requirement of heart muscle; Useful in chronic management of **stable** **angina.** (Not fo racute management)
* control **ventricular rate** in patients with **atrial fibrillation** and a rapid ventricular response
* β-blockers have a protective effect on the myocardium. Patients who have had one MI appear to be protected against a second heart attack by prophylactic use of β-blockers. In addition, administration of a β-blocker immediately after a MI reduces infarct size and hastens recovery.
* preferred rx for performance anxiety
* treatment of essential tremor.
31
NON-SELECTIVE Beta-BLOCKERS: ADVERSE EFFECTS
Uses
* Bronchoconstriction: lethal in asthmatics
* Metabolic and Endocrine Effects
* Nonselective Beta-blockers may impair recovery from hypoglycemia in insulin-dependent diabetics.
* Beta1-selective blocker is preferable.
* Also, Beta-blockers mask the tachycardia that is typically seen with hypoglycemia, denying the patient an important warning sign.
* Sedation, dizziness, lethargy, fatigue, depression
* Beta-blocker therapy should not be withdrawn abruptly (particularly in patients with CAD); tapered to avoid acute tachycardia, hypertension, and/or ischemia.
* Propranolol, and other nonselective β blockers, are contraindicated in patients with asthma.
* NOTE: β-Blockers are contraindicated in variant angina.
32
ATENOLOL & METOPROLOL
* Beta1-SELECTIVE ADRENERGIC ANTAGONISTS
Uses
* Useful in hypertensive patients with impaired pulmonary function.
* Useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents.
* selectivity of Beta blockers for Beta1 receptors is modest: therefore these drugs should be avoided if at all possible in patients with asthma.
* Long-term management of patients with angina pectoris.
* Management of patients with acute myocardial infarction to reduce cardiovascular mortality.
33
ESMOLOL
Beta1-SELECTIVE ADRENERGIC ANTAGONISTS (ultra-short acting)
USES
* Supraventricular arrhythmias.
* Arrhythmias associated with thyrotoxicosis.
* Perioperative hypertension.
* MI in acutely ill patients
* Often used for aortic dissection or postoperative hypertension
34
LABETALOL
* alpha1- AND Beta-BLOCKERS (Blocks beta 7x greater than alpha1)
Uses
* Management of hypertension.
ADVERSE EFFECTS
* Orthostatic hypotension and dizziness are associated with α1 blockade.
* Labetalol has been associated with hepatic injury in a limited number of patients.
35
CARVEDILOL
* Like labetalol, it is substantially more potent as an alpha-antagonist.
* Used in hypertension and congestive heart failure.
* Studies demonstrate reverse cardiac remodeling & reduction in mortality & hospitalization (30-40% in patients with NYHA II-IV HF)
* HR (negative inotropic effect) & inhibit renin release (1 receptors)
* Prevent deleterious effects of norepinephrine on cardiac muscle fibers remodeling, hypertrophy etc
* Can get initial exacerbation of symptoms (start at low dose & gradually increase over several weeks)
36
PINDOLOL
* PARTIAL Beta-AGONIST aka intrinsic sympathomimetic activity (ISA).
* may be preferred as antihypertensives in individuals with diminished cardiac reserve or a propensity to bradycardia.
* clinical significance of partial agonism has not been demonstrated in controlled trials, but may be of importance in individual patients.
37
alpha-METHYLTYROSINE (METYROSINE)
* Competitive inhibitor of **tyrosine hydroxylase.**
* Used for management of malignant pheochromocytoma.
* Used in preoperative preparation of patients for resection of pheochromocytoma.
38
RESERPINE
* Irreversibly damages VMAT. Vesicles cannot store norepinephrine and dopamine.
* This causes depletion of norepinephrine, since MAO degrades norepinephrine in the cytoplasm.
* Gradual decrease in blood pressure and slowing of cardiac rate.
* Used in the past to treat hypertension.
39
GUANETHIDINE
* Guanethidine displaces norepinephrine from transmitter vesicles leading to depletion of norepinephrine.
* Additionally, guanethidine inhibits release of norepinephrine. This action is primarily responsible for its antihypertensive action.
* causes a gradual decrease in blood pressure and heart rate.
* In the early 1970s guanethidine was a major antihypertensive drug for severely hypertensive patients.
40
Tamsulosin
* Three subtypes of the α1-receptor exist: α1A, α1B, and α1D. The α1A-receptor predominates in genitourinary smooth muscle. Tamsulosin is a selective antagonist at α1A-receptors. The selectivity of tamsulosin for α1A-receptors may decrease the incidence of orthostatic hypotension relative to that associated with prazosin and other nonsubtype selective α1-adrenoceptor antagonists.
* Approved for BPH. Little effect on blood pressure.
* **α1-selective adrenergic antagonists relax smooth muscle in the bladder neck, prostate capsule and prostatic urethra improving urinary flow. α1-adrenergic blockers are drugs of choice for symptom relief. Tamsulosin is less likely to cause orthostatic hypotension than the other drugs. **
Adverse Effects
* α1 blockers may cause dizziness, lack of energy, nasal congestion, headache, drowsiness, orthostatic hypotension.
* Due to a tendency to retain sodium and fluid, α-blockers are frequently co- administered with a diuretic.
* Male sexual function is not as severely affected by these drugs as it is by phenoxybenzamine or phentolamine.
41
OTHER NONSELECTIVE β-BLOCKERS
NADOLOL
* Long duration of action.
* Indicated for the long-term management of patients with angina pectoris.
* Indicated for the management of hypertension.
TIMOLOL
* Treatment of hypertension.
* Prophylaxis of migraine headache.
* Treatment of open-angle glaucoma.
