| How is the mechanism of action of adrenergic agonists? | Direct-Acting (act on a and b receptors directly produce similar effect as normal hormones from adrenal medulla, these include Epinephrine, NE, Isoproterenol, phenylephrine)
Indirect-Acting (may block uptake of NE cocaine, cause release of NE from vesicles (amphetamines, tyramines))
Mixed-Action Agonists (stimulate adrenoreceptors directly and release NE from adrenergic neuron [ephedrine, pseudo-ephedrine, and metaraminol]) |
| What are the direct acting adrenergic agonists? | Epinephrine
Norepinephrine
Isoproterenol
Dopamine
Dobutamine
Oxymetazoline
Phenylephrine
Methoxamine
Clonidine
Metaproterenol
Albuterol, pirbuterol and Terbutaline
Salmeterol and Formeterol |
| Give scheme of classifications of adrenergic receptor agonists? | . |
| What are characteristic responses mediated by adrenoreceptors? | . |
| What are cardiovascular actions of epinephrine nonselective (a1,a2,b1,b2)? | ardiovascular:
strengthens the contractility of the myocardium (positive inotropic: β1 action)
increases its rate of contraction (positive chronotropic: β1 action),
increases cardiac output
increased oxygen demands on the myocardium.
constricts arterioles in the skin, mucous membranes, and viscera (α1 effects),
dilates vessels going to the liver and skeletal muscle (β2effects)
Renal blood flow is decreased (vasoconstriction α1 effects)
the cumulative effect is an increase in systolic blood pressure, coupled with a slight decrease in diastolic pressure |
| What are respiratory actions of epinephrine non-selective? | Powerful bronchodilation by acting directly on bronchial smooth muscle (β2 action).
relieves bronchoconstriction.
inhibits the release of allergy mediators such as histamine from mast cells.
Hyperglycemia:
Significant hyperglycemic effect because of
increased glycogenolysis in the liver (β2 effect),
increased release of glucagon (β2 effect),
decreased release of insulin (α2 effect).
Lipolysis:
initiates lipolysis through its agonist activity on the β1(β3) receptors of adipose tissue
hydrolysis triacylglycerols to free fatty acids and glycerol |
| What are therapeutic uses of epinephrine? | Bronchospasm and Anaphylactic shock
treatment of acute asthma and anaphylactic shock, drug of choice within a few minutes after subcutaneous administration, greatly improved respiratory exchange is observed
drug of choice for the treatment of Type I hypersensitivity reactions in response to allergens.
Cardiac arrest
restore cardiac rhythm in patients with cardiac arrest regardless of the cause.
Anesthetics
increase the duration of the local anesthesia by producing vasoconstriction at the site of injection |
| How are pharmacokinetics of epinephrine? | 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 inhalation, or topically.
Oral administration is ineffective, because epinephrine and the other catecholamines are inactivated by intestinal enzymes.
Epinephrine, like the other catecholamines, is metabolized by two enzymatic pathways: MAO, and COMT
Only metabolites are excreted in the urine. |
| What are adverse effects of epinephrine? | a. CNS disturbances:
Sometimes, adverse CNS effects occurs such as anxiety
b. Cardiac arrhythmias:
can trigger cardiac arrhythmias, particularly if the patient is receiving digitalis. |
| How are epinephrine interactions? | a. Cocaine: In the presence of cocaine, epinephrine produces exaggerated cardiovascular actions.
b. Diabetes:
Epinephrine increases the release of endogenous stores of glucose. In the diabetic, dosages of insulin may have to be increased.
c. β-Blockers:
prevent epinephrine’s effects on β receptors, leaving α-receptor stimulation unopposed. It leads to an increase in peripheral resistance and an increase in blood pressure |
| What are cardiovascular actions of NE non selective (a1,a2,b1)? | 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 |
| What are baroreceptor reflexes done by NE? | The increased blood pressure induces a reflex rise in vagal activity by stimulating the baroreceptors.
This reflex bradycardia is sufficient to counteract the local actions of norepinephrine on the heart,
although the reflex compensation does not affect the positive inotropic effects of the drug. |
| What are therapeutic uses of NE? | treat shock, because it increases vascular resistance and increases blood pressure |
| How are pharmacokinetics of NE? | given IV for rapid onset of action.
The duration of action is 1 to 2 minutes following the end of the infusion period.
poorly absorbed after subcutaneous injection
destroyed in the gut if administered orally
Metabolism is similar to that of epinephrine. |
| What are adverse effects of NE? | similar to those of epinephrine.
In addition, norepinephrine may cause skin necrosis along injected vein (due to extreme vasoconstriction) |
| What are cardiovascular effects of isoproterenol (b1,b2) non selective? | produces intense stimulation of the heart to increase its rate and force of contraction, causing increased cardiac output
useful in the treatment of atrioventricular block or cardiac arrest.
dilates the arterioles of skeletal muscle (β2 effect), resulting in decreased peripheral resistance.
may increase systolic blood pressure slightly because of its cardiac stimulatory action
reduces mean arterial and diastolic blood pressure |
| What are pulmonary and other effects of isopreternol? | A profound and rapid bronchodilation is produced by the drug (β2 action).
rapidly alleviates an acute attack of asthma when taken by inhalation (which is the recommended route).
action lasts about 1 hour and may be repeated by subsequent doses.
c. Other effects:
increased blood sugar
increased lipolysis |
| What are therapeutic, pharmacokinetics and adverse effects of uses of isopereternol? | Therapeutic uses:
Isoproterenol is now rarely used as a bronchodilator in asthma.
It can be employed to stimulate the heart in emergency situations
rarely used therapeutically.
Pharmacokinetics:
Isoproterenol can be absorbed systemically by the sublingual mucosa
is more reliably absorbed when given parenterally or as an inhaled aerosol.
Adverse effects:
Like those of epinephrine |
| How is mechanism of action of dopamine (a1 and b1)? | Dopamine can activate:
1- α1 and β1 adrenergic receptors
- at higher doses, it can cause vasoconstriction by activating α1 receptors,
- at lower doses, it stimulates β1 cardiac receptors
2- D1 and D2 dopaminergic receptors
- occur in the peripheral mesenteric and renal vascular beds
binding of dopamine produces vasodilation.
Dopamine is rapidly metabolized to homovanillic acid by MAO or COMT
These D1 and D2 receptors are not affected by α- or β-blocking drugs |
| What are actions of dopamine? | Cardiovascular:
Dopamine exerts a stimulatory effect on the β1 receptors of the heart, having both inotropic and chronotropic effects
At very high doses, dopamine activates α1 receptors on the vasculature, resulting in vasoconstriction.
Renal and visceral:
Dopamine dilates renal and splanchnic arterioles by activating dopaminergic receptors (D1)
increasing blood flow to the kidneys and other viscera
Note: Similar dopamine receptors are found in the autonomic ganglia and in the CNS. |
| What are therapeutic uses of dopamine? and adverse effects? | 2. Therapeutic uses
- drug of choice for shock given by continuous infusion.
It raises the blood pressure by stimulating the β1 receptors on the heart to increase cardiac output
α1 receptors on blood vessels to increase total peripheral resistance.
- an increased blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis.
In this regard, dopamine is far superior to norepinephrine, which diminishes the blood supply to the kidney and may cause renal shutdown.
3. Adverse effects
nausea, hypertension, arrhythmias |
| what is dobutamine? | selective β1-receptor
a synthetic, direct-acting catecholamine β1-receptor agonist
It increases cardiac output (inotrope positive) with few vascular effects and with little change in heart rate
2. Therapeutic uses:
increase cardiac output in congestive heart failure as well as for inotropic support after cardiac surgery.
*does not significantly elevate oxygen demands of the myocardium (major advantage over other sympathomimetic drugs). (little change in heart rate)
3. Adverse effects:
Tolerance may develop on prolonged use. |
| What is oxymetazoline? | (α1, α2) nonselective (very low affinity to α2)
a direct-acting synthetic adrenergic agonist that stimulates both α1- and α2-adrenergic receptors.
direct stimulation of α receptors on blood vessels supplying the nasal mucosa and the conjunctiva to reduce blood flow and decrease congestion
used locally in the eye or the nose as a vasoconstrictor in short-term nasal spray
decongestant products as well as in ophthalmic drops for the relief of redness of the eyes associated with swimming, colds, or contact lens
is absorbed in the systemic circulation regardless of the route of administration and may produce nervousness, headaches, and trouble sleeping
When administered in the nose, burning of the nasal mucosa and sneezing may occur
Rebound congestion is observed with long-term use |
| What is phenylephrine? | (α1) selective
direct-acting, synthetic adrenergic drug that binds primarily to α receptors and favors α1 receptors over α2 receptors (α1> > α2 )
not a catechol derivative -not a substrate for COMT
is a vasoconstrictor that raises both systolic and diastolic blood pressures
no effect on the heart itself but rather induces reflex bradycardia when given parenterally (Phenylephrine 10 mg/ml Injection)
treatment of hypotensive states e.g. circulatory failure, during spinal anaesthesia
Local
often used topically on the nasal mucous membranes and in ophthalmic solutions for mydriasis
Phenylephrine acts as a nasal decongestant and produces prolonged vasoconstriction
Large doses can cause hypertensive headache and cardiac irregularities |
| What is methoxamine? | (α1> α2 )
direct-acting, synthetic adrenergic drug that binds primarily to α receptors, with α1 receptors favored over α2 receptors.
raises blood pressure by stimulating α1 receptors in the arterioles, causing vasoconstriction---an increase in total peripheral resistance.
Because of its effects on the vagus nerve, methoxamine is used clinically to relieve attacks of supraventricular tachycardia.
used to overcome hypotension during surgery involving halothane anesthetics.
Adverse effects include hypertensive headache and vomiting.
Methoxamine 20 Mg/ml Injectable Solution |
| What is clonidine? | an α2 agonist that is used in essential hypertension to lower blood pressure because of its action in the CNS
used to minimize the symptoms that accompany withdrawal from opiates or benzodiazepines.
acts centrally to produce inhibition of sympathetic vasomotor centers, decreasing sympathetic outflow to the periphery . This reduces uncomfortable symptoms of Opioid detoxification, such as sweating, hot flashes, watery eyes, and restlessness.
Transdermal clonidine is used alone or in combination with other medications to treat high blood pressure |
| What is metaproterenol? | (β2 non selective)
(Β2> β1)
chemically similar to isoproterenol, is not a catecholamine, and it is resistant to methylation by COMT
It can be administered orally or by inhalation
The drug acts primarily at β2 receptors, producing little effect on the heart
Metaproterenol produces dilation of the bronchioles and improves air-way function
The drug is useful as a bronchodilator in the treatment of asthma and to reverse bronchospasm
Little cardiac stimulation
Alupent® (metaproterenol sulfate USP) inhalation aerosol is indicated as a bronchodilator to treat asthma |
| What is albuterol? | Salbutamol VENTOLIN), pirbuterol (Maxair), and terbutaline (BRICANYL) (β2 selective) (SABA= Short Acting Beta Agonists)
short-acting β2 agonists
used primarily as bronchodilators
administered by a metered-dose inhaler
Compared with the nonselective β-adrenergic agonists, such as metaproterenol, these drugs produce equivalent bronchodilation with less cardiac stimulation |
| What is Salmeterol and formoterol? | β2-adrenergic selective, long-acting bronchodilators (LABA= Long-acting beta agonists).
A single dose by a metered-dose inhalation device,
provides sustained bronchodilation over 12 hours, compared with less than 3 hours for Albuterol.
These agents are not recommended as monotherapy and are highly efficacious when combined with a corticosteroid.
Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in symptomatic patients taking other asthma medication |
| How are indirect acting agonists? | may block the uptake of norepinephrine (uptake blockers) cocaine,
cause the release of norepinephrine from the vesicles of the adrenergic neuron amphetamine and tyramine
They do not directly affect postsynaptic receptor |
| What are amphetamines? | CNS Stimulation, central stimulatory action
release of stored catecholamines; thus, amphetamine is an indirect-acting adrenergic drug.
increase blood pressure significantly by α-agonist action on the vasculature as well as β-stimulatory effects on the heart.
use for treating attention deficiency in children (ADHD), narcolepsy, and appetite control.
should be avoided in pregnancy because of adverse effects on development of the fetus
Amphetamines are synthetic stimulant drugs that increase alertness, energy and attention, and suppress the appetite.
They are highly addictive |
| What are ADHD drugs? | Dextroamphetamine, methamphetamine, the mixed amphetamine salts, and methylphenidate can help improve attention span and alleviate many of the behavioral problems associated with this syndrome, in addition to reducing hyperkinesia.
Atomoxetine is a nonstimulant drug approved for ADHD in children and adults. Unlike methylphenidate, which blocks dopamine reuptake more than norepinephrine reuptake,
Atomoxetine is more selective for inhibition of norepinephrine reuptake.
It is not considered habit forming and is not a controlled substance. |
| What is Tyramine? | is not a clinically useful drug, but it is important because it is found in fermented foods, such as Chianti wine (see MAO inhibitors).
Types of cheese that undergo an aging process will be high in tyramine. These cheeses include cheddar, blue, parmesan, feta, and Camembert
It is a normal byproduct of tyrosine metabolism.
Normally, it is oxidized by MAO in the gastrointestinal tract, but if the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes
Like amphetamines, tyramine can enter the nerve terminal and release norepinephrine.
The released catecholamine then acts on adrenoceptors |
| What is cocaine? | has the ability to block the Na+/K+-activated ATPase on the cell membrane of the adrenergic neuron.
It blocks the reuptake of the monoamines (norepinephrine, serotonin, and dopamine) into the presynaptic terminals.
accumulates in the synaptic space, resulting in enhancement of sympathetic activity and potentiation of the actions of epinephrine and norepinephrine.
the duration of action of epinephrine and norepinephrine is increased.
Cocaine is a widely available and highly addictive drug.
Like amphetamines, it can increase blood pressure by α-agonist actions and β-stimulatory effects
In particular, the prolongation of dopaminergic effects in the brain’s pleasure system (limbic system) produces the intense euphoria that cocaine initially causes. |
| What are mixed-acting adrenergic agonists? | 1- induce the release of norepinephrine from presynaptic terminals
2- activate adrenergic receptors on the postsynaptic membrane |
| What are epheridne and pseudoepherdine? | - not only release stored norepinephrine from nerve endings but also directly stimulate both α and β receptors.
- similar to those of epinephrine, although less potent
- are not catechols and are poor substrates for COMT and MAO;
- have a long duration of action.
- Ephedrine and pseudoephedrine have excellent absorption orally and penetrate into the CNS
The chemical compound of ephedrine is likened to the structure of amphetamines; it can even be used to make methamphetamine.
This makes it a high-demand substance for illicit drug manufacturers and another key reason that ephedrine has become more difficult to obtain.
Ephedrine’s similar structure to amphetamines explains its addictive nature |
| How is action of epherdine and pseudoepherdine? | Ephedrine (α1, α2, β1, β2 releasing agent)
Ephedrine produces a mild stimulation of the CNS.
This increases alertness, decreases fatigue, and prevents sleep. It also improves athletic performance.
Ephedrine has been used to treat asthma, as a nasal decongestant (due to its local vasoconstrictor action), and to raise blood pressure
Pseudoephedrine
is primarily used to treat nasal and sinus congestion. |
