Autonomic Drugs Flashcards
Epinephrine
- direct acting adrenergic agonist
- non-selective
- IV, like all catecholamines
Epinephrine has many physiological effects in the body:
1. CV
Heart: beta1 receptors in heart - epinephrine increases HR and force of contraction –> increase SBP
Smooth muscles lining cells: alpha1 and beta2 receptors on smooth muscle cells - epinephrine increases vasoconstriction –> increases peripheral resistance –> increases DBP
–> Epinephrine will increase both systolic and diastolic pressure
Endogenous epinephrine can sometimes activate the beta2 receptor. At very low levels of epinephrine, epinephrine has higher binding affinity for beta2 than for alpha1. So at very low levels of epinephrine like you sometimes see with endogenous epinephrine you may only see activation of beta2 receptors and not activation of alpha1, which can cause vasodilation
But when using epinephrine as a drug, we always see occupation of both alpha1 and beta2 –> vasoconstriction.
- Pulmonary
Epinephrine activates beta2 receptor –> bronchodilation on bronchial smooth muscle - Metabolic effects
Epinephrine activates beta2 receptors on hepatocytes and tells them to break down glycogen and release glucose into the blood
Indications:
- stimulate the heart in cardiac emergencies
- serious hypersensitivity reactions, including anaphylaxis
- asthma
- co-administer with local anesthetics
Norepinephrine
- direct acting adrenergic agonist
- selective for both alpha and beta, specifically alpha1, alpha2, and beta1
Norepinephrine: only under certain circumstances is norepinephrine used in emergency situations. For some reason, large doses of exogenous norepinephrine can lead to slowing of the heart. It can be coadministered with local anesthetics though.
Dopamine
- direct acting adrenergic agonist
- selective for both alpha and beta, specifically alpha1 and beta1
Dopamine: increases SBP and DBP
Dopamine will also activate dopamine receptors located on renal arteries. In turn, renal arteries vasodilate –> maintains nice healthy blood flow to kidneys.
One potential problem of epinephrine in cardiac emergencies: vasoconstriction everywhere. And while epinephrine clearly gets the patient through the acute event, there is always a potential for other problems down the line because of vasoconstriction elsewhere. There are studies beginning to identify neurological deficits from compromised blood supply in brain. There is also concern for lack of blood flow to the kidneys. Dopamine = alternative to this.
Dobutamine
- direct acting adrenergic agonist
- selective for both alpha and beta, specifically alpha1, beta1, beta2
Dobutamine - consists of 2 isomers that are given together to activate receptors in the heart. It is really just a beta1 agonist. It’s a catecholamine that will only act at beta1 receptors on the heart and is only used in emergency situations in the hospital.
+ isomer: beta1 agonist, but also has alpha1 antagonist activity.
- isomer: alpha1 agonist.
Alpha1 antagonist activity of the + isomer cancels the alpha1 agonist activity of the - isomer.
Phenylephrine
- direct acting adrenergic agonist
- selective for alpha1 receptors only
Many uses:
- increase DBP via injection
- major use: nasal decongestant - aerosol you squeeze into nasal passages –> activate alpha1 receptors on the arterioles in the nasal mucosal and cause vasoconstriction –> increases volume/size of nasal mucosa so you get more air in and out of the nasal passages.
- get rid of blood shot eyes (eyedrops) –> vasoconstriction of blood vessels in the eye.
Gets rid of blood shot eyes but causes dilated pupils (alpha1 receptors located on the iris dilator muscle)
Clonidine
- direct acting adrenergic agonist
- selective for alpha2 receptors only
Clonidine - alpha2 agonist.
- used to treat chronic HTN
- given orally
- mechanism: in the CNS, clonidine activates alpha2 receptors –> decrease in sympathetic output from the brain –> decrease in SBP and DBP, heart rate, force of contraction, and vasodilation. Ignore what clonidine is doing in the periphery - attribute all of its effects to the CNS.
Clonidine is also used to treat people who are addicted to alcohol or opiates. This helps them get through withdrawal syndrome. A large component of withdrawal syndrome is an increase in sympathetic tone from the brain. Clonidine reduces sympathetic tone during withdrawal syndrome.
Clonidine lowers intraocular pressure in patients with high BP and glaucoma. Alpha 2 agonists decrease the rate of vitreous humor formation in the eye. So instead of being given systemically, clonidine can be given as eyedrops for these patients. However, it is irritating to the eye.
Therefore Brimonidine, another alpha2 agonist is used in eyedrops. It is not irritating to the eye.
–> alpha2 agonists are also used to treat glaucoma.
Brimonidine
- direct acting adrenergic agonist
- selective for alpha2 receptors only
- eyedrop (non irritating to the eye) that decreases the rate of vitreous humor formation in the eye –> lowers intraocular pressure in patients with high BP and glaucoma
Isoproterenol
- direct acting adrenergic agonist
- selective for beta1 and beta2 receptors only
Isoproterenol - activates both beta1 and beta2 receptors. Can be used for asthma because it will activate beta2 receptors and cause bronchodilation. Similar problem that epinephrine has though - activates beta1 receptor of the heart, can feel the effects on the heart
Albuterol
- direct acting adrenergic agonist
- selective for beta2 receptors only
Albuterol - selective for beta2, don’t see much activation of beta1 (will sometimes see though if concentration is high enough because they’re selective, not specific)
generally inhaled via aerosol form
Ritodrine/Terbutaline
Ritodrine - discontinued, replaced by Terbutaline, also a beta2 agonist. It is used to suppress uterine contractions in premature labor.
Amphetamine
- indirect acting adrenergic agonist
- releaser
- used therapeutically for ADHD, narcolepsy, and chronic fatigue syndrome. Can induce a feeling of euphoria at high levels - there is abuse potential. All CNS effects.
Amphetamine acts on Uptake 1 transporter and reverses the flow of norepinephrine. It is normally taken up back into the sympathetic neuronal varicosity, but amphetamine reverses this pump.
It does the same thing to the transporter in storage vesicle. It will pump the norepinephrine out of the storage vesicle, out of the varicosity to elevate norepinephrine levels at the neuroeffector junction.
–> should be able to predict what the peripheral effects of amphetamines are: activate beta1 receptors in the heart (increase in HR and contractility –> increased SBP)
Norepinephrine doesn’t bind to beta2 receptor –> on smooth muscle they act 100% on alpha 1 –> vasoconstriction
–> increase peripheral resistance –> increase DBP
–> increase in SBP and DBP
At high doses of amphetamine, there is always a concern about ventricular arrythmias. Elevating norepinephrine levels in the neuroeffector junction at the heart always comes with some risk of inducing ventricular arrythmias (dangerous, very lethal)
Methylphenidate
- indirect acting adrenergic agonist
- releaser
- same mech as amphetamine, maybe safer
- for ADHD
Tyramine
- indirect acting adrenergic agonist
- releaser
- not a drug, natural breakdown product of tyrosine, consumed in different foods
- patients on MAOI cannot consume foods high in tyramine. if they do, there is a substantial increase in norepi.
Cocaine
- indirect acting adrenergic agonist
- uptake inhibitor
- blocks the uptake 1 transporter
- local anesthetic
It is the only local anesthetic that leads to its own vasoconstriction -
not given with norepinephrine or epinephrine because it upregulates norepinephrine at the site of injection
Tricyclic antidepressants
- indirect acting adrenergic agonist
- uptake inhibitor
MAOI
- indirect acting adrenergic agonist
- inhibitor of metabolism
Ephedrine
- mixed adrenergic agonist - acts like both direct and indirect acting
Ephedrine is used to treat incontinence (causes relaxation of detrusor muscle and constriction of internal urethral sphincter muscle.) It is sometimes used in the hospital to treat serious hypotension (can be injected or given orally)
The biggest issue we have with ephedrine comes from the fact that ephedrine is naturally occurring in certain plants and is contained in lots of nutritional supplements.
OTC use was banned by the FDA.
Cannot legally purchase any product with ephedrine in it in the US without prescription but the internet is a very powerful thing…
These are a problem. Patients with pre-existing CV disease take ephedrine containing supplements and end up with MI and strokes.
Phentolamine
- adrenergic antagonist
- non-selective alpha adrenergic antagonist (alpha1 and alpha2)
If we block alpha 1 receptors like in phentolamine, we see vasodilation –> decrease in DBP
Alpha antagonists not only cause vasodilation in arteries/arterioles, they also cause vasodilation in venules –> shifts blood from arteriole side to venous side
–> decrease in venous return –> decrease in SBP
Phentolamine causes drop in SBP and DBP
It is used in emergency situations in hospitals to lower BP. It is not used chronically to treat HTN because 1. phentolamine will cause severe orthostatic hypotension since it blocks many alpha1 receptors and you need these on the arteries/arterioles to cause vasoconstriction in the baroreceptor reflex and 2. reflex tachycardia: phentolamine increases HR because it blocks alpha2 receptors in the heart –> more epinephrine comes out –> increase in HR
Same event occurs with vascular smooth muscle because there are alpha1 receptors there.
–> Elevated norepinephrine levels at vascular smooth muscle don’t have any effect because phentolamine is blocking the alpha1 receptor.
But in the heart, you don’t have alpha1 receptor on the effector cell, you have the beta1 receptor. Phentolamine doesn’t block the beta1 receptor. When phentolamine blocks alpha2 in the heart, beta1 can be activated by increased norepinephrine –> increased HR
May also see an increase in the force of contraction, but not an increase in SBP because there is less blood for the heart to deal with - it’s trying harder but there’s less venous return. –> Phentolamine is only used in the hospital.
Prazosin
- adrenergic antagonist
- selective alpha1 adrenergic antagonist
Selective alpha blockers can be used chronically to treat HTN
Prazosin blocks alpha1 receptor -
doesn’t increase the HR. Taken orally. Effectively lowers both SBP and DBP.
2 issues:
1. first dose effect - the first time you give Prazosin to the patient, it causes substantial orthostatic hypotension because it blocks many alpha1 receptors. However after the first dose, the orthostatic hypotension becomes much less of an issue. Degree decreases substantially or disappears altogether for some patients
–> deal with this by giving first dose of prazosin to patient at night.
- epinephrine reversal - if a patient is taking an alpha1 blocker and now has a cardiac emergency which normally requires an injection of epinephrine, if these pts get epinephrine and alpha1 receptors are blocked, epinephrine that normally binds to alpha1 receptor binds instead to beta2 receptor –> causes more vasodilation, the exact opposite of what you want the epinephrine to do.
This however doesn’t happen all the time because it depends on the dose of alpha1 blocker and the dose of epinephrine
In a cardiac emergency you want to use some other drug other than epinephrine - may want to use norepinephrine because it will not bind to beta2 receptor
Tamsulosin
- adrenergic antagonist
- selective alpha1a adrenergic antagonist
You find alpha1a receptors on the muscle capsule of the prostate. The prostate surrounds the urethra in males. in elderly men, you start to see hyperplasia of the prostate but can only expand so much because of the muscular capsule. When the muscular capsule begins to push back on the expansion of the prostate, the first thing that gets squeezed is the ureter –> difficulty in urination
Drugs like tamsulosin block the alpha1a receptor in the muscle on the prostate capsule –> muscle capsule relaxes and prostate can expand more to take pressure of the urethra
Propanolol
- direct adrenergic antagonist
- non-selective beta adrenergic antagonist (beta1 and beta2)
- first generation
Propranolol - used to treat chronic hypertension, given orally
Blocks the beta1 receptor –> HR goes down –> force of contraction goes down –> SBP goes down
Blocks the beta2 receptor (makes no sense) –> more vasoconstriction but that doesn’t happen, you see vasodilation and decrease in DBP
Why? We don’t know.
Uses:
- HTN
- angina - decrease the workload of the heart, slowdown HR, reduce force of contraction, reduce oxygen consumption by the heart muscle
- arryhythmias - at high doses
- MI - improve prognosis - if patient arrives in ER in the middle of the MI and give beta blocker, prognosis is good. Can take a beta blocker up to several hours after MI and can still cause a better prognosis.
- glaucoma - drop in intraocular pressure: by blocking beta2 receptors in the ciliary body in the eye, you can decrease the rate of formation of aqueous humor. Timolol (eye drop) is often used because it doesn’t irritate the eye.
- migraines - beta blockers decrease freq and severity of migraines - don’t know mechanism
potential issues:
1. asthmatics - never give them a non-selective beta blocker - never give drug that blocks beta2 receptor –> can precipitate asthma attack (need beta2 for relaxation of bronchial muscle for bronchodilation)
Blocking the beta2 receptor in non-asthmatic patient does nothing
- also contraindicated in insulin-dependent diabetics - why?
We have 2 systems to keep glucose in our blood when we’re hungry: 1. glucagon from the pancreas tells the liver to break down glycogen and release glucose into the blood and 2. epinephrine tells hepatocytes to breakdown glycogen and release glucose into the blood. You only need one of these.
In insulin-dependent diabetics, within the first 10 years of diagnosis, patients are usually not producing glucagon. This is not a big deal because you don’t need glucagon as long as you have epinephrine to tell the liver to breakdown glycogen and release glucose. But what you can’t do is block the beta2 receptor because that would prevent epinephrine from binding to beta2 receptor on hepatocytes. Since you have no glucagon to replace that, these patients cannot regulate their blood glucose levels. Anything that blocks beta2 receptor cannot be used for insulin-dependent diabetic. - Sudden withdrawal - you can get very serious consequences
when you have been taking a beta blocker chronically and you suddenly stop. When you have been blocking a receptor chronically, the beta receptors that you had been blocking will upregulate. Beta1 receptors in the heart will try and overcome the beta blockade - the cells have some ability to sense that something is being blocked and will try to overcome that but will not be able to overcome the effects of the drug. You could get doubling of beta1 receptors in the heart but as long as the patient takes the beta blocker there’s no issue. Sudden withdrawal however will cause normal levels of epi and norepi but twice as many beta1 receptors that are not blocked anymore –> enormous increase in HR and force of contraction –> MI, hemorrhagic stroke
Patient needs to be slowly tapered off the drug so that the receptors can slowly come back to normal levels before the drug is completely terminated - Hyperthyroidism - beta blockers are sometimes used to suppress symptoms
In hyperthyroidism, the thyroid is producing much higher levels of T3 and T4. T3 and T4 help regulate the number of adrenergic receptors in various tissues. When you have an excess of T3 and T4, there is an increase in the number of adrenergic receptors located in many different tissues, including the heart. The beta1 receptor is the most important adrenergic receptor in the heart so elevated T3 and T4 will increase the number of beta1 receptors there. –> One symptom of hyperthyroidism, the one symptom that usually takes the pts to the doctors is that they are tachycardic and have palpitations. It takes a while to get T3 and T4 under control in hyperthyroidism so during that time, you want to suppress symptoms/effects on the heart and as a result, beta blockers are often given in initial treatment of patients with hyperthyroidism.
Timolol
- direct adrenergic antagonist
- non-selective beta adrenergic antagonist (beta1 and beta2)
- first generation
- used to treat glaucoma - decreases intraocular pressure by blocking beta2 receptors in the ciliary body in the eye, you can decrease the rate of formation of aqueous humor. Timolol (eye drop) is often used because it doesn’t irritate the eye.
Metoprolol
- direct adrenergic antagonist
- selective beta1 adrenergic antagonist
- second generation
- can be used cautiously in asthmatics and insulin-dependent diabetics; asthma/diabetes has to be well controlled for at least a year
Labetalol
- direct adrenergic antagonist
- beta blocker with additional actions: alpha1 antagonist
- third generation
- used in pregnancy, does not cause any fetal malformations
