Agonist (sympathoimetics)

You can activate adrenergic system in many ways: direct receptor activation, promotion of NE release, inhibition of reuptake/inactivation.

Adrenergic Neurons and Receptors

Making Norepi/epi (Catecholamines)

Phenylalanine is a essential amino acid obtainted from food. This is converted into tyrosine (non-essential) via the phenylalanine hydroxylase. Norepi is made from tyrosine which is taken up into adrenergic neurons via sodium-cotransporters. Then tyrosine get converted into L-dopa by tyyrosine hydroxylase (Rate limiting step). L-dopa is converted to dopamine by DOPA decarboxylase. Dopamine is taken up into a vesicles where it is converted to Norepi by the Dopamine-B hydroxylase enzyme.

Epi differs from norepi by one methyl group and is secreted by the adrenal medulla 20% of the time (Norepi is 80%). Norepi can be converted to epi via phenylethanolamine N-methyltransferase.

Releasing Norepi/epi

When the neuron is activated via action potential, Ca2+ rushes in and stimulates the exocytosis of the norepi containing vesicles. This only occurs at postganglionic sympathetic neurons (preganglionics release ACh)

When Epi and norepi are released from the adrenal medulla they both can enter the blood stream and exert their effects on the different receptors.

Receptors

All receptors are GPCRs.

When Norepi is release it diffuses through the synaptic cleft and binds adrenergic receptors → function depends on what organ we’re at. We have alpha 1 and 2, beta 1, 2, and 3.

Once norepi binds our Gq (stimulatory), alpha-1 and beta 1 we go through the phospholipase C pathway increases IP3 and DAG which increase Ca2+ in smooth muscle cells → vasoconstriction and contraction. In beta-1 (heart) stimulate smooth muscle contraction → increases contractility and HR. Beta-1 are linked to the Gs flavor of GPCR.

For alpha 2, we use the adenyl cylase (g-inhibitory (Gi)) reducing cAMP so we cannot release anything, no hormone or molecule secretion. Reduce excitability of the cell there located in.

Beta 2 is linked to a 7-TM GPCR (Gs) which produces vasodilation. Increases the cAMP and is inhibitory. Differs from alpha 1 based on the tissues the receptors are located in. Beta 2s have a higher affinity to epi than norepi.

Beta 3 receptors augment thermatogenesis

A lot of the specificity depends on the location of the receptors.

Recycling and breakdown

Re-uptake is the most important part of inactivation and the cell that the NE is acting upon can uptake NE as well. There are 2 transports for NE for reuptake. Option 1 is a high affinity transport into the nerve terminal and is the primary mechanism for determining SYNAPTIC NE. The norepi that is not degraded, can get taken back up into the cell via norepi reuptake transporter where it can get put back into the synaptic vesicle. Re-uptake is the most important part of inactivation. NE is taken up WHOLE (unlike ACh). Option 2 is transport into extraneural structures and this is the primary mechanism for circulating Epi.

Amphetamine/Cocaine/TCAs blocks the reuptake of the NE (also dopamine) in the neuron, that’s why you get high. NE stays in the synapse and can act longer.

Catechol methyltransferase works on Norepi and degrades it into inactive metabolites which are excreted out in the urine. Or it can be metabolized by the mitochondria enzymes (monoamine oxidases) and inactivated in the cell. We use to use MAO blockers to treat depression but these aren’t as safe as current antidepressants. The principle metabolite is vanillylmandelic acid (VMA) and is secreted in the urine (like in a Pheo or neuroblastoma).

Adrenergic Target Organ Effects

Alpha 1 receptors → increase smooth muscle contraction → vasoconstriction (increase BP and decrease blood flow to an area) or inhibition defecation/urination (more of a ADR) or dilator pupilae (pupils dilate)

Alpha 2 receptors → inhibit secretions → presynaptic nerve terminal cannot release norepi (checks and balance system) or pancreatic beta cells cannot secrete insulin so blood glucose increases. Alpha 2 receptors are on the neurons to act as the breaks → slows activity of the neuron and prevents the further release of NE. Help regulate neurotransmitter release.

Beta 1 receptor are on 2 parts of the heart: the nodal cells (increase conduction → increase HR → CO) and the contractile cells (increase contractility → increase SV → increase CO). On the juxtaglomerular cells in the kidney → increase renin → increase RAAS → increase BP.

Beta 2 receptors → relaxing smooth muscles → vasodilation of heart and skeletal muscle (decrease in total peripheral resistance)(we need oxygen at these muscles if we’re fighting a shark) → increase blood flow, decrease BP. In the bronchioles → bronchodilation → easy breathing baby (more airflow). In the liver → gluconeogenesis and glycogenolysis. In the alpha cells of the pancrease → increase glucagon. In the uterus → inhibits contraction in preterm labor.

Beta 3 receptors → fat tissue → lipolysis. Or Detrusor muscle → inhibits urination

Alpha 1 Agonist

Alpha 1 receptors are on arteries AND veins. Alpha 1 receptors on arteries increase systemic vascular resistance increases bp. If we constrict the veins we increase preload, increasing SV, increasing CO, increase BP. We can reverse hypotension with phenylephrine (useful in shock) or midorine. Midorine works really well in orthostatic hypotension because we can increase venous return.

Alpha 1 receptors in the pupil → we get dilated. If we’re trying to look at the retina (mydriasis) or do a ophtho procedure we can use phenylephrine.

In epistaxis or increased nasal secretions we can use alpha 1 agonist to inhibit this process by reducing blood flow to the area. We can use phenylephrine (in epistaxis) and oxymetazoline (more common in secretion effect). Watch your self you might have an ADR (especially with oxymetazoline) you might get a rebound congestion.

With phenylephrine, if we increase BP the natural reflex is to drop the HR to compensate for the high blood pressure AKA reflex bradycardia. Large doses can cause HTN headaches and cardiac irregularities.

Alpha 2 Agonist

Technically sympatholytics (inhibit the transmission of nerve impulses in the sympathetic nervous system). Alpha methyldopa can be used to treat HTN, especially in pregnancy.

Depletes Norepi release in CNS → can affect patient’s overall function (alertness/cognition) → sedation/lethargy effect (ADR). Clonidine and guanfacine can chill out our patients like in ADHD.

In the lungs → decreased respiratory rate/depth.

In the heart → decrease HR and contractility → reduce CO → BP. Clonidine can be used to treat HTN.

In the vessels → reduce systemic vascular resistance → decrease BP. Clonidine can be used to treat HTN.

In drug abuse (alcohol, opioids, benzos) this system gets really affected, the patient goes through withdrawals if they stop. Clonidine and Lofexidine can block the massive norepi surge that the withdrawal causes.

Apraclonidine and brimodine are used in glaucoma or ocular HTN.

Guanfacine, brimodindine, lofexidine are also alpha 2 agonist. Xylazine is often combined with fentanyl so there’s a slight issue there.

ADRs: for Clonidine → constipation and xerostomia, rebound HTN

Beta 1 Agonist

In the heart, we can use beta 1 agonists to increase conduction (increase HR) and contractility (increase SV) increasing CO. Dobutamine is a primary beta 1 agonist that is used in bradycardia or in cardiogenic shock/acute heart failure. Some contraindications are if a patient has a high heart rate → tachyarrythmias may be an ADR. Increased contractility means increased demand, so if a patient has coronary heart disease and can’t keep up with the demand this would worsen their chest pain (this is utilized in stress test). Watch in A.fib peeps because it increases AV conduction.

Beta 1 and 2 Agonist

Isoproterenol has an equal amount of beta 1 and 2 affinity. Therefore it increases HR, increase contractility (increase CO - positive inotropic), and vasodilation (decrease BP). Pretty much only used in severe bradycardia. Watch in patients with tachycardia. We can use this in asthma (not common) because it causes bronchodilation. Rarely used.

Beta 2 Agonist

In the lungs, we can use Albuterol/salmeterol/Formoterol to bronchodilate especially in asthma in COPD. Albuterol is short acting but works very quickly. Salmeterol and friends are used for long term maintenance. Terbutaline is great for acute, severe asthma, not really used in the US. ADRs include tremors and tachycardia (not on inhalation).

In the uterus, we can Terbutaline use to inhibit preterm labor → gives us 48 hours.

In hyperkalemia, we can use albuterol to increase the activity of the Na+K+ATPase pulling potassium into the cell and out of the bloodstream.

In a patient with normal potassium, you could drop the potassium levels. Hyperglyecemia is also an ADR because the beta 2 agonist increase glucagon and gluconeogeneis/glycogenolysis. Tremors are also an ADR. A minor effect, is that beta 2 agonist may have a tinee-tiny beta 1 so watch that heart rate.

Other ADRs include restlessness, apprehension, and anxiety.

Beta 3 Agonist

Inhibits detrusor activity → inhibits urination. We can use Mirabegron/Vibrgron to treat overactive bladder or urinary urgency/frequency. Watch in patients with uncontrolled HTN.

Alpha and Beta Agonist

These aren’t like other girls. Epi has high affinity for all receptors (hella action at alpha 2). NE is good for all the receptors EXCEPT beta 2. Affinity differences are based on the slight differences in chemistry. Since NE can’t hit beta 2, it will have the ultimate affect of a higher peripheral resistance and higher BP, no vasodilation in this house.

Norepineprine (Levophed) acts on ALL the receptors but mostly alpha 1 agonist (at higher doses you start to hit that beta). In the heart, you can increase contractility/conduction with high doses of norepi. On the arteries, we’re gonna hit that alpha 1 and increase SVR and INCREASE BP (diastolic). On the veins, we’re gonna increase venous return → leading to an increase in systolic pressure. (overall increase in bp). Used in shock states of hypotension. We still have that reflex bradycardia because of the baroreceptors (usually stronger than the beta 1 conduction affect so you get an overall slight drop in heart rate). When we constrict the arteries we increase the afterload which will decrease SV, decrease CO → so we won’t see a change in CO since we hit those beta 1 which would increase CO.

Dopamine and Epi are very similar in their effects. Epi hits beta more than alpha. Dopamine hits dopamine then beta then alpa. At lower doses, they have more of a beta effect, at higher doses we see the alpha effect. The overall effect they have on the cardiovascular system, HUGE increase HR and contractility → increase CO. In the arteries there’s beta 1 and 2, low dose epi prefers beta 2 which means we get less alpha 1 activity (less vasoconstriction, less bp). At a higher dose we would see increase in alpha activity (vasoconstriction, raise bp) we hit more beta 1s. Only at high doses will we see that raise in bp, so they can be use in a shock state. At the average dose we can use it for acute heart failure or cardiogenic shock because we increase contractility. Because we can increase heart rate we can treat bradycardia and codes.

Epi specifically can also stimulate beta 2 in bronchioles causing bronchodilation we can use it to treat asthma, COPD, anaphylaxis. Drug of choice for anaphylactic reactions. Treatment of MI. Vasoconstriction in local anesthetics like lidocaine → keeps anesthetic in the area. ADRs (dose related) for epi include angina, arrythmias, cerebral hemorrhage secondary HTN, pale skin, acute renal failure.

Indirect Acting

Amphetamine and tyramine leads to the release of more NE and the inhibition of MAO. Leading the increase of bp and heart rate.

Cocaine blocks the uptake transport. NE and epi accumulate in the synaptic space. Leading the increase of bp and heart rate.

Selegiline is a MOA inhibitor

Entacapone is a COMT inhibitor

Antagonist (Blockers)

Alpha 1 Antagonist (-osins)

These drugs prefer the alpha 1 receptors. Examples of these are tamsulosin, prazosin, terazoasin, alfuzosin, indoramin, urapididil, bunazosin, and doxazosin (the OSINs).Doxazosin is the longest acting.

VASODILATION

On the blood vessels, specifically the veins, if we block the receptors we decrease venous return, decreasing CO. However, if someone moves from sitting to standing to quickly then we get double wammied. Watch for orthostasis, especially in old folks. In the arteries, if we block the receptors we decrease systemic vascular resistance and drop the blood pressure → HTN treatment (not usually 1st line). If a patient has BPH and HTN then Alpha 1 blockers are a great choice. If we drop the bp, the baroreceptors fire less which tells the CNS bp is low, increasing the activity of sympathetic nervous system → reflex tachycardia. Used historically in CHF, but does not increase lifepan.

Since there are alpha 1 receptors on the sphincter muscles, if we block those we can stimulate urination, which is great in the case of urine incontinence secondary to BPH.

In the pupil muscle, if we block the alpha 1 receptors we inhibit dilation → pupillary constriction. If a patient has any cataract surgery the pupil can constrict and prolapse (intra-operative floppy iris syndrome).

Prasosin can be used to help with PTSD related nightmares it can reduce alpha-1 mediated stress response in sleep.

Vertigo, sexual dysfunction.

Alpha 1 + 2 Antagonist (Phen-)

Phentolamine and phenoxybenzamine work to block the activity of the alpha receptors. Phentolamine binds to the activity site of the receptor (shorter duration about 4 hours). Phenoxybenzamine binds an allosteric site, causing a conformational change so the norepi/epi cannot bind (long duration like 24 hours) → irreversible and noncompetitive. The only mechanism is to make more receptors.

On blood vessels we have beta 2 and alpha 1, if we block the alpha → decrease vasoconstriction → decrease systemic vascular resistance → decrease BP. In a Pheochromocytoma, we have hella epi and norepi which causes increased blood pressure. If we block the alpha 1 receptor, the beta is still available so we improve BP by vasodilating, leading to lower bp. A good indication for these drugs is a HTN crisis secondary to a Pheo. Phenoxybenzine for long term, phentolamine for short term.

Some drugs (like coke) inhibit the reuptake of norepi and the enzyme (MAO) that breaks down the norepi. Leading to more and more catecholamines to be released. If a patient combines their prescribed MAO-inhibitor with wines/cheese (lots of tyromine) the MAO enzyme is inhibited so very little norepi is broken down and more is released. These MAO inhibitors drugs induce a HTN crisis, so we can use alpha blockers to prevent Norepi from binding the alpha-1s so they only bind the beta-2 → no high bp in this house. (NOTE in the case of cocaine induced HTN alpha blockers are second line). Phenoxybenzamine is the better choice.

If we have Norepi/epi in the blood (like when given IV), but if it leaks out they can bind to the alpha 1 receptors on the tiny small cutaneous vessels on the skin → no oxygen → necrosis of skin. This is known as vasopressor extravasation. We can use phentolamine to overcome this.

When the drug binds the alpha-2 receptor, we stimulate the production of norepi and increase sympathetic tone (we lose that checks and balance system). Norepi can’t bind the alpha 1 on the vessels, it can still bind the beta 1 receptors in the heart → reflex tachycardia.

ADRs: postural hypotension, nasal stuffiness, inhibited ejaculation, GI irritation

Beta 1 Antagonist (-olol)

These are cardio-selective. Most common 1st generation examples of these are atenolol, acebutalol, bisoprolol, esmaolol, and metoprolol. These have a higher affinity for beta 1 than beta 2 (very very little beta 2 action). Metoprolol is the most common one used in clinic.

3rd generation beta 1 antagonist include betaxolol, celiprolol, nebivolol.

If we have a massive electrical activity in the atria causing a high heart rate we can block this affect. This would inhibit the AV node conduction which will decrease the heart rate and tachyarrhythmia (used in a-fib/a-flutter/SVT). Esmolol has a very short half-life so use for SVT.

In the blood vessels with a stable, chronic plaque, those muscle cells aren’t getting a lot of juice. Chronic decrease in oxygen supply, if for some reason we get a increase in demand we can help out by using drugs to decrease that demand. If we decrease heart rate → we decrease oxygen consumption. If we decrease contractility → reduce CO → decrease oxygen demand. Used in angina/coronary artery disease.

In hypertrophic cardiomyopathy, we got a left ventricular outflow tract obstruction so its super difficult to get the blood out of the heart → decrease CO. If we decrease contractility that overgrowth of muscle doesn’t bulge in as much. We want to give drugs that inhibit contractility which decreases the effect of the left ventricular outflow tract obstruction. If we slow the heart rate, we prolong the filling time which would stretch that outflow tract obstruction out even more. We improve CO.

In heart failure or post-MI we have a reduction in systolic function so we are going to have a reduction in CO. This affects the profusion of particular organs, if the kidneys don’t get enough blood they start screaming → RAAS → increase in BP, in preload (leading to LV dilation), and afterload (heart has to compensate and we get LV Hypertrophy). A reduction in CO acts on baroreceptor which responds by activating the sympathetic nervous system → Increase HR, heart contractility, vasoconstriction (increase afterload) → remodeling of the heart → increased mortality. When we give beta blockers we inhibit RAAS and the Norepi release onto the heart which reduces cardiac remodeling.

Pindodol and Acebutolol can be used to treat HTN patients with bradycardia because they are a partial agonist affect. This prevents the action of a stronger source.

ADRs: Bradycardia, reduced CO (bad in decompensated heart failure)

Beta 1 + 2 Antagonist (-olol )

1st generation consist of nadolol, timolol, and propanolol, penbutolol, pindolol, sotalol,levobunolol, metipranolol (most common)

3rd generation consist of carteolol, carbedilol, bucindolol, labetolol.

In the eye, we have beta 2 receptors on the ciliaris. If we block these we can decrease intraoccular pressure by decreasing the production of aqueous humor. Timolol and Nadolol can be used in glaucoma. (chronic use only)

Thyroid Storms are when the thyroid pumps out a lot of T3 and T4. Thyroid hormone increases the sensitivity of the heart to norepi/epi by increasing the number of beta 1 receptors. Since we’re sensitized, even with normal amounts of norepi/epi we get a HUGE response → increased HR, contractility → CO → tachy-arrythmias. We can give propanolol to block all those beta receptors, not just the ones in the heart.

In portal hypertension, the pressure in this portal system is high which can cause esophageal varices, which increases the risk of upper GI bleeds. We can give propanolol which will block beta 1s on the heart leading to a reduced CO, lowering splanchnic blood flow, so less is going through the portal venous system, reducing the pressure. Propanolol and Nadolol also blocks the beta 2 on the splanchnic blood vessels causing vasoconstriction which leads to less blood flow going through the portal system. Prophylactic.

In the CNS, we got blood vessels with beta receptors next to lots of pain receptors. In diseases like HA or migraines these pain receptors are overstimulated due to dilated blood vessels. Propanolol vasocontricts these vessels decreasing the stimulation of those pain receptors → can’t touch this. Prophylactic.

In the muscle spindles, beta 2 receptors are responsible for contractions and tremors if overstimulated. In essential tremors we can give propanolol to block the beta 2 and reduce the afferent/efferent signals and decrease tremors.

Propanolol can also be used to treat angina pectoris and HTN.

ADRs: hit beta 1 and beta 2 so you could see decreased HR and CO, as well as, bronchospasm, hypokalemia, hyperglycemia, fatigue,arrythymias upon withdrawl, sexual dysfunction.

Beta + Alpha Blockers (-etaolols)

Certified haters hate all the betas and alphas → Labetaolol, carvedilol. These are technically 3rd gen beta blockers. Used in HTN patients and CHF by reducing heart rate and contractility.

Inhibits beta 1 receptors on the heart as well as the alpha 1s on the veins/arteries. This will reduce HR, contractility, CO, BP, SV, and systemic vascular resistance. In general, reduces bp. Give to patients with HTN, Labetaolol may have a greater efficacy in this case. You can give labetaolol to pregnant patients with HTN. Also used in hypertensive emergencies.

In heart failure, we use carvedilol because we are trying prevent the RAAS and baroreceptors from reeking havoc and leading to cardiac remodeling.

In portal hypertension, we can use carvedilol prophylatically to prevent esophageal varices. Decrease HR, CO, sphlanchnic blood flow, less portal venous blood flow. If we inhibit alpha 1 we decrease the pressure in the portal system.

ADRs: hit beta 1 and beta 2 so you could see decreased HR and CO, as well as, bronchospasm, hyperkalemia, hypoglycemia. Since we hit the alpha receptors, we increase the risk of orthostasis. Dizziness.

Beta Blockers OD/ADR

A potential ADR of beta-1 blockers is potential bradycardia or AV block. Since we reduce contractility this could kill a patient in decompensated heart failure or cause cardiogenic shock. Reverse with glucagon!

In the lungs, we have beta-2 receptors so this is going to cause intense bronchospasm so watch yourself with asthma and COPD peeps.

In the liver and pancreas, we have beta-2 receptors so if we block these we may see hypoglycemia. This is going to activate the sympathetic nervous system which will increase sweating and heart rate this is supposed to give you awareness of having a low glucose. HOWEVER, this sympathetic affect is blocked so you get hypoglycemia unawareness.

In the cells, beta 2 receptors stimulate sodium-potassium pump. If we block those, potassium doesn’t get into the cells so we get hyperkalemia.

In the CNS, if we block those beta receptors you might cause fatigue or lethargy.