Phenylephrine

Naphazoline
Xylometazoline

What are some effects of Phenylephrine?

contraindications and uses?

phenylephrine is an alpha-1 agonist.  It therefore increases BP and causes pupil dilation. it is also a decongestant

Contraindications

hypertension: will be exacerbated when the alpha-1 receptors cause vasoconstriction.
 cardiac diseases, cerebrovascular disease, hyperthyroidism

Uses

postural hypotension: alpha-1 constriction will help maintain BP

 nasal decongestion,

mydriasis- for opthalmology 

local vasoconstriction

Clonidine

Apraclonidine

Tizanidine

What are the actions of Clonidine?

what are its uses?

Clonidine is an alpha-2 agonist
It is used in the treatment of high blood pressure.  Its mechanism of action is through a decrease in central sympathetic tone by binding presynaptic Gi protein.   This results in decreased CO and decreased TPR.

Hypertensive crisis if withdrawn suddenly.  because continual stimulation will cause down-regulation of alpha-2 receptors, when clonidine is withdrawn suddenly, there will be too few alpha-2 receptors left to keep the central sympathetic tone in check.  This will result in an extreme influence by the sympathetics (increased HR, vasoconstriction) with the result of severe hypertension.

~100% oral bioavailability

Isoproterenol is a beta-1, 2, 3 agonist.  It will produce an increased HR (due to beta-1 and baroreceptor reflex tachycardia), vasodilation (beta-2). The systolic BP will remain unchanged because the decreased TPR from vasodilation will be balanced out by the increased cardiac output (heart rate). The diastolic BP drops because of the unopposed b2 vasodilation (there is no alpha-1 activation to cause vasoconstriction)

IV only

Uses: when patient has low contractility and HR but high TPR, torsade de pointes, Beta-blocker overdose

Dobutamine is a beta-1 selective agonist.  It therefore increases HR and contractility by its stimulation of the cAMP pathway.

Dobutamine would be used in situations of cardiac failure or cardiogenic shock because it will help restore depressed Left Ventricle function.

Albuterol

Salmeterol

Terbutaline

Formoterol

Albuterol is a Beta-2 agonist.  It causes bronchodilation and enhances secretions and mucociliary clearance in the lungs.

It also suppresses the release of inflammatory compounds (mast cells have beta-2 receptors.  activation of these receptors inhibits degranulation and therefore inhibits histamine release)

Albuterol can also be used to prolong labor because b2 receptors in the endometrial smooth muscle cause relaxation of the uterus! (know this for mini and final!)

tolerance development (via down-regulation)

inhalation is main route of delivery

Like all beta receptors, beta-2 receptors activate Gs proteins, which stimulate adenylyl cyclase.  This increases cAMP levels, which activates PKA.  This stimulates Ca++ efflux and also increases the INACTIVATION of myosin light chain kinase, which no longer pplates myosin heads, which reduces contraction.

Beta-2 agonists (albuterol) can be given to relax the pregnant uterus and delay labor!

Epinephrine is an a1, a2, b1, b2, b3 agonist

Epinephrine is contraindicated in myocardial infarction because it increases cardiac workload and oxygen demand

BP up: increase in CO surpasses decrease in TPR
HR up: beta-1
systolic up: because of increased SV (contractility)

diastolic down: because of b2 mediated vasodilation in skeletal muscle

TPR down: because of beta 2 vasodilation

Norepinephrine is an a1, a2, b1 agonist

note that norepinephrine does NOT act at beta-2 receptors.  This will account for its different overall effects than epinephrine!

BP up:because of a1 vasoconstriction and b1 increased CO

HR down: despite b1 activation, the great increase in blood pressure stimulates the baroreceptor system.  This then produces a vagus-mediated depression of HR that overcomes the b1 influence.  (recall: beta in heart mainly effects contractility, parasympathetic mainly affects HR)

systolic up: because of increased SV from b1 and a1 constriction

diastolic up: because of unopposed a1 vasoconstriction

TPR up: because of unopposed a1 vasoconstriction

BP down: because of unopposed b2 mediated vasodilation

HR up: because of b1 and decreased baroreceptor firing

systolic up: because of b1-increased contractility

diastolic down: because of b2 mediated vasodilation

TPR down: because of unopposed b2 mediated vasodilation

cardiogenic shock is inadequate circulation of blood because the ventricular function is depressed.  Therefore, you would administer Dobutamine because its beta-1 agonist activity would increase the contractility and restore ventricular function.

Dobutamine is a selective b1 agonist

Norepinephrine

Phenylephrine

Dopamine (at HIGH doses)

Norepinephrine (drug of choice!) and Phenylephrine both agonize a1 receptors, but not b2.  They therefore constrict all vessels.

Dopamine is tricky in that at low doses it stimulates dopamine receptors in the kidney, leading to vasodilation and increased renal blood flow.  At moderate doses dopamine also stimulates beta-1 receptors, increasing contractility of the heart.  At high doses, dopamine also stimulates alpha receptors. At high doses, its actions therefore resemble norepinephrine, but with a selectively beneficial effect on kidney blood flow!

Epinephrine

Epinephrine inhibits inflammatory action by its beta-2 inhibition of mast cell degranulation. it also stimulates the heart to keep beating via b1 receptors, and opens airways via b2 mediated bronchodilation  These are all desired outcomes for someone suffering from anaphylaxis!

Clonidine

Methyldopa

Methyldopa is taken up and converted into a molecule that acts at a2 receptors and limits sympathetic tone, thereby decreasing BP.

Clonidine is an a2 agonist, which acts in the NTS and rostral ventrolateral medulla to decrease adrenergic tone as well

(recall a2 receptors work through Gi proteins)

Epinephrine

It causes local vasoconstriction through it's alpha-1 stimulation, minimizing systemic transportation of the anesthetic

Pretty much anything that activates beta2 receptors because this induces bronchodilation:

Albuterol (pure beta2 agonist)

Epinephrine (inludes beta2 activity)

Ephedrine (like epinephrine but less potent and longer lasting.  Can be taken orally, unlike epi)

HR up

SV up

CO up

all of these effects are mediated through stimulation of b1 (and b2) receptors

HR down (reflex bradycardia due to increased BP)

SV up
CO no change or down (decreased heart rate counteracts increased stroke volume)

HR up

SV up

CO up

all effects due to stimulation of b1 (and b2) receptors

HR down

SV no effect

CO down

Heart rate decreases due to reflex bradycardia.  Because phenylephrine is an a1 agonist only, it does not directly influence contractility, so there is little effect on stroke volume.  Because SV is the same and HR is decreased cardiac output also decreases (CO=SV x HR)

BP up (or no change)

HR down

Systolic up

Diastolic up

TPR up

Timolol

Epinephrine
Apraclonidine

Latanaprost

Cholinomimetics

 Timolol is a b2 antagonist that decreases aqueous humor production.

Epinephrine (while it would increase production by b2, it's a2 stimulation decreases production and the a1 stimulation aids outflow.  These two effects overwhelm the b2 effect.

Apraclonidine decreases aqueous humor production

Latanaprost is a PGF2a drug that increases outflow through the uveoscleral route

Cholinomimetics these contract the ciliary muscle, fascilitating outflow through the trabecular meshwork and canal of Schlemm

Tyramine is an adrenergic agonist that increases the release of NE, EPi, Dopamine

It is a normal byproduct of tyrosine metabolism.

It is converted to octopamine, which displaces NE from the secretory vesicles and increasing its release.

Cocaine blocks catecholamine reuptake in the CNS and PNS. 
(binding to transporters and preventing their function)

It has strong cardiovascular effects because it leads to an increase in synaptic NE

Ephedrine is a sympathomimetic amine and
a1, a2, b1, b2 agonist (not b3)
It's actions are therefore similar to Epinephrine, though they are longer lasting and are not as potent.  Additionally, unlike epinephrine, ephedrine may be taken orally.

Ephedrine also increases Norepinephrine release.

 Used clinically as nasal decongestant and expectorant.

Reserpine blocks adrenergic storage in vesicles.  Therefore, more adrenergics are free in the axon terminal and are exposed to MAO enzymes. There is therefore increased MAO metabolism of catecholamines, which decreases their availability and release.

 Reserpine is both an antihypertensive and antipsychotic drug

Reserpine MAY cause depression, leading to increased incidence of suicide among patient populations on this drug.  This validity of this side effect is controversial.

Metyrosine blocks the synthesis of catecholamines (up to 70%) by inhibiting Tyrosine Hydroxylase, the first step in catecholamine synthesis from tyrosine.

It is used as an antihypertensive drug and in the treatment of pheochromocytomas

yohimbine is an a2 antagonist

Yohimbine can be used to boost sexual performance and to increase blood pressure.  By inhibiting a2 receptors, their antagonism of central sympathetic tone is relieved and the sympathetic system now exherts a stronger influence (ejaculation, CO, and vasoconstriction)

Atenolol is a b1 antagonist

It is therefore in essence the opposite of dobutamine and is used to treat hypertension, and tachycardia.  It's selectivity for beta-1 receptors makes it better than a non-selective beta-blocker (propranalol) for asthmatic patients.  Recall the importance of beta 2 receptors in bronchodilation

Phenoxybenzamine is a non-selective alpha antagonist that irreversibly blocks alpha-1, and to a lesser extent alpha-2, receptors

It can be used in the treatment of pheochromocytomas

Propranolol

Timolol

Pindolol

Sotalol

Metaprolol

Atenolol

Esmolol

Esmolol is a quick acting drug with a half-life of 10 minutes, and is often used during surgery because of these properties.  Administration is by IV

Labetolol is an a1-antagonist, b1/b2 partial agonist.  This results in marked decrease in TPR due to the blocking of a1 vasoconstriction and the partial agonist action at b2 (vasodilation in skeletal muscle beds)... both of these actions result in vasodilation!

Labetolol also has a local anesthetic activity

Phenoxybenzamine is an irreversible non-selective alpha antagonist (majority of its effects are through alpha-1 receptors)

Phenoxybenzamine is used in the preopperative treatment of pheochromocytomas.

Its administration results in vasodilation and a reflex increase in heart rate due to depressed firing from the baroreceptor system

Prazosin is a reversible alpha-1 antagonist.  Because alpha-1 antagonist result in vasodilation, it is used in hypertensive emergencies (ex: clonidine withdrawal, pheo, tyramine syndrome)

It is also commonly used to treat Raynaud's Disease, which is characterized by excessive sympathetic vasoconstriction of peripheral vasculature (fingers and toes) through alpha-1 receptors.  This is especially pronounced in cold weather.

Tamsulosin is a reversible alpha-1 antagonist.  It is commonly used to improve urinary flow in a patients with benign prostatic hyperplasia (BPH) because it relaxes the sphincter of the bladder.

Propranolol is a non-selective beta antagonist.
It can therefore be used to decrease HR and contractility and decrease aqueous humor production. 

Another common use is the prophylactic treatment of migraines and migraine Tx in pregnant women.

Propranolol results in bronchoconstriction by inhibiting beta-2 receptors, so watch out for asthmatic patients.

Metoprolol,
Atenolol

Esmolol

These are all beta-1 antagonists

Beta 1 antagonist are used to treat hypertension, arrythmias, angina and Hypertrophic Cardiomyopathy.  In the treatment of pheochromocytomas,beta-1 antagonists are prescribed after the administration of an alpha-1 blocker.

Recall, esmolol is often the drug of choice to counter tachycardia during surgery.

Gq to PLC to increased IP3/DAG

You can always "quiz" yourself with norepinephrine:  quiz spelled 'QIS'... a1=Gq, a2=Gi, B1=Gs

A b1-blocker with rapid onset and short duration

used in surgery

Drug of choice if aortic dissection is suspected

half-life ~ 10min

B1 receptors stimulate renin release from the juxtaglomerular cells.

This makes sense in that:
When there is a decrease in BP, there is a decrease in blood flow to the kidneys, and the GFR decreases.  The macula densa senses the resulting drop in Na+ that reaches it, stimulating renin release.  At the same time, the sympathetic system kicks in to try to increase TPR and restore blood pressure.  This will stimulate the beta-1 receptors, also increasing renin release, which will promote aldosterone release, Na+ and water retention and a restoration of BP.

Albuterol

B2 agonists relax the uterine smooth muscle!