Isoproterenol

Non-selective Beta adrenergic receptor.  Increases HR (B1) with a decrease in TPR (B2).  Because there is little A1 response, there is no reflex vagal discharge. 

Bronchial and GI smooth muscle relaxation also occur

Use primarily as a cardiac stimulant

Side effects are similar to epinephrine, but less acute, metabolized by COMT

Dobutamine

B1 selective agonist with modest a1 activity.  There is increased CO with no associated change in peripheral resistance

Used in short term treatment of cardiac decompensation, increased CO and SV in pts with acute MI

AE:  Inc HR and BP, arrhythmias, inc myocardial O2 demand, development of tolerance

Terbutaline

Selective B2 receptor agonist, primarily used in tx of obstructive airway disease and acute bronchospasm.  Can also be used parenterally for status asthmaticus (worsening of asthma).  Also decreases release of leukotrienes and histamine

More resistant to MAO and COMT than other drugs, so it has longer duration of action. 

Albuterol

Selective B2 receptor agonist, primarily used in tx of obstructive airway disease and acute bronchospasm.  Also decreases release of leukotrienes and histamine.  Commonly seen in asthmatic inhalers

More resistant to MAO and COMT than other drugs, so it has longer duration of action. 

Methoxamine

Selective a1 agonist that causes vasoconstriction and greatly inc PVR, with reflex dec in HR.  Therefore, it is useful in patients in shock and with hypotension, also in maintenance of BP during surgical procedures. 

Largely replaced by adenosine, verapamil or cardioversion now

Phenylephrine

Selective a1 agonist that causes vasoconstriction and greatly inc PVR, with reflex dec in HR.  Commonly used to dilate pupils (mydriatic) and also as a nasal decongestant (stops secretions)

Largely replaced by adenosine, verapamil or cardioversion now

Can be used to diagnose Horner's Syndrome with direct local application since patients will have supersensitive receptors

Clonidine

Selective a2 agonist that acts on receptors in the CNS to decrease symp outflow.  This produces a decrease in BP and HR. 

Oral administration for anti-HTN, while IV administration produces a transient inc in BP followed by a prolonged decreased BP. 

Used in HTN, migraine, and Tourette's/ADHD with methylphenidate

AE:  Dry mouth and sedation!!  Also, commonly associated with withdrawal syndrome if discontinued abruptly.

Apraclonidine

Selective a2 agonist that decreases intraocular pressure via decreasing production of aqueous humor.

Effective in glaucoma

Methyldopa

Metabolized to alpha-methylnorepinephrine which activates central a2 receptros to dec sympathetic outlfow and decrease BP

Used in HTN

Amphetamine

Indirect acting sympathomimetic that increases release of NE from nerve terminals and decreases Uptake 1.  This has similar effects to a CA agonist, increasing BP, triggering reflex vagal discharge, and also enhances concentration, and produces euphoric effects

Can lead to restlessness, talkativeness, psychological dependence, and "psychosis."  Can be used for obesity, narcolepsy and appetite suppression, but it's non-selective blocking of dopamine reuptake makes it extremely addictive

Methamphetamine

Crystal meth - Indirect acting sympathomimetic that increases release of NE from nerve terminals and decreases Uptake 1.  This has similar effects to a CA agonist, increasing BP, triggering reflex vagal discharge, and also enhances concentration, and produces euphoric effects.  Its CNS effects tend to be greater than its peripheral effects, making it extremely addictive

Can lead to restlessness, talkativeness, psychological dependence, and "psychosis."  Can be used for obesity, narcolepsy and appetite suppression, but it's non-selective blocking of dopamine reuptake makes it extremely addictive

Methylphenidate

Ritalin - Indirect acting sympathomimetic that increases release of NE from nerve terminals and decreases Uptake 1.  Has similar effects as CA agonist: increases BP, triggers reflex vagal discharge, and also enhances concentration, and produces euphoric effects.  Effective for ADHD because it has pronounced mental effects

Can lead to restlessness, talkativeness, psychological dependence, and "psychosis."  Can be used for obesity, narcolepsy and appetite suppression, but it's non-selective blocking of dopamine reuptake makes it extremely addictive

Atomoxetine

Indirect acting sympathomimetic that increases release of NE from nerve terminals and decreases Uptake 1.  Has similar effects to a CA agonist: increases BP, triggers reflex vagal discharge, and enhances concentration, produces euphoric effects.  Effective in ADHD

Can lead to restlessness, talkativeness, anorexia.  Unlike other indirect sympathomimetic, this one is specific to inhibiting NE reuptake, and does not inhibit dopamine --> No dependence/reward circuitry, very little abuse of drug

MDMA

Ecstasy - Indirect acting sympathomimetic that increases release of NE from nerve terminals and decreases Uptake 1.  This has similar effects to a CA agonist, increasing BP, triggering reflex vagal discharge, and also enhances concentration, and produces euphoric effects

Can lead to restlessness, talkativeness, psychological dependence, and "psychosis."  Can be used for obesity, narcolepsy and appetite suppression, but it's non-selective blocking of dopamine reuptake makes it extremely addictive

Cocaine

Similar to other indirect sympathomimetics but only decreases Uptake 1 (no inc in EPI release).  This has similar effects to a CA agonist, increasing BP, triggering reflex vagal discharge, and also enhances concentration, and produces euphoric effects

Can lead to restlessness, talkativeness, psychological dependence, and "psychosis."  Can be used for obesity, narcolepsy and appetite suppression, but it's non-selective blocking of dopamine reuptake makes it extremely addictive

Ephedrine

Both a direct and indirect sympathomimetic, acting on alpha and beta receptors, and also inc NE release.  Similar to NE and EPI with longer duration.  Inc HR, CO, PVR, produces bronchodilation and CNS stimulation.  Useful for bronchodilation and hypotension

Associated with tachyphylaxis, many AE incl terrible palpitations, HTN, arrhythmias, tremors, stroke.  Very limited use because of this.

Tyramine

Indirect sympathomimetic that causes release of NE from nerve terminal and acts as a competitor for NE reuptake. 

Found in many foods incl cheese, pickled foods, red wine and is rapidly degraded by MAO.  See problems when patients are taking MAO inhibitors with patients developing hypertensive crises and death

Not used therapeutically

Phenoxybenzamine

Irreversible non-selective alpha adrenergic blocker that dec PVR, dec BP (only in upright position), increases NE release (via a2 blockade), and increases HR and CO (because b1 receptors are maintained)

AE include postural hypotension, reflex tachycardia and arrhythmias

Effective in pheochromocytoma (CA producing tumor of adrenal medulla)

Phentolamine

Reversible, non-selective alpha adrenergic blocker that dec PVR, dec BP in upright position, increases NE release (via a2 blockade), and increases HR and CO (because b1 receptors are maintained).  Also stimulates GI smooth muscle and increases gastric acid secretion

AE include hypotension, reflex tachycardia and arrhythmias

Effective in short term HTN control in pheochromocytoma, and treatment of hypertensive crises.  More potent than tolazoline

Tolazoline

Reversible, non-selective alpha adrenergic blocker that dec PVR, dec BP in upright position, increases NE release (via a2 blockade), and increases HR and CO (because b1 receptors are maintained).  Also stimulates GI smooth muscle and increases gastric acid secretion

AE include hypotension, reflex tachycardia and arrhythmias

Effective in short term HTN control in pheochromocytoma, and treatment of hypertensive crises.  Also used in persistent pulmonary HTN of the newborn.  Less potent than phentolamine

Prazosin

Selective a1 receptor blocker that decreases PVR, VR with no significant change in HR or CO (no effect on b1). 

Most patients experience first dose phenomenon, with postural hypotension and syncope.  Start at night. 

Used in tx of HTN, refractory CHF (to dilate BV) and benign prostatic hyperplasia (to reduce resistance to flow)

Yohimbine

Selective a2 receptor blocker that increases symp outflow centrally and inc release of NE peripherally (by decreasing negative feedback). 

Used for treatment of male sexual dysfunction, though largely replaced by NO now

Ergot Alkaloids

Many actions including blockade of alpha receptors.  Also blocks serotonin (5HT) receptors and DA receptors with many effects in the CNS

USed for migraines and stimulation of postpartum contraction of the uterus

CV Effects of Beta Blockers

Little effects on heart at rest, with profound effects on heart in stress, or heart of hypertensive.  Decreases HR, FOC, AV CV, and inhibit the vasodilating response to b-adrenergic stimulation

Marked attenuation of exercise-induced increases in HR and FOC, which can prevent angina with exertion.  BP is also decreased because of decreased heart activity, though PVR does initially rise 

AE:  Long term administration in hypertensives leads to persistent fall in CO

Respiratory and Metabolic

Effects of Beta Blockers

Bronchodilation mediated primarily via b2 so use of beta blockers in asthmatics can produce life-threatening bronchoconstriction. This can be avoided by using a b1 selective blocker.  Can also treat bronchoconstriction to be able to continue use of beta blocker

Catecholamines mobilize glucose in response to hypoglycemia and side effects of this (inc HR etc) are commonly used by diabetics to sense hypoglycemia.  Use of beta blockers blunts these peripheral signs, so b2 blockers are preferred in diabetics

Side Effects of Beta Blockers

Indications for Beta Blockers

HAM CHAGAM

Hypertension, Angina, Myocardial Infarction

CHF, Hyperthyroidism, ventricular and supraventricular Arrhythmias, Glaucoma, Acute panic attacks (decreases symptoms, emotion itself),  Migraine prophylaxis

Propanolol

Prototypic non-selective beta blocker, highly lipophilic and well absorbed with PO.  No ISA. Undergoes extensive first-pass metabolism so high doses required, and highly protein bound, so drug interactions common

Commonly used in CHF, migraines and stage fright

Nadolol and

Timolol

(2 mechanisms)

N - Non-selective beta blocker with no ISA and long duration of action, allowing dosing only 1/day

T - Short acting, non-selective beta blocker with no ISA used for glaucoma and functions by decreasing production of aqueous humor

Pindolol

Prototypic drug with intrinsic sympathomimetic activity (ISA aka partial agonist).  Though it is a beta blocker, at rest there is mild stimulatory activity of the beta system, while there is full beta blocker activity with stress. 

Non-selective beta blocker

Labetolol

Non-selective beta blocker that also blocks a1 receptors, and can inhibit reuptake of NE.  There is a decreased peripheral BP with no reflex tachycardia because of the beta blocking activity

no ISA

Sotalol

Non-selective beta blocker that acts as an anti-arryhythmic agent

Carvedilol

Atenolol

B1 selective beta blocker, that is hydrophilic and therefore has limited CNS activity.  No ISA

Metoprolol

B1 selective beta blocker used for HTN and stable angina, but contraindicated in patients with acute MI associated with bradycardia, heart block or heart failure.

No ISA

Esmolol

Short duration, b1 selective, beta blocker with actions similar to metoprolol (used in HTN and stable angina). 

No ISA.  Must be given IV

Acebutolol

Acetylcholine

Primarily acts on muscarinic receptors on parasympathetic target organs with direct effects on CV system including slowing heart rate and conduction velocity.  Also, if given exogenously, they can cause peripheral vasodilation

Side effects include all undesired outcomes (urination, gut motility, lacrimation, salivation, bronchoconstriction, pupil dilation)

Can also stimulate autonomic ganglia

Carbachol

Choline ester that acts on both nicotinic and muscarinic receptors.  This makes it relatively counterproductive to use because of activation at autonomic ganglia. Resistant to hydrolysis by AChE

Some preference for urinary and GI tract make it rel effective, but use primarily limited to local application to  eye, which contracts the ciliary muscle and opens the trabecular meshwork to allow aqueous humor outflow in tx of glaucoma

AE include DUMBELS, don't use in asthmatics, those with hyperthyroidism, coronary insufficiency or peptic ulcer

Bethanechol

Choline ester that acts on muscarinic receptors with little nicotinic activity.  This makes it more useful than carbachol. Resistant to hydrolysis by AChE

Some preference for urinary and GI tract make it effective for treatment of urinary retention or constipation. 

AE include DUMBELS, don't use in asthmatics, those with hyperthyroidism, coronary insufficiency or peptic ulcer

Pilocarpine

Alkaloid that acts primarily on ACh muscarinic receptors and is especially stimulatory on sweat glands. 

Can also be used to treat glaucoma via local application which contracts the ciliary muscle, opens the trabecular meshwork and allows outflow of aqueous humor.  Better tolerated than anti-AChEs

Muscarine

Endogenous alkaloid that is also found in poisonous mushrooms.  Acts almost exclusively at ACh muscarinic receptors and can produce salivation, lacrimation, nausea, bradycardia, hypotension, shock, diarrhea, headache. 

Treat intoxication with anti-muscarinic atropine

Edrophonium

Anticholinesterase alcohol that is polarized, so it has preferred action at the NMJ.  Functions by reversibly binding to the active site of AChE leading to decreased degradation of ACh

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are undesired cholinergic effects

Can be used to determine AChE dosing efficacy in Myasthenia Gravis.  If the muscle weakness is due to MG, giving will increase muscle strength.  If the muscle weakness is due to depolarization block, giving will actually worsen the muscle tone

Donepezil

Anticholinesterase alcohol that is non-polar.  Functions by reversibly binding to active site of AChE leading to decreased degradation of ACh

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are any undesired cholinergic effects

Use is primarily treatment of mild to moderate alzheimers, but does not slow disease progression

Neostigmine

Anticholinesterase carbamate ester that is polarized, so it has preferred action at the NMJ.  Functions by forming a covalent bond with the active site of AChE leading to decreased degradation of ACh.  Longer duration than alcohols

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are any undesired cholinergic effects

Used in Myasthenia gravis, termination of effects of neuromuscular blockers, postoperative ileus (initiates GI motility)

Physostigmine

Anticholinesterase carbamate ester.  Functions by forming a covalent bond with the active site of AChE leading to decreased degradation of ACh.  Longer duration than alcohols

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are any undesired cholinergic effects

Used in glaucoma

Pyridostigmine

Anticholinesterase carbamate ester.  Functions by forming a covalent bond with the active site of AChE leading to decreased degradation of ACh.  Longer duration than alcohols

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are any undesired cholinergic effects

Used in myasthenia gravis (longer duration than neostigmine)

Ambenonium

Anticholinesterase that functions by reversibly binding to active site AChE and inactivating it leading to decreased degradation of ACh.  Longer duration than alcohols

Affects all parasymp target organs as well as muscles and has predictable effects there.  In muscles, however, low doses can promote contraction, while higher doses lead to paralysis due to a loss of ion gradient (depolarization block).  AE are any undesired cholinergic effects

Used in Myasthenia gravis (long duration)

Echothiophate

Organophosphate Anti-ChE that phosphorylates the active site of AChE to irreversibly inhibit it.  The phosphorylated enzyme can then undergo an aging process which strengthens the bond. 

Has predictable effects on parasymp target organs and the NMJ and can lead to depolarization block.  Side effects are DUMBEL. 

Used in long duration treatment of glaucoma

Malathion

Organophosphate anti-ChE that is primarily used as a pesticide. Functions by irreversibly phosphorylating the active site of AChE.  Enzyme can undergo an aging process that further strengthens the bond.

AE include DUMBELS, lots of intoxication in humans because of irreversible binding

Sarin, Soman, DFP

Organophosphate anti-AChE that function by irreversibly phosphorylating the active site of AChE.  This can further undergo an aging process which strengthens the bond. 

These three agents are used as nerve gases and cause rapid respiratory distress and NM paralysis.  Poisoning has to be treated early with 2-PAM and atropine to reverse the effects

2-PAM

Reactivate AChE after inactivation by organophosphates.  Exerts a strong nucleophilic atack to break the phosphorus-enzyme bond. Effective as an antidote for nerve poisoning.  Effective at NMJ but do not enter the CNS, so they must be supplemented with atropine for full effects

Ineffective if the "aging process" has already occurred

Atropine

Competetive ACh antagonist, specific to muscarinic receptors.  It has limited CNS penetration and is typically the anti-cholinergic of choice

Can be used for GI tract disorders (duodenal ulcer, increased tone/motility etc), pupillary dilation (accompanied with relaxation of ciliary muscle), decreasing secretions, increasing heart rate, and in urinary incontinence. 

AE include all above, that are not desired.  Do not use in patients with glaucoma, prostatic hypertrophy (further retention), or those with GERD (slows GI emptying)

Scopolamine

Muscarinic antagonist that has good CNS penetration and is therefore useful in treatment of motion sickness.  It also has central depressive effects, so it can cause fatigue and tiredness. 

AE include all effects of inhibiting parasympathetic outflow, plus the CNS depression

Cyclopentolate

Muscarinic antagonist that is primarily used to treat ophthamologic concerns.  It acts as a mydriatic and allows flattening of the lens for distant vision.  Relatively short duration

AE include all effects of inhibiting parasympathetic outflow, plus the CNS depression.  Avoid use in pts with glaucoma, prostatic hypertrophy, or GERD

Pirenzepine

Muscarinic antagonist that has slight selectivity for M1 receptors, so its effects are more exaggerated in the GI tract.  It is therefore useful for peptic ulcer, though other agents have largely replaced it. No CNS effects

AE include all effects of inhibiting parasympathetic outflow, without any CNS depression.  Avoid in patients with glaucoma, prostatic hypertrophy, or GERD

Tolterodine

Muscarinic antagonist that is relatively non-specific, but has slightly higher affinity for M2 and M3 (targets the bladder).  It is therefore useful in urinary incontinence.

AE are relatively few because it does have some selectivity, though normal ACh inhibition can be seen. Urinary retention can result

Ipratropium

Muscarinic antagonist used as an inhalational for treatment of asthma and other obstructive pulmonary diseases.  Produces bronchodilation, and is poorly absorbed

AE very few because it is poorly absorbed and effects therefore limited to mouth and airways

Tubocurarine

Non-polarizing (competetive), neuromuscular blocker.  Competetively blocks ACh action at NMJ but doesn't interfere with contractile capabilities of muscle.  Characteristics of paralysis are small, rapidly moving muscles with limbs, neck, trunk first then intercostals, then diaphragm. Interaction with anti-cholinesterases reverse or decrease the block because of the increased ACh levels at the NMJ

Can be used as an adjunct to anesthesia, facilitate intubation

AE include hyperkalemia, CV collapse, induction of histamine release (with associated effects)

Succinylcholine

Depolarizing neuromuscular blocker; acts in 2 phases.  In phase 1, drug acts as nicotinic agonist and eventually induces a depolarization block (with flaccid paralysis).  In phase 2, with continued exposure, the membrane repolarizes, but remains insensitive to ACh and is similar to non-depolarizing.  However, anti-cholinesterases will not decrease the block, because of receptor desensitization

Can be used as an adjunct to anesthesia, facilitate intubation

AE include hyperkalemia, CV collapse, malignant hyperthermia (autosomal dominant disease with severe muscle contractions and heat generation on application of anesthesia)

Nicotine

Trimethophan

Ganglionic blocking agent that inhibits autonomic outflow, so its effects depend on the predominant system affecting each organ.  It causes the opposite effects of the predominant tone.

All organ systems have predominant parasympathetic tone except vasculature, apocrine sweat glands, and the ventricles.  An example of effects are vasculature vasodilates because predominant tone is sympathetic and vasoconstriction is inhibited. 

Used in hypertensive crisis (largely replaced) and autonomic hyperreflexia

Hexamethonium

Ganglionic blocking agent that inhibits autonomic outflow, so its effects depend on the predominant system affecting each organ.  It causes the opposite effects of the predominant tone.

All organ systems have predominant parasympathetic tone except vasculature, apocrine sweat glands, and the ventricles.  An example of effects are vasculature vasodilates because predominant tone is sympathetic and vasoconstriction is inhibited. 

Used in hypertensive crisis (largely replaced) and autonomic hyperreflexia

Reserpine

Blocks transport of dopamine into presynaptic vesicles in adrenergic neurons and the adrenal medulla, effectively inhibiting NE and EPI synthesis. 

Effective in hypertension, but not used very much anymore

Bretylium

Inhibits action potential that allows release of NE and therefore acts by inhibiting release.

Useful in hypertension.

Metyrosine

Tricyclic Anti-Depressants

Similar to other indirect sympathomimetics but only decreases Uptake 1 (no inc in EPI release).  This has similar effects to a CA agonist, increasing BP, triggering reflex vagal discharge, and also enhances concentration, and produces euphoric effects