Naturally occurring catecholamine

Strong agonist of Alpha and Beta1 Receptors

Weak Agonist of B2 receptors

Effects on heart and BP:  Increase Contractility (B1)

Increase Systolic BP

Greatly Increase SVR and Diastolic BP (Alpha1)

Decreases Heart Rate: Baroreceptor Reflex induces strong Vagal Response.

Naturally Ocurring Catecholamine

Strong Agonist of both Alpha and Beta Receptors

Effects on BP and Heart:

Increase contractility and HR (Increased Systolic Pressure) via B1 receptors

Dilates Skeletal Muscle Arterioles (Decreased SVR and Diastolic Pressure)

Net Increase in MAP (not large enough to strongly activate baroreceptor)

Also increases rate of gluconeogenesis and lipolysis via cAMP mech

A phenylethylamine that can be taken up into nerve terminal and vesicle.

Acts indirectely to displace stored norepinephrine from vesicles (acute sympathomimetic effects bc NE leaves via exocytosis)

Long-term: reduces Norepinephrine levels and acts as a "false neurotransmitter" (after metabolism to octopamine)

Is metabolized by MAO--Increased levels with MAO inhibitors

A phenylethylamine that is taken up neuronally and into vesicles.

Acts indirectly to displace NE, causing sympathomimetic effects

Drug of abuse and competive inhibitor of sympathetic neuronal uptake of Norepinephrine (along with tricyclic antidepressants)

Potentiates sympathetic neurotransmission (More NE in synapse for longer)

Is NOT taken up into Neuron

Tricyclic Antidepressants

(eg imipramine)

Competive inhibitor of sympathetic neuronal Norepinephrine uptake (along with cocaine)

Potentiates Sympathetic Neuronal transmission--more NE in the synapse for a longer time

Is NOT actually taken up into nerve terminal.

Selective and Irreversible Inhibitor of Vesicular Uptake Mechanism

Depletes Intraneuronal Norepinephrine (and Dopamine) levels because NE cannot get into protective vesicles. 

Sometimes causes an initial sympathomimetic effect, followed by decrease in BP and loss of cardiovascular reflexes.

Acts in both brain and periphery

Monamine Oxidase Inhibitors

Action: increase catecholamine levels by reducing rate of metabolism

Ex: Isocarboxazid

Monamine Oxidase is a mitochondrial enzyme that converts catecholamines into adrenergically inactive aldehydes.

Monamine Oxidase is present in liver and GI (processes adrenergically active things in food), and symp. nerve endings (regulates catecholamines in cytosol).

2 isoforms- MAO-A metabolizes serotonin (inhibited for depression treatment); MAO-B metabolizes Dopamine (inhibited for Parkinson's treatment)

Important in Metabolism of Catecholamines (mainly drugs as opposed to naturally occuring catecholamines)

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St. John's Wort is a "natural" example

Catechol-O-methyltransferase Inhibitors

ACTION: Increase catecholamine levels by inhibiting their metabolism

COMT normally metabolizes and inactivates Epinephrine and Norepinephrine by methylating the meta-OH group (EPI-->metanephrine, NE-->normetanephrine)

Found in kidney and liver

Entacapone is a selective inhibitor (used in conjunction with L-dopa for Parkinson's)

Catecholamine (adrenergic agonist)

Strong Beta Agonist

Weak Alpha Agonist

Effects on Heart and BP:

Increases Contractility, HR and Systolic Pressure (B1)

Dilates Abdominal and Skeletal muscle arterioles--decreases SVR (B2)

Effect on BP depends on physiologic state

Strongest Beta Agonist (of NE and EPI)

Alpha 1 Agonist

Used to for decongestion of mucous membranes in Nose and Eye. 

Used to induce mydriasis--acts on radial muscle/iris

Also for anti-hypotension.

Direct-Acting Alpha-2 Agonist

Lacks both hydroxyl groups--Readily passes Blood-Brain Barrier--has CNS effects

Acts on A2 receptors in hypothalamus--causes vasodilation by preventing sympathetic outflow--Anti-hypertensive

Treats withdrawal from narcotic addiction (CNS effect)

Beta-2 selective agonist--Common treatment of acute, episodic asthma attacks

Oral Inhalation causes bronchodilation via B2

Problems for prophylactic treatment:  Potentially densensitzes airway B2 receptors, reducing effectiveness.

Long-acting partial Beta-2 agonist--useful in maintenence therapy of asthma

Does not cause as much desensitization as a full B2 agonist

Combined with inhaled corticosteroids (which treat underlying inflammation)

Very Lipophilic--May act on a different population of B2 receptors

Drug for short-term treatment of acute heart failure

Ionotrophic, but not Chronotrophic (B-1 agonist?)

No effect on peripheral resistance

Epinephrine

Via Beta-2, inhibits mast cell degranulation (and thus histamine, bradykinin, etc.)

Prevents glottal and pharyngeal edema

Supports Blood Pressure (counteracts vasodilation from response)

Weak Beta-1 agonist

Used to increase cardiac output

Activation of Dopamine receptors on vascular smooth muscle-->increased perfusion of vital organs w/o decrease in BP

Effects on HR and BP:

Increases heart rate and contractility (increase systolic)

Decreases peripheral resistance (decrease/constant diastolic)

Increases BP

May induce congestive heart failure

Life-threatening bradycardia

Up-regulating receptors, leading to withdrawal syndrome.

Specific Beta-1 Antagonist

Used for hypertension and congestive heart failure maintenance

Much longer half life than Metoprolol

Pindolol and Acebutolol

Beta blockade is not "complete" in that the drug causes some sympathoexcitation (ie heart rate is not completely reduced)

Tamsulosin, Doxazosin, Terazosin

Increases Blood Flow (most tissues) and Decreases BP

Improved over non-selective A-antagonists because there is no tachycardia (A-2 autoregulation of NE release)

Used for: hypertension and hypertension crisis

Pheochromocytoma (tumor of adrenal medulla-->Increased Catecholamine production)

Congestive Heart Failure

Prostate Hypertrophy

Alpha 1 Antagonist

Decreases Smooth Muscle Contractions in Neck of Prostate-->Decreased Proliferation

5HT1B/D Receptor (Serotonin) Agonist

Acute Treatment of Migraines.

Mech?  Cuts off anastomoses via intracranial constriction, preventing ischemia, one of the potentially causes of migraines

Direct-Acting Parasympathomimetic Drug (Muscarinic-Selective)

Is metabolized by AChE more slowly (one third the rate)

Because it is still relatively short-acting, sometimes used to test for bronchial hyperactivity

Side Effects: SLUDS, asthma attacks, heart block

Direct acting Parasympathomimetic (Non-selective nicotinic/muscarinic)

Used for topical glaucoma management--iris pulls open canal of Schlemm

Not metabolized by AChE, long acting

1. GI atony

2. Nonobstructive Urinary Bladder atony

3.  Glaucoma

4. Myasthenia Gravis

Direct Acting Parasympathomimetic Drug (Muscarinic Selective Agonist)

Not susceptible to AChE--long acting

mainly affects GI and Urinary Bladder at normal doses

Used to increase tone and contractions of above

Natural Plant Alkaloid (muscarinic agonist)

Not susceptible to AChE--long acting

Treats glaucoma--iris opens canal of Schlemm when constricting pupil

Reversible Cholinesterase Inhibitor

Very Short Acting--Diagnostic for Myasthenia Gravis

Reverses weakness in MG, not for other neurodegenerative diseases.

For dosing:  If Edrophonium reduces weakness in a medicated person-->dose too low

If it does not-->Initial dose is too high and causes weakness via persistent depolarization

A Quaternary Alcohol--Ionically associates with AChE, slowing its action

Reversible AChE Inhibitor

Increases gastric motility and secretions

Increases Urinary bladdar contractions

Improves transmission at NMJ

Used for Myasthenia Gravis therapy (longer acting than edrophonium)

Used for Nonobstructive GI issues

Quaternary Amine--Charged and does not cross blood-brain barrier--targets periphery.

Reversible AChE Inhibitor

Used to treat Glaucoma--Causes Miosis and opening of Canal of Schlemm via Iris Muscarinic Receptors

Tertiary Amine--Not Charged, Enters Brain

Type of Organophosphate

Irreversible Inhibition of AChE

Inhibits by the ester remaining tightly bound to AChE-->must form new enzyme to regain function

Used in treatment of Glaucoma--last resort b/c they cause cataracts.

Antidote to Organophosphate AChE Inhibition

Used along with Atropine to block muscarinic effects and ventilation

Can remove ester from active site.

Does not act on CNS

Muscarinic Receptor Antagonist

In eye-->Dilation (not for glaucoma bc it increases pressure)

In GI-->Reduces secretions and motility

Decreases sweating

Side Effects--> Tachycardia (negligible on BP)

Used to treat Cholinergic Crisis

Muscarinic Antagonist from BellaDonna Plant

More CNS activity than Atropine-->Drowsiness and Amnesia

Scopolamine

Inhibits Muscarinic Receptors of Vestibular System when used transdermally

Muscarinic Antagonist

Inhaled to treat asthma and other airway disease which has a strong parasympathetic component.  Causes Bronchodilation

Quaternary Amine--Does not cross blood-brain barrier

Depolarizing (Non-competitive) Cholinergic Blocker

Causes Initial Transient Stimulation, followed be persistant depression. 

At NMJ--causes paralysis via depolarization blockade

Sensory receptors--stimulates pain receptors, chemoreceptors at carotid body, and various mechanostretch receptors

CNS--At low doses (smoking)-->Alerting Effect

At moderate doses-->Tremors and Vomitting and Diarrhea

At high doses-->convulsions, coma and death via respiratory arrest.

Non-depolarizing (Competitive) Ganglionic Blocker

Competes with ACh for the nicotinic receptor at Ganglion

You block whatever system provides primary autonomic tone.

Eg.  Sympathetic for arterioles-->results in vasodilation

Parasympathetic for iris-->Dialation

Competitive (non-depolarizing) Neuromuscular Blocking Agent

Blocks ACh at motor end plate.

Paralyzes skeletal muscle (1st eye, jaw, swallowing, peripheral muscles, abdominal and intercostal muscles, and finally diaphragm)

Causes Histamine Release

Enhanced by anesthetics

Antagonized by neostigmine and edrophonium

Competitive (Non-depolarizing) Neuromuscular Blocking Drug

Shorter acting than D-Tubocurarine (35-45 min)

D-tubocurarine>atracurium>vecuronium (25-40min) > Mivacurium (15 min)

Can be antagonized by edrophonium or neostigmine

Depolarizing Neuromuscular Blocker

Produces Persistent Depolarization of Motor End Plate

Rapid and Brief (initial twitching followed by ~5 minutes of paralysis)

Metabolized by pseudo-ChE...some patients do not form this enzyme and have higher risk of side effects

CANNOT BE ANTAGONIZED

Contraindications to Cholinimimetics

1. Asthma

2. Peptic Ulcer

3.Coronary Insufficiency

4.Hyperthyroidism (causes atrial fibrillation)