• Epinephrine, Norepinephrine, Dopamine
• Catecholamines
• Synthesized in neural tissues 
• Stored in synaptic vessels
• Isoproterenol is an exogenous catecholamine

Sympathetic Stimulation

• Heart rate: ↑
• Feel cold - shunt blood to muscles
• Breathing - Dilation of bronchi
• Pupils dilate - enhance visual acuity
• Mobilize body's stored energy

NE is synthesized from a series or precursors:

1. Phenylalanine (extra neuronal) →
2. Tyrosine (extra neuronal tyrosine is transported into the neuron) →
3. DOPA (neuronal cytoplasm) →
4. Dopamine (DA) (formed in cytoplasm and transported into vesicles) →
5. Norepinephrine (Vesicles)

When action potential arrives, NE is released from its stored vesicles into the synaptic cleft

(in the same process that ACh is released)

1. bind to postjunctional receptor
2. extraneuronal uptake (by post synaptic neuron)
3. Diffuse into blood
4. Metabolized by monoamine oxidase (MAO)
5. Neuronal reuptake (by presynaptic neuron)
6. Bind to prejunctional receptor

Receptors for epinephrine and norepinephrine

Two types of receptors:

1. Alpha (α): α₁, α₂ (α₂ not very important)
2. Beta (β): β₁, β₂

• mimic the action of NE
• also called sympathomimetics
• stimulate adrenergic receptors

• Shock: Anaphylaxis
• Cardiovascular: bradycardia, hypotension, CHF, Cardiac arrest
• Asthma (bronchodilation)

1. Catecholamines (have a catechol nucleus)
2. Noncatecholamines (no catechol nucleus)

• Norepinephrine, Epinephrine, Dopamine
• Isoproterenol (Isuprel)
• Epinephrine is prototype
• drug of choice to relieve bronchospasm
• laryngeal edema in anaphylactic shock
• cardiac arrest
• added to local anesthetics for vasoconstriction (reduces blood loss)
• Not given PO: destroyed by GI/liver enzymes
• Rapidly metabolized, very short t 1/2

• Ephedrine, phenylephrine, terbutaline (bronchodilator given for asthma)
• Metabolized slowly by MAO and NOT inactivated by COMT
• Longer half lives
• can be given orally
• crosses BBB: centrally active
• ephedrine available OTC

• Rapidly metabolized by: 
  • Monoamine oxidase (MAO)
  • Catechol-O-methyltransferase (COMT)
  • Oral administration is ineffective (enzyme present in intestinal wall) 

Monoamine oxidase (MAO)

• Rapidly metabolizes catecholamines
• present in liver, intestinal wall and presynaptic nerve endings

NOT effective due to enzyme present in intestinal wall 

• NE and dopamine require slow infusion, subcutaneous or intramuscular

• CNS: Excitement, stimulation, anxiety (can lead to convulsion, coma, and death)
• CVS: increased heart rate, increased BP
• Vasoconstriction: Epinephrine
• Eye: Mydriasis/ Decreased IOP
• Respiratory: Bronchodilation
• Metabolic: Glycogenolysis and increased BMR
• Blood vessels: Constriction in skin/ Mucosa

Mydriasis

Decreased IOP - outflow of excess aqueous humor due to constriction of radial muscles

Mainly on Heart

• cardiac arrest- epi to "kick start" a stopped heart, use when all other methods have failed
• Heart failure- β₁ receptor activation results in positive inotropic effect (force of contraction) thus improved cardiac performance
• shock (profound hypotension, tissue perfusion)
• May cause tachycardia (excessive heart rate)
• May cause dysrhythmias (irregular heart rate)

Lungs and uterus

• activated by epinephrine, salbutamol (selective agonist)
• Asthma - Bronchodilation
  • selective β₂ agonist are preferred (Terbutaline)
  • salbutamol:  [ventolin] drug of choice for asthma (may cause tremors, restlessness, which will decrease b receptor down regulation)
• delay preterm labor: β₂ receptor activation relaxes uterine smooth muscle (Isoproterenol_

α₁ agonists: Phenylephrine, methoxamine

α₂ agonists: Clonidine (not used clinically)

α₁ antagonists: Prazosin, doxazosin, terazosin

α₁ > α₂ antagonists: phenoxybenzamine

α₁ = α₁ antagonists: Phentolamine

α₂ antagonists: Yohimbine (not used)

β₁ agonist: Dobutamine

Beta 1+2 agonist: Salbutamol

β₂ agonist: Terbutaline, Isoproterenol

β₁ antagonist: Atenolol, acebutolol, Metoprolol

β_{1 = β2 antagonist: Propranolol, Pindolol}

β2 antagonist: Buloxamine

• Lungs have  β₂ receptors only
• can not give β₂ antagonists to asthmatics (will cause bronchoconstriction)
• Can give a β₁ selective antagonist

D₁ Agonist: Dopamine

D₂ Agonist: Bromocriptine

D₃ Agonist: Quiniprol

D₄ Antagonist: Clozapine

• α receptors increase peripheral vascular resistance and venous capacitance: Vasoconstriction
• β₂ receptors promote smooth muscle relaxation: Vasodilation
  
• Overall effects of a sympathetic drug on blood vessels depends on relative activities of that drug at α and β receptors and the anatomic sites of the vessels affected 

• Mainly β₁ receptors, some β₂ and α effects

β receptor activation:

• ↑ Ca²⁺ influx in cardiac cells (↑ contractility)
• ↑ pacemaker activity, a positive chronotropic effect (↑ rate) (SA node)
• ↑ in conduction velocity in AV node and ↓ in refractory period
• ↑ intrinsic contractility (allows atria to fill ventricle), positive inotropic effect 

• α receptors activate radial pupillary dilator muscle of the iris 
• Receptor activation causes mydriasis
• α agonist increase the outflow of aqueous humor from the eye
• β antagonist decrease the production of aqueous humor

• β₂ receptors on bronchial smooth muscle
• activation causes relaxation
• β agonists: Salbutamol (Ventolin)
• upper respiratory tract mucosa contain α₁ receptors
• Stimulation of α₁ causes decongestant action of adrenoceptors

• β receptors
  
  • activation causes relaxation via hyperpolarization and ↓ spike activity in these cells
• α₂ selective agonists
  
  • ↓ muscle activity indirectly by reducing the release of Acetylcholine and possibly other stimulants in the GIT
    

• Human genitourinary contains α and β₂ receptors
• β receptors mediate relaxation of uterus clinically useful in pregnancy
• α receptors present on the bladder base, urethral sphincter and prostate
• α receptors activate mediate contraction and therefore promote urinary continence

• Salivary glands contain adrenoceptors that regulate the secretion of amylase and water
• Apocrine sweat glands respond to adrenoceptor stimulants with ↑ sweat production

• Adipose cells:
  • β adrenoceptor activation ↑ lipolysis 
  • α₂ receptors activation inhibit lipollysis
• Liver:
  • Sympathomimetic drugs enhance glycogenolysis, leading to ↑ glucose release into the circulation - mainly via β receptors
  • Do not give to diabetic pts

• Insulin secretion
  • stimulated by β receptors and inhibited by α₂ receptors
• Renin secretion
  • stimulation by β and inhibited byα₂ receptors
• Parathyroid hormone, calcitonin, thyroxine and Gastrin all modulated by adrenoceptors

1. Direct acting: adrenergic agonists
2. Promote NE release 
3. Inhibit NE reuptake
4. Inhibit NE Inactivation

Epinephrine

Isoproterenol

Act on α₁ or β receptors on post-junctional cell

Adrenergic receptor activation:

promotion of NE relaease

Amphetamines

• cause release of NE from vesicles in presynaptic cell

Adrenergic receptor activation:

Inhibition of NE reuptake

Prevent presynaptic cell from reuptaking NE, leads to excess NE in synapse

Cocaine
Tricyclic antidepressants:

imipramine (Tofranil)

amitryptyline (Elavil)

doxepin (Sinequan)

Adrenergic receptor activation:

Inhibition of NE inactivation

Prevents NE from being inactivated in presynaptic cell by MAO

MAO inhibitors:

phenelzine (Naril)

tranyleypromine (Parcate)

drugs that block adrenergic receptors 

2 group:

1. Alpha-adrenergic blocking agents
2. Beta-adrenergic blocking agents

Non-selective: Block α₁ & α₂ 

(phentolamine, phenoxybenzamine) 

Selective: Block α₁ only

(Prazosin, Terazosin)

Non-selective: Block β₁ & β₂

Selective: Block β₁ only

Blood vessels: Vasodilation 

Essential hypertension: lowers blood pressure via massive vasodilation

α₁ blockage:

1. in bladder and prostate of pts with benign prostatic hyperplasia (BPH)
2. Raynaud's Disease

α₂ blockage: no clinical applications

Catecholamine secreting tumor in the adrenal medulla

• Patient has very high BP

• smoking induced disease (Nicotne)
• peripheral vascular disorder, vasospasm in toes and fingers

Prazosin (Minipress):

competitive α₁ antagonist (selective)

Indication - Hypertension

Other α₁ antagonists:

Terazosin (hytrin)

Phentolamine (Regitide)

Phenoxybenzamine (Dibenzyline) 

• competitively block receptors in the autonomic nervous system
• 90% of their names end with -olol
• effects: Initially vasoconstriction (BP will decrease within 2-3 days)followed by vasodilation, bradycardia and bronchoconstriction

produces vasodilation

vronchodilation 

tachycardia

Propranolol

atenolol

metoptolol

β₁ blockage of cardiac tissue results in:

• ↓ heart rate
• ↓ force of contraction
• ↓ velocity of impulse conduction via AV node

Therefore, given to pts after MI

• cause bronchospasm
• minimal clinical uses

• Heart failure
• hyperthyroidism
• migraine
• stage fright
• glaucoma

• Bradycardia
• reduced cardiac output
• AV heart block
• Do not use in cardiac failure
• not used in obstructive pulmonary disease (may cause embolism)
• not used in diabetics as they may induce hypoglycemia

Not clinically used

• adrenergic neuron blocking agents: block entire neuron
  • Reserpine
  • Guanethidine
• Centrally acting alpha2 agonists
  • clonidine
  • methyldopa & methyldopate

agents that act presynaptically and reduce the release of NE

• Reserpine

an adrenergic neuron blocking agent

• Mech. of action: 
  • Depletion of NE from nerve endings via
    • prevention of NE synthesis
    • release of NE stored in vesicles
    • released NE is then inactivated by MAO
  • Has both peripheral and central effects
    • centrally: depletes other transmitters (ie Serotonin)

Ephedra plant Used for 2000 years in china

Found in Ma-Huang

introduced into western medicine in 1924 as 1st orally active sympathomimetic

• Releases stored catecholamines
• acts directly on adrenoreceptors
• nonselective and mimics ephinephrine
• Mild stimulant (accesses CNS)

• Nasal decongestant
• pressor agent (↑ BP)
• stress incontinence in women
• natural "phen-fen"

inhibit neurotransmission at neuromusculat junctions

(cause muscle weakness and paralysis)

Two groups:

Nondepolarizing: Tubocurarine = flacid paralysis

Depolarizing: Succinylcholine = constricted paralysis

Tubocurarine

arrow poison

Paralyzes muscles in order of:

1. small facial and eye muscles
2. larger muscles of limb and trunk
3. intercostals and diaphragm

• stimulate Histamine release from mast cells (flushing of skin, erythema, bronchospasm, hypotension, edema)
• Respiratory arrest (paralysis of respiratory muscles)
• Cardiovascular: Hypotension, bradycardia, dysrhythmias and cardiac arrest

Potentiate muscle relaxing effects of curare drugs:

Inhalation anesthetic agents (halothane)

Antibiotics (aminoglycosides, tetracyclines)

Decrease effects of curare durgs:

cholinesterase inhibitors

acetycholine

IV injections

peak effect - 0.5 to 1 hr

short half life < 1.5 hrs

• muscle relaxation during surgery
• endotracheal intubation
• electroconvulsive therapy
• mechanical ventilation
• diagnosis tool for Myasthenia Gravis

Long acting:Doxacurium, methocurine, pipercuronium, rocuronium

Intermediate acting: atacurium, sistracurium, pancuronium, vacuronium

Short acting: Mivacurium

Depolarizing neuromuscular blocker

• binds and simulates nicotinic receptors at NMJ
• Then blocks the nicotinic receptors, resulting in muscle relaxation
• no known antidote
• Cholinesterase (AChE) rapidly inactivates it 

Prolonged NM paralysis and apnea (unable to breath on own), due to atypical AChE (Pseudocholinesterase) inherited (drug not metabolized at normal rate)

Malignant hyperthermia - genetically linked, prolonged continuous muscle contraction → fever

postoperative muscle pain

• Adjuncts to surgical anesthesia - producing muscle relaxation and facilitate mechanical ventilation
• Adjunct to electroconvulsive therapy - preventing injury caused by involuntary muscle contractions
• Diagnosis of Myasthenia gravis

Mecamylamine (Inversine)

Trimethaphan (Arfonad)

• Hypertensive emergency
• "Controlled hypotension" during neurosurgery, providing a bloodless surgical field