Physiology Auto. Nervous System & Pharmacology

BP, Blood volume, Temp., Distention of hollow organs, Arterial PO2, PCO2 & pH

Hypothalamus - Temp. & Osmolarity (fluid volume)

Midbrain - Visual

Medulla - Respiration (rate & depth), HR, BP

PNS & SNS (sympathetic nervous system)

PNS:
Craniosacral outflow
Long preganglionic neuron
Short postganglionic neuron
Ganglia often embedded in tissue
Parasympathetic ganglion: ACh & N2 (Nn) receptor
Neuroeffector junction: ACh & M receptor

SNS (sympathetic):
Thoracolumbar outflow
Short preganglionic neuron
Long postganglionic neuron
Ganglia beside spinal cord (exception: celiac, superior & inferior mesenteric ganglia have preganglionic fibers ending on sympathetic ganglia outside this chain)
Sympathetic ganglion: ACh & N2 (Nn) receptor
Neuroeffector junction: NE & α & β receptors (adrenergic receptors)

CN III, VII, IX, X

S2 - S4

1) PNS & SNS preganglionic neuron releases ACh which binds to nicotinic receptors on postganglionic neuron
(Nicotinic receptor is example of ionotropic receptor linked to ion channel - "Ligand-gated" channel)

2) ACh binding causes conformational change, ion channel opens & Na+ flows down electrochemical gradient
(Channel is nonspecific, allowing K+ to also cross, however majority is Na+ inflow)

3) Na+ inflow causes depolarization, which triggers opening of voltage gated Na+ channels and generation of action potential

4) Action potential is propagated along postganglionic neuron & eventually causes release of neurotransmitter release

Adrenal medulla is innervated by sympathetic preganglionic fibers, which release ACh, act on nicotinic receptors on the adrenal medulla which is then stimulated to synthesize & release catecholamines (epinephrine & norepinephrine)

ANS:
-Involuntary control
-Targets visceral organs
-Cell bodies in sympathetic chain or organ
-ACh, NE & M or Nicotinic (N2 or Nn) receptors
-ACh binds, opening of receptor, Na+ influx, small depolarization (end plate potential), open voltage gated Na+ channels & rapid influx of Na+ causing action potential

Somatic nervous system:
-Voluntary control
-Targets skeletal muscle
-Cell bodies in cranial nerves & ant. horn of spinal cord
-ACh & nicotinic receptors (N1 or Nm)
-ACh binds, opening of receptor, Na+ influx, small depolarization (end plate potential), open voltage gated Na+ channels & rapid influx of Na+ causing action potential which travels the muscle fiber from end plate and results in Ca2+ being released from sarcoplasmic reticulum into sarcoplasm. The increased Ca2+ triggers muscle contraction

Cholinergic receptors:
Nicotinic (N1, N2) & Muscarinic (M1, M2, M3, M4, M5)

Adrenergic receptors:
α1, α2, β1, β2, β3

Action of Ach on Muscarinic receptors and organs

NE on adrenergic receptors & target organs

Circulating Ach acts on M receptors located on capillary endothelial cells (not smooth muscle), which ↑ cytosolic Ca2+ which activates NOS (nitric oxide synthase) and NO is produced. NO diffuses out of cell, into neighboring vascular smooth muscle where it activates guanylate cyclase which facilitates conversion of GTP to cyclic GMP. cGMP causes smooth muscle relaxation leading to vasodilation of blood vessels of corpora vavernosum and penile erection

Cardiac muscle & NE:
-β1 receptor
-↑ contraction & cAMP
-Activation of β1 receptors ↑ cytosolic Ca2+ via cAMP & PKA (positive ionotropic effect)

Smooth muscle & NE:
-β2 receptor
-Relaxes smooth muscle & ↑cAMP
-α1 receptor
-Contracts smooth muscle & ↑IP3 & DAG

-Activation of β2 receptors ↑cAMP & PKA, however, PKA appears to phosphorylate myosin light chain kinase which reduces affinity of calmodulin (smooth muscle equivalent of troponin) for Ca2+ which inhibits contraction. β2 activation also dissociates beta & gamma subunits of Gs protein causing K+ channels to open, K+ flows out and membrane potential decreases, reducing excitability of muscle & contraction more difficult

Sweat glands appear to be innervated by SNS but have muscarinic receptors. It's likely they are innervated by preganglionic sympathetic fibers which release ACh which then act on muscarinic receptors on sweat glands. ↑sympathetic activity induces sweating...thus drugs that inhibit muscarinic receptors (Atropine) inhibit sweating

NE released from postganglionic sympathetic fibers acts on postsynaptic α1 (mostly smooth muscle) & presynaptic α2 receptors. α2 receptors act like a negative feedback loop, inhibiting further release of NE

Some organs are constantly subjected to either parasympathetic or sympathetic activity at rest, hence tonic control. The advantages: e.g. blood vessels...decreased sympathetic activity results in vasodilation & increased blood flow, whereas increase in sympathetic activity results in vasoconstriction and reduced blood flow. Thus there can be an increase or decrease in constriction but without a resting tone, only constriction would be able to take place.

Nicotinic receptors (nAChR):
-Nm on skeletal muscle
-Nn on autonomic ganglia

Muscarinic receptors (mAChR)
-M1 on autonomic ganglia, CNS & β cells of pancreas
-M2 on Heart & Auto. ganglia
-M3 on smooth muscle & glands

Botulinum toxin degrades SNARE protein, stopping action of ACh & particularly in skeletal muscle contractions.

Anticholinesterases or AChE inhibitors will elevate synaptic concentration of ACh to enhance postsynaptic effects of ACh.

Binding of Ach opens Na+ channel & there is Na+ influx (and
slight K+ efflux). Overall depolarization of the muscle cell resulting in a muscle action potential, and also depolarization of the parasympathetic and sympathetic postganglionic neurons.

Acetylcholine Esterase Inhibitors
-Improves dementia and Alzheimer's disease cognitive symptoms. Requires a titration phase and they delay development of cognitive and functional impairment by ~6 months

ACh released from cholinergic nerve binds to nicotinic receptor & causes conformational change, activating (opening) receptor and allowing Na+ to enter and depolarize the muscle cell.

ACh dissociates very quickly from receptor b/c affinity is very low, and rapidly broken down by AChE.

As ACh dissociates the channel reverts to its closed "resting" state.

The nAChR (nicotinic ACh receptor) undergoes conformational change, becoming desensitized and locking the channel.

The attached ACh to nicotinic receptor has a greater affinity and since ACh can't activate the muscle nor can it dissociate, flaccid paralysis ensues.

First signs being muscle weakness followed by paralysis w/ increased level of ACh. Thus any drug preventing the breakdown of ACh can cause respiratory paralysis (diaphragm). Drugs that directly stimulate nicotinic receptors but not quickly broken down by AChE can cause same effects.

1) Synthesis of ACh
2) Release of ACh
3) Degradation of ACh
4) Nicotinic receptors: as agonists & antagonists
5) Muscarinic receptors: as agonists & antagonists

Inhibition of ACh release:
-Botulinum Toxin "Botox"- Inhibits release of ACh from cholinergic nerves by preventing synaptic vesicle w/ presynaptic nerve membrane. The fall in ACh release results in muscle weakness & high conc. paralysis (botulism patients can suffer respiratory paralysis)
Clinical uses: used to paralyze selected muscle groups in which there is excessive tone (Focal Dystonias - Spasmodic torticollis, condition resulting in sternocleidomastoid tonically contracted on one side)

"Anticholinesterases" or AChE Inhibitors ("indirect acting cholinomimetics" b/c they mimic effects of ACh)

Reversible Anticholinesterase

1) Neostigmine - Semisynthetic derivative of physostigmine, less lipid soluble & doesn't cross blood brain barrier
Clinical uses: treat Myasthenia Gravis (characterized by autoantibodies attacking skeletal muscle nicotinic receptors and reducing number) by prolonging effects of ACh at junction such that those nAChR still functioning become more efficient.

Anticholinesterases also used to improve abdominal distention by stimulating M3 receptors on GIT smooth muscle to increase motility and tone

"Anticholinesterases" or AChE Inhibitors ("indirect acting cholinomimetics" b/c they mimic effects of ACh)

Irreversible Anticholinesterases (Organophosphates) - (covalently bound, affects overcome by new enzyme being produced taking up to 6 weeks)

1) Parathion - used as pesticides & herbicides killing insects by causing respiratory paralysis

Signs & symptoms of poisoning:
1) Excessive stimulation of nicotinic receptors: muscle weakness and paralysis
2) Excessive parasympathomimetic effects: salivation, bronchoconstriction, miosis, bradycardia, increased GIT motility & tone

Treatment: Pralidoxine reactivates cholinesterase enzyme so long as given within a day & Atropine to counter parasympathomimetic effects

Nicotinic agonist

1) Succinylcholine (suxamethonium) ("depolarizing blocker) - derived from ACh and has strong affinity for nicotinic receptors on skeletal muscle & slowly degraded by pseuocholinesterase (some people have defect in this enzyme causing an increase in 1/2 life). Succinylcholine thus "locks" the receptor closed (opposite effects of anticholinesterase drugs) resulting in paralysis.

When fist injected, muscle contractions can be seen under skin ("fasciculations"), yet no further activation by ACh leads to paralysis

Clinically used for muscle paralysis such as tracheal muscles and intubation for administration of inhaled anesthetics. Has a very short 1/2 life of minutes.

Nicotinic Antagonists

1) Tubocurarine - Neuromuscular (Nm) antagonists

Clinical uses: produces skeletal muscle paralysis as an active antagonist of ACh, binding to Nm receptors and commonly used during surgical procedures. Much easier to retract muscles when relaxed and also has a much longer 1/2 life than succinylcholine, thus used for surgical procedures whereas succinylcholine used for intubation

Succinylcholine is a nicotinic agonist producing depolarization blockade.
Tubocurarine is a competitive nicotinic antagonist which acts solely by occupying receptor and preventing ACh from contracting muscles.

NO!
Increasing ACh would overcome tubocurarine, displacing it from binding site on nicotinic receptors.
However...
Increased ACh would exacerbate depolarization blockade of succinylcholine.

Administering ACh is not practical b/c of such a short 1/2 life. Rather increase ACh indirectly through anticholinesterases like neostigmine when surgical procedure is ending and this will overcome effects of tubocurarine.

Muscarinic receptor antagonists (parasympatholytics) - competitive antagonists of ACh at all muscarinic sites

1) Atropine

Side effects: 1) Mydriasis, 2) Tachycardia, 3) Reduced secretions (salivary, bronchial, GIT), 4) Reduced GIT motility & tone, 5) Reduced bladder motility, 6) Reduced sweating thereby increasing temp

Clinical uses: 1) Ophthalmological exam, 2) Reverse sinus bradycardia caused by excessive vagal tone, 3) Reduce salivation & bronchial secretions during anesthesia, 4) Reduce GIT motility & tone in diarrhea, 5) Counteract effects of muscarine poisoning & anticholinesterase drug poisoning

S ↓Salivation
L ↓Lacrimation
U ↓Urination
D ↓Diaphoresis
G ↓GIT motility
E Emesis (vomiting)

"Hot as a hare" - reduced sweating
"Blind as a bat" - block of accomodation, dilated pupils, photophobia
"Dry as a bone" - reduced salivation
"Mad as a hatter" - CNS effects
"Red as a beet" - Flushing due to cutaneous vasodilation (atropine releases histamine)

Treatment: Physostigmine increases ACh levels which can overcome effects of atropine on receptors. Physostigmine is more useful than neostigmine b/c it crosses the blood brain barrier & overcomes effects of atropine in CNS

A postganglionic sympathetic action potential causes the nerve terminal to open voltage-gated Ca2+ channels.

The rapid influx of Ca2+ triggers the exocytosis of NE from synaptic vesicles.

NE termination:

Synaptic cleft:
1) Reuptake into presynaptic neuron (via NET - NE transporter) - (Uptake 1)
2) Metbabolized to inactive metabolite
3) Diffusion away from synaptic cleft

Within nerve terminal:
1) Taken back up by VMAT (Uptake 2)
2) Metabolized by MAO (monoamine oxidase) to produce VMA (vanillyl mandelic acid) or HVA (homovanillic acid) metabolites
3) COMT (catechol-O-methyltransferase) found most notably in liver also metabolizes NE

NE synthesized de novo & recycled NE

Epi. is released from adrenal medulla. Low conc. acts primarily on β receptors whereas High conc. acts on α1 receptors

- Low Epi. causes β1 to ↑HR, ↑force of contraction (cardiac output), ↑ O2 consumption & systolic BP
- Low Epi. causes β2(coronary & skeletal muscle blood vessels) vasodilation which results in a fall in diastolic BP.
***Overall mean blood pressure will not change b/c of β1 & β2 combined effects
- High Epi. causes α1 vascular smooth muscle vasoconstriction

Clinical Uses:
1) Acute asthmatic attacks: β2 activity of Epi. casuses bronchodilation (has to be administered parenterally since inneffective orally & short 1/2 life)
2) Anaphylactic shock: (characterized by generalized vasodilation, bronchoconstriction & edema) High dose Epi. (EPIPEN) causes vasoconstriction via α1 receptors (returns BP)
3) Surgical procedures: Injected Epi. causes localized vasoconstriction & when combined w/ local anesthetic prevents diffusion of anesthetic (dentistry)

NE acts mainly on α1 & β1 with little effects on β2.

B/c of its lack of action on β2 receptors compared to Epi., NE has different effects on BP. NE ↑systolic & diastolic BP...NE ↑HR w/ β1 receptors of heart which ↑mean BP & results in reflex bradycardia (baroreceptors)...NE ↑cardiac contraction force but since HR is reflexely dec., NE has little effect on cardiac output (pg 33&34 notes)

NE thus ↑stroke volume by ↑force of contraction, but since HR is reflexely decreased, NE has little effect on overall cardiac output

Clinical uses:
1) Emergency treatment of circulatory collapse (shock)

Imipramine

Blocks NET

Benefits: Increases NE levels in CNS
Side effects: Not specific in action blocking 5HT reuptake & several postsynaptic receptors in periphery such as muscarinic, α1, 5-HT & histamine receptors
Clinical use & adverse effects: Treat depression (associated w/ low levels of NE in brain) however causes "promiscuous" actions at other sites

Phenylephrine

Causes vasoconstriction & increase total peripheral resistance & BP

Clinical use:
1) Emergency treatment of shock
2) Nasal decongestant (due to vasoconstrictor effect on nasal mucosa)
3) Ophthalmic hyperemia

Side effects:
Hypertension

Dobutamine - β1 agonist
Primary action: ↑HR, force of contraction & cardiac output
Clinical uses: Acute management of heart failure (emergency situation - short 1/2 life due to COMT metabolism) (not generally used to treat chronic heart failure b/c althought they ↑contraction force they also ↑HR thus make failing heart work harder)

Albuterol - β2 agonist
Primary action: Relax bronchial smooth muscle causing bronchodilation as well as uterine relaxation
Clinical uses: Relief of bronchoconstriction in asthma (bronchodilators - short 1/2 life)
Side effects: Slight activity on β1 agonists may ↑HR or even slight tremor from β2 activity on skeletal muscle

Prazosin

Primary action: ↓peripheral resistance & dilation of veins which leads to reduced venous return to heart causing ↓cardiac output and BP

Clinical uses: Antihypertensive & treatment of BPH (benign prostatic hyperplasia - relax internal sphincter of bladder and smooth muscle associated w/ prostate gland)
Side effects: Postural (othostatic - standing) hypotension related to "1st dose phenomena" - baroreceptor reflex to vasoconstrict vessels to maintain BP when standing up from seated position yet prazosin will inhibit this response causing dizziness

Propranolol

Primary action: ↓HR & force of contraction leading to ↓BP in hypertensive people but not normotensive people

Clinical use:
1) Hypertension - ↓cardiac output, peripheral resistance & fall in renin secretion by kidneys
2) Angina - ↓O2 consumption of heart
3) Cardiac arrhythmias - slows conduction velocity through AV node
4) Chronic cardiac failure
5) Essential tremor - due to blockade of β2 receptors on skeletal muscle

Side effects:
1) Sedation & dyspnea
2) Also block β2 in bronchial smooth muscle causing life-threatening bronchoconstriction in asthmatics & COPD
3) Hypoglycemia triggers sympathetic response (↑HR, anxiety, sweating & tremors) seen after insulin injection w/o eating yet "beta blockers" mask signs & symptoms of hypoglycaemia

Contraindications: Asthmatic, COPD & Type 1 diabetic patients

Carbachol

It binds and activates the ACh receptors

Clinical uses:
Treating glaucoma and during opthalmic surgery