Central Nervous system

Brain/ spinal cord

Peripheral Nervous System: 2 branches

Autonomic Nervous system

Somatic Nervous system

• Branch of the PNS
• Involuntary
• provides involuntary control over smooth muscles, cardiac muscles and glands
• Regulates nerves to heart, digestive tract, reproductive tract, salivary glands and parts of the eye
• Has 2 branches: sympathetic and parasympathetic

Somatic Nervous system

Branch of the autonomic NS

"fight of flight" responses

• branch of the autonomic NS
• Respiration-cardiovascular-digestion
• decreased heart rate
• fall in BP
  • decrease in cardiac output (due to last 2)
• constriction of pupil (miosis)
• contraction of the GIT (can lead to diarrhea)
• watery secretion of saliva (drooling)

Cholinergic receptors (ACh)

Adrenergic Receptors (NE)

Dopamine Receptors (DA)

Cholinergic receptors

(ACh) (Cholinoceptor)

Paracympathetic

2 subtypes:

Nicotinic receptors (N):

Nicotine in tobacco

Muscarinic receptors (M):

poisonous mushrooms (amanita muscaria) 

(causes death due to muscle contraction)

Adrenergic receptors (NE) 

(Adrenoceptor)

Sympathetic

Alpha (α₁ & α₂) receptors

Beta (β₁ & β₂) receptors

Acetylcholine is main neurotransmitter

• small membrane bound synaptic vesicles
  • contain high [ ] of ACh
  • vesicles are synthesized in the neuron and transported to the terminal
• A.P causes voltage gated Ca²⁺ channels to open
• Ca²⁺ moves into cell
• ACh docks at docking proteins
• ACh is released into synapse (exocytosis)

• synthesized from Acetyl-Co-A and Choline in mitochondria
• via choline acetyl transferase (CAT)
• rapid process (allows rapid response)

transported from extra-cellular fluid into nerve terminal by a Na-dependent high choline transporter (carrier) (CHT)

• combines with acetyl-Co-A to form Ach

   ACh storage

synthesized ACh is transported into vesicles by a vesicle-associated transporter (VAT)

• proton efflux is coupled with the uptake of ACh 

transports synthesized ACh in to vessicles

• can be blocked by Vesamicol, depleting vesicular (stored) ACh

blocks VAT, depleting vesicular (stored) ACh

• use of this can lead to patient being depleted of energy

• Quantal release at resting potential (for muscle tone)
• A.P. (membrane depolarization) triggers Ca²⁺ influx via the nerve terminal Calcium channels. (a Ca²⁺ mediated exocytosis process)(blocked by Conotoxin)
• SNARE proteins are located on vesicle surface
• SNAP proteins are located on inner surface of neuronal membrane
• Ca²⁺ interacts with SNARE, triggers fusion of vesicle and terminal membranes → exocytotic expulsion of ACh

inhibits nerve terminal Ca²⁺ channels

• reduces ACh release
• inherently released by snails
• used in patients who suffer form sever muscle contraction disorders (cause flaccid paralysis)

vesicular proteins

located on the surface of vesicles

• ex) Synaptotagmin and Synaptobrevin

located on inner surface of neuronal membrane

• docking proteins
• ex) SNAP-25 and Syntaxin

blocks release of ACh via the enzymatic removal of two amino acids form one or more of the fusion proteins (SNAP-25 and Syntaxin)

• prevents docking of ACh, therefore cannot be released and muscles cannot contract

Acetylcholinesterase (AChE) metabolizes ACh to choline and acetate

• half life of ACh in the synapse is very short
• ACh diffuses away into blood or is taken up by surrounding tissue and metabolized by Pseudocholinesterase (lower specificity for ACh)

metabolizes ACh to Choline and Acetate in the synapse (only located in synapse)

• if not present, ACh would remain in synapse longer, [ACh] would ↑ and lead to muscle spasm

metabolizes ACh in tissue

• lower specificith for ACh

Heart: Negative inotropic (↓force of contraction) and negative chronotropic effect (↓frequency). Lead to decrease in Cardiac output

Blood Vessels: Relaxation of smooth muscle. Vasodilation (↓BP)

Bronchi: Bronchoconstriction, bronchospasm

GIT: ↑ motility, contraction and secretion. Diarrhea

Eye : Miosis and Cycloplegia. Decreases Intraocular pressure

paralysis of ciliary muscle of eye

• loss of accommodation: cant focus on moving objects

Directly or indirectly acting

• Indirectly acting are further divided into: Reversible or irreversible

act directly on receptor

1.  Pilocarpine: Used for Glaucoma; Decreases IOP
2. Bethanechol: Used for Urinary retention; causes contraction of urinary bladder muscle

• should not be used in patients with mechanical obstruction of the bladder or GI tract (ie kidney stones, trama...)

act by inhibiting the destruction of ACh by cholinesterase

1. Reversible Agents: better therapeutic use
2. Irreversible Agents

Indirectly acting cholinergic agent

Easily removed from receptor

• Physostigmine (used for drug overdoses-of anti-cholinergics)
•  Neostigmine (used for Myasthenia Gravis)
• New: Donepezil, Rivastigmine (Alzheimer's)

Indirectly acting cholinergic that binds very strongly to receptor

•  Organophosphates: Malathion, Parathion, Sarin, Tabun (used as insecticides and nerve gases)
• Can be absorbed by skin from insecticides on clothing of farmers

Direct acting cholinergic

• Used for Glaucoma
• ↓ outflow resistance and therefore helps in ↓ IOP 
  
• Adverse effects:
  • Sweating, nausea, chills, flushing, urinary frequency, dizziness
• Contradictions: Patients with uncontrolled or poorly controlled asthma
• Precaution: FDA Pregnancy

as day precedes ACh ↓

Symptoms:

1. slurred speech
2. ptosis (drooping of eyelids)

Indirectly acting cholinergic

• reversible
• crosses BBB
• Clinical uses:
  • Topical - eye ointment (miotic)
  • IV - antidote to atropine-like drugs

Indirectly acting, Reversible Cholinergic

• does not cross BBB
• Clinical uses: 
  • antidote to tubocurarine (used to relax muscles pre-op)
  • Myasthenia Gravis
• Adverse Effects: as in cholinergic stimulation - salivation, flushing, decrease BP etc

Indirectly acting, reversible cholinergic

• used for Alzheimer's Disease
• increases ACh in the brain by inhibiting its metabolism (inhibition of cholinesterase)
• Well absorbed and 96% plasma protein bound 
• metabolized in liver
• not a cure for Alzheimer's disease
• slow the progression

extension of pharmacological effects:

• bronchospasm (never give to asthmatics)
• salivation/drooling
• lacrimation
• urination
• defecation
• CNS symptoms: confusion, coma

• caused by insecticides
• Treatment: Pralidoxime + Atropine (anti-cholinergic)
• If possibility, 1st thing to do is remove all clothing

• Used to treat organophosphate poisoning
• Regenerates the bound receptors thus stopping action (removes the "irreversibly" bound organophosphate)

• Asthma: Bronchoconstriction
• Hyperthyroidism: Atrial fibrillation
• GI obstruction: Perforation
• Heart disease: Tachycardia
• Peptic Ulcer: Increased acid secretion

1. Glaucoma: Pilocarpine Opthal. 2% drops
2. Myasthenia Gravis
3. Urinary retention
4. Post-op (to treat spasms)

1. Myasthenia gravis & Glaucoma: Physostigmine and Neostigmine
2. Atropine poisoning: Physostigmine
3. (also used as insecticides/poison gas)

Competitive cholinergic inhibitors 

• Prevent action of ACh
• release is not affected
• receptor is competitively blocked
• only block Muscarinic action... no effect on Nicotinic
• action blocked: smooth muscles, glands, heart  (NOT skeletal muscles)

• Plant sources: Atropine
• atropa belladonna (deadly nightshade)
  • "beautiful lady"; pupillary dilation
•       Examples: 
  • Atropine
  • Scopolamine

1. Atropine & Scopolamine (orally or topical)
2. Cyclopentolate (Transdermal)
3. Ipratropium (Atrovent Inhaler/Oral)
4. Tiotropium (Spiriva)

• decreased secretions
• smooth muscles: Relaxed
• Bronchodilation and Constipation
• Eye: Mydriasis and Cycloplegia
• CVS: Positive Inotropic and chronotropic effects result in tachycardia

• Secretions: decrease salivation
• Relax GI muscle except sphincters and reduce intestinal motility
• Decrease gastric acid secretion

Urinary Tract Effects

• Inhibit the contractility of the urinary bladder and may cause urinary retention

• Inhibit the contractility of the urinary bladder and may cause urinary retention

GI

Urinary Tract

 Respiratory 

CNS

• Atropine: causes mild stimulation followed by slower and longer lasting sedative effects (CNS depression)
• Scopolamine: more sedating than atropine
• Uses: 

1. Transdermal Scopolamine patches - prevent motion sickness (Transderm V)
2. Parkinson's diseases - tremor and stiffness 

Extensions of the pharmacological effects

• Blurred vision (cycloplegia) b/c cannot accommodate 
• Photophobia (mydrasis) : blind in bright light
• Xerostomia: Dry mouth (can't swallow)
• Tachycardia
• Urinary/ GI retention

• Glaucoma: increased IOP in glaucoma
• prostatic Hypertrophy (BPH): urinary retention
• Intestinal or urinary obstruction: Perforation risk
• Cardiovascular disease: Tachycardia/ Arrhythmias

used of anticholinergics

• Pre-operative: to ↓ bronchial, GIT secretions
• GT disorders: hyperacidity and ↑ motility: Ulcers/ traveler's diarrhea
• Irritable bowel syndrome: Dicyclonine
• Parkinson's disease: benztropine
• Eye exams: refractive measurements
• motions sickness: Scopolamine
• post prostatectomy bladder spasm/ involuntary voiding: Oxybutynin (Ditropan)

• nicotine is highly fatal poison
• 1 drop is enough to kill human
• rapidly crosses the BBB, causes CNS stimulation
• High doses cause Respiratory paralysis 
• constricts blood vessels and reduces blood flow to the extremities (Raynauds Phenomenon)
• Buergers Disease: vasoconstriction in chronic smokers

• Nicotine Inhaler: Nicotrol (nasal)
• Nicotine gum: Nicorette
• Champix (varenicline)
• Nicotine transdermal, Nicoderm

• used to quit smoking
• delivers nicotine to buccal mucosa
• adverse effects:
• local (oral) irritation: taste disturbance, jaw and neck pain
• nausea, diarrhea, hiccup
• Headache, influenza-like symptoms, back pain, paresthesias, flatulence and fever

Drug interactions of Nicotrol

Pregnancy

children

asthma and chronic lung disease

Pheochromocytoma

stomach ulcers

• Acute: pallor, cold sweat, nausea, salivation, vomiting, abd pain, diarrhea, headache, dizziness, disturbed hearing and vision, tremor, mental confusion and weakness
• Lethal dose produce convulsions quickly and death follows as a result of peripheral or central respiratory paralysis or less frequently cardiac failure.