Pharm Lecture 3

For the sympathetic nervous system,

a) describe the pre-ganglionic fibers

b) describe the post-ganglionic fibers

c) what NT does it release

a) short

b) long

c) NE (Epi from adrenal medulla)

For the parasympathetic nervous system,

a) decribe the pre-ganglionic fibers

b) describe the post-ganglionic fibers

c) what NT does it release

a) long

b) short

c) ACh

Which NS is adrenergic and which is cholinergic?

- sympathetic NS: adrenergic

- parasympathetic NS: cholinergic

What is homeostasis in relation to the adrenergic and cholinergic systems?

Adrenergic and cholinergic systems often have opposing effects on organ function --> balance each other out

What does activation of sympathetic system typically cause?

- "fight or flight"

- CV stimulation, energy production

What does activation of parasympathetic system typically cause?

- "rest and digest"

- slows heart rate, promotes digestion, defecation, micturition (urinating)

What are the two kinds of receptors in the cholinergic system? Where is each type found?

1) muscarinic: parasympathetic effector organs

2) nicotinic: all autonomic ganglia + somatic NMJ

What are the two kinds of receptors in the adrenergic system? What does each do?

1) alpha: mediates sm muscle contraction (a1)

2) beta: sm muscle relaxation (b2) + cardiac stimulation (b1)

All parasympathetic effects are mediated by:

Muscarinic receptors (M1-M5)

Sympathetic effects are mediated by: (3)

- Alpha-adrenoreceptors

- Beta-adrenoreceptors

- Muscarinic receptors (but only for sweating!)

What would occur in the head as a result of sympathetic activation and which receptor does it correspond to? (4)

- Mydriasis (alpha-1)

- Vasoconstriction (alpha-1)

- Salivation (alpha-1)

- Sweating (M3, M2)

What would occur in the head as a result of parasympathetic activation and which receptor does it correspond to? (5)

- Miosis (M3, M2)

- Accommodation (M3, M2)

- Lacrimation (M3, M2)

- Mucus secretion (M3, M2)

- Salivation (M3, M2)

What would occur in the lungs/heart as a result of sympathetic activation and which receptor does it correspond to? (2)

- Bronchodilation (beta-2)

- Increased HR, AV conduction and contractility (beta-1)

What would occur in the lungs/heart as a result of parasympathetic activation and which receptor does it correspond to? (3)

- Bronchoconstriction (M2=M3)

- Mucus secretion (M3, M2)

- Decreased HR and AV conduction (M2)

What would occur in the abdomen as a result of sympathetic activation and which receptor does it correspond to?

- Glycogenolysis (beta-2)

- Decreased motility (alpha and beta)

What would occur in the abdomen as a result of parasympathetic activation and which receptor does it correspond to? (2)

- Increased HCl secretion (M3, M2)

- Increased motility (M3, M2)

What would occur in the kidneys/bladder as a result of sympathetic activation and which receptor does it correspond to?

- Renin secretion (beta-1)

- Urinary retention (alpha-1)

What would occur in the kidneys/bladder as a result of parasympathetic activation and which receptor does it correspond to?

Micturition (M3)

What would occur in the uterus as a result of sympathetic activation and which receptor does it correspond to?

uterine relaxation (B2)

What would occur in the penis as a result of...

a) sympathetic activation

b) parasympathetic activation

...and which receptor does it correspond to?

a) ejaculation (a1)

b) erection (M3)

What would be the parasympathetic response on the heart? What would be the sympathetic response?

Parasympathetic

- decreased HR, AV conduction, CO

Sympathetic

- increased HR, strength of contraction, CO

What would be the parasympathetic response on the lung bronchioles? What would be the sympathetic response?

Parasympathetic:

- Constriction

Sympathetic:

- Dilation

What are 2 ways you can treat asthma?

- use a bronchodilator!

1) use an anti-cholinergic (inhibits parasympathetic response)

2) use a med that stimulates sympathetic response

What would be the parasympathetic response on the liver glycogen? What would be the sympathetic response?

Parasympathetic:

- No effect

Sympathetic:

- Glycogen breakdown

- Blood glucose increases

What would be the parasympathetic response on the fat tissue? What would be the sympathetic response?

Parasympathetic:

- No effect

Sympathetic:

- Breakdown of fat

- Bloody fatty acids increase

What would be the parasympathetic response on the stomach/intestine? What would be the sympathetic response?

Parasympathetic:

- Increased secretion of HCl/digestive enzymes

- Increased motility

Sympathetic:

- Decreased secretion

- Decreased motility

How would you treat diarrhea?

use an anti-cholinergic because it'll decrease GI motility

What would be the parasympathetic response on the urinary bladder? What would be the sympathetic response?

Parasympathetic:

- Relaxes sphincter

- Detrusor muscle contracts

- Urination promoted

Sympathetic:

- Constricts sphincter

- Relaxes detrusor

- Urination inhibited

What would be the parasympathetic response on the rectum? What would be the sympathetic response?

Parasympathetic:

- Relaxes sphincter

- Contracts wall muscles

- Defecation promoted

Sympathetic:

- Constricts sphincter

- Relaxes wall muscles

- Defecation inhibited

What would be the parasympathetic response on the eye? What would be the sympathetic response?

Parasympathetic:

- Iris contraction (miosis)

- Adjusts for near vision

Sympathetic:

- Iris dilates (mydriasis)

- Adjusts for far vision

What would be the parasympathetic response on the male sex organs? What would be the sympathetic response?

Parasympathetic:

- Promotes erection

Sympathetic:

- Promotes ejaculation

What could be some possible side effects of an ANTI-cholinergic drug?

Cholinergic drugs will produce parasympathetic effect --> anticholinergic will have sympathetic effects

May see constipation, urinary retention (bad for geriatric patients due to prostatic issues/UTIs)

What are 4 other NTs and their functions?

1) substance P: analgesics interfere with substance P binding/production for pain management

2) serotonin or 5 hydroxytryptamine (5-HT): CNS

3) ATP: energy production

4) nitric oxide: vasodilation

What is acetylcholine synthesized from?

choline + acetate --> stored in vesicles --> released into synapse

What are the medications that affect cholinergic neurotransmission? (5)

- Hemicholinium

- Vesamicol

- Botulinum toxin (Botox)

- Cholinesterase inhibitors (physostigmine)

- Black widow spider venom

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What does hemicholinium do?

- blocks choline reuptake by the neuron

- inhibits ACH synthesis

- anti-cholinergic effect

What does vesamicol do?

- blocks ACH storage in vesicles

- anti-cholinergic effect

What does botulinum toxin do?

- blocks release of ACh

- anti-cholinergic effect

What do cholinesterase inhibitors like physostigmine do?

- inhibit breakdown of ACH --> will lead to increased levels of ACH in the cleft

- increases the cholinergic effect

What does black widow spider venom do?

- increases release of ACH

- increases the cholinergic effect

How is NE synthesized?

tyrosine --> dopa --> dopamine --> NE

What are the drugs affecting adrenegric neurotransmission?

- Metyrosine

- Reserpine

- Bretylium

- Cocaine

- Amphetamine

- Monoamine oxidase inhibitors (phenelzine)

What does metyrosine do?

- inhibits conversion of tyrosine to dopamine

- anti-adrenergic effect

What does reserpine do?

- blocks vesicular storage of dopamine and norepinephrine

- anti-adrenergic effect

What does bretylium do?

- blocks release of NE

- anti-adrenergic effect

What does cocaine do?

- blocks neuronal reuptake of NE (stays in cleft longer)

- increases adrenergic effect --> toxicity

What does amphetamine do?

- indirectly increases transport of NE into the synapse

- increases adrenergic effect --> toxicity

What do monoamine oxidase inhibitors like phelezine do?

- inhibit metabolism/breakdown of norepinephrine --> more NE in the cleft

- increases adrenergic effect --> toxicity

What is the baroreceptor reflex? What regulates it?

- Drugs that increase BP produce reflex bradycardia (increase in BP triggers parasympathetic activation)

- Drugs that decrease BP produce reflex tachycardia (decrease in BP activates sympathetic system)

- regulated by: vasomotor center

For the M1 receptor, what are the...

a) principal locations

b) mechanism of signal transduction

c) effects

a) Autonomic ganglia, presynaptic terminals, CNS

b) increase IP3

c) modulation of NT

For the M2 receptor, what are the...

a) principal locations

b) mechanism of signal transduction

c) effects

a) Cardiac tissue (SA and AV node)

b) decrease cAMP

c) decreased HR and conduction

For the M3 receptor, what are the...

a) principal locations

b) mechanism of signal transduction

c) effects

a) smooth muscle and glands

b) increase IP3

c) contraction of sm muscle + stimulation of glandular secretions

The M3 receptor can also affect vascular smooth muscle. What is the...

a) mechanism of signal transduction

b) effects

a) increased cGMP (due to NO)

b) vasodilation

For the muscle type nicotinic receptor, what are the...

a) principal locations

b) mechanism of signal transduction

c) effects

a) NMJ

b) increased Na+ influx

c) muscle contraction

For the ganglionic type + CNS type nicotinic receptors, what are the...

a) principal locations

b) mechanism of signal transduction

c) effects

a) autonomic ganglia + CNS (respectively)

b) increased Na+ influx

c) neuronal excitation

What are the 2 types of Ach receptor agonists?

1) direct acting: bind and activate Ach receptors

2) indirect acting: increase synaptic conc. of ACh

What are the 2 ways indirect acting ACh receptor agonists can increase synaptic conc. of ACh?

1) by inhibiting cholinesterase: prevents breakdown of ACh (reversible and irreversible)

2) by augmenting ACh signal transduction: increase c-GMP levels and vasodilative effects

What are the 3 direct acting ACh receptor agonist groups?

- Choline esters

- Plant alkaloids

- Other drugs

Name the 3 choline esters (direct acting ACH receptor agonists).

- Acetylcholine

- Bethanechol

- Carbachol

ABCs

Name the 3 plant alkaloids (direct acting ACH receptor agonists).

- Muscarine

- Nicotine

- Pilocarpine

Mary needs plants

Name the 2 other drugs that are direct acting ACh receptor agonists.

- cervimeline

- varenicline

What are some general properites of choline esters? (3)

- quaternary ammonium compounds

- poorly absorbed from GI tract

- not distributed in CNS (not a lot of systemic effects)

For ACh,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

a) muscarinic and nicotinic (it has a lack of specificity)

b) yes (rapidly), so it has a short duration of action

What are 2 limited clinical uses of ACh and their routes of administration?

1) intraocular: cataract surgery or other ophthalmic surgery requiring immediate miosis

2) intracoronary: diagnostic coronary angiography (intracoronary injection --> vasoconstriction --> diagnoses vasospastic angina)

For bethanechol,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) routes of administration?

a) selectively activates muscarinic

b) no

c) oral or subcutaneous

What is the function of Bethanecol? What is it a clinical use of it?

- stimulates bladder or GI muscle WITHOUT affecting HR/BP

- clinical use: treats acute postoperative + postpartum functional or neurogenic urinary retention

For carbachol,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) routes of administration?

a) muscarinic and nicotinic

b) no

What are 2 functions of carbachol and their routes of administration?

1) topical ocular: lowers intraocular pressure in tx (treatment) of glaucoma

2) intraocular: produces miosis during ophthalmic surgery

For muscarine,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) routes of administration + clinical use?

a) muscarinic

b) no

c) none

Where is muscarine found?

- in poisonous mushrooms (can produce side effects of diarrhea, sweating, salivation, lacrimation)

- causes cholinergic toxicity

For nicotine,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) routes of administration?

a) nicotinic

b) no

c) oral or transdermal

What products are nicotine contained in? What is its clincal use?

- contained in cigarettes and tobacco products

- available as gum, patch, electronic cigs for use in smoking cessation

For pilocarpine,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) what is it?

a) muscarinic

b) no

c) a tertiary amine alkaloid

What are 3 clinical uses of pilocarpine and their routes of administration?

1) topical ocular: treats glaucoma

2) oral: treats xerostomia (dry mouth) by stimulating salivary gland secretion

3) can also treat Sjögren's syndrome

What is Sjögren's syndrome?

Autoimmune condition characterized by dry eyes, dry mouth, and arthritis

For cevimeline,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) route of administration?

d) clinical use?

a) synthetic direct acting muscarinic agonist

b) no

c) oral

d) used to treat xerostomia

When administering cevimeline, what patients should you be cautious about?

- caution in patients with asthma + cardiac arrhythmias

- typical side effects: increased sweating, nausea, and visual disturbances

For varenicline,

a) receptor specificity?

b) is it hydrolyzed by cholinesterase?

c) routes of administration?

d) clinical use?

a) partial nicotinic agonist

b) no

c) oral

d) smoking cessation

When administering varenicline, what patients should you be cautious about?

caution in patients with CV disease --> can increase the risk of cardiac events based on phase 4 post marketing surveillance

What are the reversible (indirect acting) cholinesterase inhibitors? (7)

- Neostigmine

- Pyridostigmine

- Physostigmine

- Donepezil

- Tacrine

- Galantamine

- Rivastigmine

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What are the actions of neostigmine, pyridostigmine, physostigmine? What are they usually given in conjunction with?

- reversable cholinesterase inhibitors (block reuptake of ACh into the neuron --> more ACH into the cleft)

- used in myasthenia gravis

- given w/corticosteroids + other immunosuppressants

What is myasthenia gravis (MG)?

- muscle weakness

- antibodies target nicotinic receptors in skeletal muscle by destroying the NMJ

What are the actions of donepezil, tacrine, galantamine, and rivastigmine?

- reversable cholinesterase inhibitors (block reuptake of ACh into the neuron --> more ACh into the cleft)

- centrally acting

- used in Alzheimer's

What are the irreversible cholinesterase inhibitors? (4)

aka organophosphates

- Echothiophate

- Isoflurophate

- Mathalion

- Soman

What are the actions of echothiophate, isoflurophate, mathalion and soman?

- irreversible cholinesterase inhibitors (there will always be a high amount of ACH in the cleft)

- used as pesticides (EIM) and in chemical warfare (soman)

- responsible for a large number of accidental or intentional poisonings

What is unique about organophosphates and their absorption?

- they are highly lipid soluble --> immediate absorption through all body sites (ex: skin, mucous membrane, etc.)

- toxicity can occur very quickly (through ocular, dermal exposure, or after oral ingestion)

Why are organophosphates irreversible?

- form a covalent bond with cholinesterase (one of the strongest bonds)

- further bonding of the two is enhanced and stabilized --> "aging"

What are some side effects of excess muscarinic activation by organophosphates? (7)

- Salivation

- Lacrimation

- Urinary incontinence

- Miosis

- Spasm

- Bronchoconstriction

- Intestinal cramps

What are some side effects of excess nicotinic activation by organophosphates?

1) Muscle weakness

2) Seizures

3) Respiratory depression

4) Coma

- all from excess ACh activation in CNS (overwhelms the receptors!)

What are 4 ways to manage organophosphate poisoning?

1) decontamination

2) CV and respiratory support

3) atropine: blocks excessive ACh (universal antidote!)

4) pralidoxime: regenerates cholinesterase

When should pralidoxime be used?

- should be given as soon as possible

- otherwise, "aging" reduces pralidoxime capability to regenerate cholinesterase

What are phosphodiesterase inhibitors?

- a type of indirect acting cholinergic agonist

- PDE-5 inhibitors inhibit breakdown of cGMP

- this increases cGMP levels and promotes vasodilation

What are 3 PDE-5 inhibitors?

- Sildenafil (Viagara)

- Vardenafil

- Tadalafil

For Sildenafil (Viagra), Vardenafil, and Tadalafil...

a) what do they treat

b) what is the MOA (mode of action)

a) treat erectile dysfunction

b) increases vasodilative effects of ACh --> increases penile blood flow --> facilitates erection (via increased production and release of NO)

Compare and contrast the half life and duration of action for sildenafil, vardenafil, and tadalafil

sildenafil and vardenafil

- half life = 4 hours

- duration of action = 4-6 hours

tadalafil half life

- half life = 15-17.5 hours

- duration of action is up to 36 hours

Why do we advise patients to not take more than 1 dose of tadalafil in 24 hours?

Has a long half life and duration of action (up to 36 hours)

What are some adverse effects and interactions of PDE-5 inhibitors?

adverse effects

- usually mild and transient (headache, nasal congestion, dyspepsia, myalgia, visual disturbances)

interactions

- DO NOT use with nitrates (can cause profound hypotension, reflex tachycardia, worsening of angina)

- dosage adjustment needed with inhibitors of CYP3A4 (since they're metabolized that way)

What are cholinergic antagonists? What are the 2 types?

- inhibit effects of parasympathetic nerve stimulation

- divided into muscarinic and nicotinic antagonists

What do muscarinic antagonists do and what are the 2 types?

- relax sm muscle, decrease gland secretions, stimulate the heart

- 2 types: belladonna alkaloids + synthetic muscarinic antagonists

What are the 3 belladonna alkaloids?

- Atropine

- Hyosciamine

- Scopolamine

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