1.

Synthesis
- tyrosine (tyrosine hydroxylase)
DRUGS AFFECTING THE dihydroxyphenylalanine/DOPA
AUTONOMIC NERVOUS SYSTEM (decarboxylase) dopamine
- rate-limiting step is hydroxylation of
Parts of the Nervous system tyrosine
1. Central nervous system 2. Uptake into vesicles
- brain, spinal cordc - dopamine enters vesicle (B-
2. Peripheral nervous sytem hydroxylase) norepinephrine
- neurons outside the brain and spinal cord - norepinephrine is protected from
degradation in vesicle
a. Somatic - reserpine inhibits transport into vesicle
• Voluntary 3. Release
• innervates skeletal muscles - Ca causes release of NE
b. Autonomic - guanethidine blocks NE release
• Involuntary 4. Binding to receptor
5. Removal
• innervates organs
b.1 Sympathetic - methylated by catechol O-
methytransferase (COMT)
b.2 Parasympathetic
- oxidized by monoamine oxidase
(MAO)
- recaptured/reuptake by neuron- inh. by
cocaine
- urine metabolites: vanillylmandelic acid
(VMA), metanephrine, normetanephrine

Synthesis and Release of Acetylcholine

DIFFERENCES OF SOMATIC AND 1. synthesis of acetylcholine
AUTONOMIC NERVOUS SYSTEM - transport of choline inhibited by
hemicholinium
SOMATIC AUTONOMIC 2. uptake into storage vesicles
Without ganglia With ganglia - protected from degradation
One neuron 2 neuron
Ach Ach/NE 3. release of neurotransmitter
Nicotinic Nicotinic/adrenergic/ - botulinum toxin- blocks release
muscarinic - spider venom- promotes release
Skeletal muscle all
voluntary involuntary 4. binding to receptor
5. degradation by acetylcholinesterase
Ach acetate + choline
6. recycling of choline
DIFFERENCES OF
SYMPHATETIC/PARASYMPHATETIC
SYMPHATETIC PARASYMPHATETIC
NE ACH
Pre-ganglionic- Preganglionic-long
short
thoracolumbar craniosacral
Nicotinic/ Nicotinic/muscarinic
adrenergic
1:20 1:1

Synthesis and Release of Norepinephrine

 Male Ejaculation Erection
genitalia
Uterus Relaxation- β2 Contraction
labor

AUTONOMIC NERVOUS SYSTEM

RECEPTORS

AUTONOMIC NERVOUS SYSTEM ACTIONS

Sympathetic/ Parasympatheti
Adrenergic c/ Cholinergic
‘Fight or flight’ ‘Rest and digest’
system system
- dominant - dominant
during stressful during tranquil
situations conditions
Ganglion Acetylcholine- Acetylcholine-
nicotinic nicotinic receptor
receptor
Target Norepinephrine- Ach- muscarinic
organ adrenergic receptor
receptor (α,β)
adrenal
medulla:
epinephrine/
adrenaline-
adrenergic
receptor

Pupils Pupil dilates Pupil constricts

(mydriasis) (miosis)
Lacrimal tearing
glands
Salivary Thick, viscid Copious, watery
glands secretions saliva
Trachea bronchodilates- Bronchoconstrict
and β2 s,
Bronchiole inc. secretions
s (Lungs)
Heart Inc. HR/ Dec. HR/
tachycardia bradycardia
(chronotropic) Dec. contractility
Inc. contractility
(inotropic)- β1
Blood Skeletal
vessels muscle-
vasodilates
Skin, mucus
membrane,
GIT-
vasoconstricts
inc.
resistance HT
N-α1
GIT Dec. motility Inc. motility
constipation diarrhea
Bladder Bladder relaxes, Bladder
Sphincter contracts,
closes urinary sphincter
retention- α1 opens
urination
 - congestive heart failure
DOPAMINE RECEPTORS - renal failure to increase blood flow-
dopamine receptors- dilation of renal
vessels

Low dose : dopamine receptors

Moderate dose : β-receptors
High dose : α-receptors

Direct acting selective

Alpha agonists
α1- agonists
1. Phenylephrine (Neo-Synephrine, Dimetapp)
- nasal decongestant, shock, mydriatic
S/E: HTN

2. Phenylpropanolamine
(Neozep, Decolgen, Tuseran, Disudrin,
ANS DRUG CLASSIFICATION Sinutab), Pseudoephedrine (Sudafed)
1. Symphatomimetics - nasal decongestant
3. Methoxamine
2. Symphatolytics - hypotension
3. Parasyphatomimetics α2- agonists
4. Parasymphatolytics - clonidine (Catapres)
methyldopa (Aldomet)
- tx of HTN- dec. NE release
Adrenergic Agonists/
Beta agonists
Sympathomimetics a. β1 agonists
Phenylethylamine -dobutamine (Dobutrex)
- parent compound -congestive heart failure
- benzene + ethylamine S/E: tachycardia, arrhythmia
Cathecholamines b.β2 agonists
- contain OH at 3, 4 (catechol ring) - albuterol/ salbutamol (Ventolin)
- epinephrine, norepinephrine, Terbutaline (Bricanyl), metaproterenol
isoproterenol, dobutamine, dopamine - asthma
- maximal a, B activity - terbutaline- premature labor/ tocolytic –
- rapid inactivation by COMT in the dec. uterine contraction
intestines- cannot be given orally S/E: stimulates B1 at high doses:
- polar- poor CNS penetration palpitations, tremors
Non-cathecholamines c. β1 and β2 agonists
- absence of one or both OH in 3,4 - isoproterenol
- phenylephrine, ephedrine, amphetamine - cardiac arrest, asthma (rare)
- longer duration of action since it is not S/E: HTN, palpitations, arrhythmia
activated by COMT
- can be given orally Indirect-acting
- good CNS penetration - promotes NE release
1. Tyramine
C. Substitution on the alpha carbon - red wine, beer, cheese, chocolates
- methylation blocks oxidation by MAO - can cause HTN in patients taking MAO
- ephedrine, amphetamine inhibitors (depression)
- may promote NE release- indirect-acting
activity 2. Amphetamines
- attention deficit hypereactivity disorder
D. Substitutions on the beta carbon (ADHD), appetite suppression
- OH- direct-acting activity S/E: HTN, tachycardia, dependence,
insomnia, seizures psychosis
Direct acting Non- selective
- directly bind to the receptor Mixed = Direct and Indirect Agonists
α, β agonists 1. Ephedrine
a. epinephrine/ adrenaline - alkaloid from ma huang (Ephedra
- anaphylaxis (bronchodilator) sinica)
- cardiac arrest - urinary incontinence, bronchospasm,
- local anesthetics hypotension, nasal congestion,
eg. lidocaine (1:100,000)- prolongs narcolepsy
effect S/E: HTN, tachycardia, arrhythmia,
S/E: HTN, arrhythmia, MI, insomnia
pulmonary edema/hemorrhage 3. Metaraminol
b. Norepinephrine (Levophed) - hypotension
- shock/ hypotension-
inc. HR, contractility; vasoconstriction
inc. BP
c. Dopamine (Docard)
- shock/ hypotension
 - propranolol- migraine, stage fright,
hyperthyroidism
- timolol- glaucoma
- S/E: bradycardia, heart block,
bronchospasm in patients with
COPD/asthma
Brochoconstriction- contraindicated for
asthmatics
2. Selective blockers
- metoprolol, atenolol, esmolol,
acebutolol
- also blocks B2 receptors at high doses
4. Combined alpha and beta blockers
- Labetalol, carvedilol
5. With partial agonist activity/
intrinsic symphatomimetic activity
- Pindolol, acebutolol
- Cause some bronchodilation
- For treating patients with asthma

SYMPHATOLYTICS
Adrenergic antagonist/ blockers

Direct acting
- directly blocks receptors
Alpha-blockers PARASYMPHATOMIMETICS
1. α1 blockers
- prazosin, doxasozin, terazosin DIRECT-ACTING CHOLINERGIC AGONISTS
- HTN- dec. vasoconstriction-
dec. resistance dec. BP A. Choline esters
- benign prostatic hyperplasia-prevents - Ach hydrolyzed by Achase
urinary retention - Bethanechol, Carbachol are resistant
S/E: orthostatic hypotension especially to Achase; carbamic acid esters
after the first dose - β-methyl group in methacholine,
2. α2 blocker bethanechol reduces nicotinic activity
- yohimbine
- impotence- penile injection 1. Acetylcholine
3. α1, α2 blockers
a. phenoxybenzamine - no clinical use because of widespread
effects and rapidly hydrolyzed by
- irreversible, long-acting Achase
- HTN due to pheochromocytoma - S/E: DUMBELS
(adrenal medulla tumor epinephrine 2. Bethanechol (Urecholine)
release) - inc. intestinal motility after surgery
S/E: postural hypotension (bowel)
b. phentolamine - urinary retention (bladder)
- reversible, short-acting - “BBB”
- pheochromocytoma induced HTN -S/E: DUMBELS
S/E: postural hypotension 3. Carbachol
- glaucoma
Beta blockers 4. Methacholine
1. Nonselective blockers - diagnosis of asthma
- propranolol, timolol, nadolol B. Alkaloids
- used for HTN, post-MI, angina - pilocarpine, arecoline- tertiary amines; well
pectoris, SVT, absorbed
heart failure - muscarine- quaternary amine; less absorbed
1. Pilocarpine
- alkaloid from Pilocarpus sp.
- glaucoma- miosis, drains aqueous
humor
dec. ocular pressure
S/E: enter CNS- hallucinations,
seizures; DUMBELS
2. Arecoline
- from betel nut (Areca catechu)
3. Muscarine
- from mushroom Amanita muscaria
INDIRECT-ACTING CHOLINERGIC
AGONISTS / CHOLINESTERASE INHIBITORS
1. organic derivatives of phosphoric acid
(organophosphates)
2. carbamic acid esters of alcohols bearing
quaternary or tertiary ammonium groups
(carbamate insecticides, neostigmine,
physostigmine, pyridostigmine)
3. simple alcohols bearing a quaternary
ammonium group (edrophonium)
A. Organophosphates
- irreversibly inhibit Achase due to
covalent binding
- lipid soluble, well absorbed, good CNS
penetration except for echothiophate
(quaternary amine)
a. isofluorophate, echothiophate- glaucoma
b. malathion, parathion- pesticides; converted to
the active malaoxon, paraoxon
c. tabun, sarin, soman- chemical warfare/ ‘nerve
gas’
- S/E: DUMBELS
- Antidote:
1. pralidoxime- reactivates
Achase by removing OP; should
be given before Achase loses
one of its alkyl groups (aging)
2. atropine- anticholinergic/
muscarinic blocker
B. Carbamates
- physostigmine, insecticides- tertiary
amine; more lipid soluble; well absorbed
- neostigmine- quaternary amine; poorly
absorbed
1. Physostigmine
- aka eserine
- alkaloid from Calabar bean/ordeal
bean Physostigma venenosum
- intestinal and bowel atony, glaucoma
- antidote for anticholinergic poisoning-
atropine, phenothiazine, tricyclic
antidepressant
2. Neostigmine (Prostigmin)
– treatment of myasthenia gravis
(autoimmune- destroys nicotinic
receptors weakness, ptosis)
– antidote for tubocurarine poisoning-
neuromuscular/nicotinic blocker
4. Pyridostigmine (Mestinon)
- tx of myasthenia gravis
5. Carbamate insecticides
- carbaryl, methylcarbamate (Baygon)
C. Quaternary amine
1. Edrophonium (Tensilon)
- diagnosis of MG (Tensilon test-
inc. strength, dec. ptosis)
*Spider venom
- promotes release of acetylcholine
PARASYMPHATOLYTICS
CHOLINERGIC ANTAGONISTS/ BLOCKERS
1. Muscarinic blockers
- atropine, scopolamine- esters of tropic acid
and organic base tropine or scopine.
- scopine have an oxygen bridge between
carbon 6 and 7
- homatropine is a semisynthetic compound
produced by combining tropine with mandelic
acid
a. Atropine
- aka hyoscyamine
- prototype
- alkaloid from deadly nightshade
(Atropa belladonna) and jimsonweed
(Datura stramonium)
Belladonna/pretty lady- dilated pupils
effects: reverse of DUMBLS:
Constipation
Urinary retention
Mydriasis, paralysis of accommodation
(cycloplegia) blurring of vision
Bronchodilation, tachycardia
Dry mouth, dec. sweating
hallucinations
Mnemonics:
hallucinations- ‘mad as a hatter’
blurring of vision- ‘blind as a bat’,
glaucoma
dry mouth- ‘dry as a bone’
tachycardia, cutaneous vasodilation/
flushing- ‘red as a beet’
dec. sweating- ‘hot as hare’
Uses:
1. Ophthalmoscopic examination-
mydriasis (contraindicated for patients
with glaucoma)
2. Organophosphate poisoning
3. Bradycardia
S/E: constipation, urinary retention etc…
b. Scopolamine (Buscopan, Transderm-Scop)
- aka hyoscine
- alkaloid from henbane (Hyoscyamus
niger)
- prevent motion sickness- transdermal
patch
 -S/E: constipation, urinary retention…
c. Homatropine (Isopto Homatropine),
Cyclopentolate (Cyclogyl), Tropicamide Parasympathetic Ganglion blocked
(Mydriacyl) dominant
- ophthalmoscopic examination Heart- bradycardia Tachycardia
d. Ipratropium (Atrovent) Eye- miosis Mydriasis
- quaternary amine- more peripheral GIT- inc. motility Dec. motility
effect (lungs), Bladder- urination Retention
less CNS effects
- asthma
Sympathetic Ganglion blocked
e. Pirenzepine dominant
- peptic ulcer Arterioles- Vasodilation
vasoconstriction
f. Benztropine (Cogentin), Trihexyphenidyl Sweat glands- inc. Dec. sweating
(Artane), Biperiden (Akineton) sweating
- Parkinson’s disease
Other drugs that block muscarinic Botulinum toxin (BOTOX)
receptors: - from Clostridium botulinum
1. antihistamines - blocks release of acetylcholine
2. antipychotics - wrinkle treatment, blepharospasm,
3. tricyclic antidepressants
- ‘floppy baby’ syndrome- honey-fed
S/E: constipation, urinary retention etc…
infant
2. Neuromuscular blockers/ Skeletal Muscle
Relaxants
- block nicotinic receptors in muscles
paralysis
- resembles acetylcholine:
succinylcholine- 2 Ach
pancuronium- 2 Ach fragments
- 2 quaternary nitrogens- prevents entry
to the CNS
a. Nondepolarizing
- tubocurarine from Curare (Strychnos
sp.) used as arrow poison in South
America
- pancuronium, atracurium, vecuronium
- facilitates intubation for mechanical
ventilation, muscle relaxant during
surgery
- S/E: brochoconstriction, hypotension
due to histamine release; respiratory
paralysis
- Antidote: neostigmine
b. Depolarizing
- succinylcholine
- depolarizes (transient fasciculations)
repolarizes (flaccid paralysis)
- facilitates intubation for mechanical
ventilation, muscle relaxant during
surgery
- S/E: bronchoconstriction (due to
histamine release), hypotension,
respiratory depression, arrhythmia,
malignant hyperthermia (fever, muscle
rigidity)

Antidote: dantrolene-
Block Ca release dec. Muscle
contraction
3. Ganglionic blockers
a. Hexamethonium, mecamylamine,
trimethaphan
- block ganglia without prior stimulation
- hypertension- rarely used due to lack
of selectivity
b. Nicotine
- initially stimulate then block ganglia
- tobacco, cigarettes (Nicotiana
tabacum) dependence
- patch, gum (Nicorette), nasal spray-
smoking cessation, prevents nicotine
withdrawal
c. Lobeline
- from Indian tobacco (Lobelia inflata)