1. Pharmacology of the
Autonomic Nervous System
Part 2
Dr. Sakhile Ndlalane
Levy Mwanawasa teaching Hospital
Lusaka
Zambia
1
2. Recommended Background Reading :
Chapters 7, 8, 9, and 10
Basic and Clinical Pharmacology
Bertram Katzung
(13th Edition)
2
3. Learning Objectives:
1) List and describe the mechanism of action, therapeutic
indications, and adverse effects of cholinergic agonists and
cholinesterase inhibitors.
2) List and describe the mechanism of action, therapeutic
indications, and adverse effects of muscarinic and nicotinic
receptor antagonists.
3) List and describe the mechanism of action, therapeutic
indications, and adverse effects of direct, indirect, and
mixed acting adrenergic agonists.
4) List and describe the mechanism of action, therapeutic
indications, and adverse effects of adrenergic and -
adrenergic blocking agents.
3
5. PARASYMPATHOMIMETICS
(CHOLINOMIMETICS):
Drugs that facilitate or mimic some or all of the actions of
the parasympathetic nervous system.
Muscarinic
receptor
agonists
Anticholinesterases
5
Reversible
Indirect Acting
Irreversible
Direct Acting
Nicotinic
receptor
agonists
6. 6
Direct Acting Cholinergic
Agonists
• Acetylcholine *not used therapeutically – N/M
• Carbachol * (Miostat) – N/M
• Bethanechol * (Urecholine) – M
• Pilocarpine (Pilocar, Ocusert) – M
• Indications – Urinary retention after surgery or postpartum,
Glaucoma
• Adverse effects –
– Muscarinic (M): salivation, flushing, bronchospasm,
sweating, nausea, abdominal pain – acid indigestion and GI
cramping, diarrhea, and possibly, decreased blood
pressure.
– Nicotinic (N)- Fasciculations, respiratory arrest
12. PARASYMPATHOLYTICS
(ANTICHOLINERGICS):
Drugs that reduce or inhibit some or all of the actions of
the parasympathetic nervous system.
Muscarinic
receptor
antagonists
Ganglionic
blocking drugs
(Nn) 12
Neuromuscular
blocking drugs
(Nm)
Nicotinic
receptor
antagonists
13. 13
Parasympatholytics
Muscarinic receptor antagonists
• MOA- Block muscarinic receptors on the effector
organs of the parasympathetic nervous system and on
the sweat glands
• Indications – Varied - specificity for muscarinic
receptors is a key reason behind their usefulness.
• Adverse effects –
– Autonomic
• PNS - dry mouth, blurred vision, tachycardia,
urinary retention, and constipation
• SAS - Inhibition of sweating
– CNS - restlessness, confusion, and hallucinations
• Common mnemonic : “hot as a hare, blind as a bat, dry
as a bone, red as a beet, and mad as a hatter"
18. Raymond Ahlquist (1948) on
Adrenergic receptor function
• “Alpha receptors are excitatory
everywhere but the gut”
• “Beta receptors are inhibitory everywhere
but the heart”
18
19. 19
Adrenergic Agonists
• Catecholamines - Name is based on their
chemical structure (hydroxyl groups at the 3 and
4 position of a benzene ring):
– High potency - activate both alpha and beta receptors
– Rapid inactivation - Destroyed by COMT (Catechol O-
methyltransferase) and by MAO (Monoamine oxidase)
which are both located at the neuron and in the gut
wall. Catecholamines are not effective when given
orally
– Poor CNS penetration - They are polar but they still
may cause some CNS effects
– 5 catecholamines - epinephrine, norepinephrine,
dopamine, dobutamine, and isoproterenol
21. 25
Adrenergic agonists Cont.
• Non-catecholamines -
– Not destroyed by COMT and MAO
deactivation is limited, so they have longer
half lives
– Better CNS penetration due to increased lipid
solubility
22. SYMPATHOMIMETICS:
Drugs that facilitate or mimic some or all of the
actions of the sympathetic nervous system.
26
Indirect Acting
Direct Acting
Drugs that
facilitate NE
release
α-adrenergic
agonists
β-adrenergic
agonists
Drugs that
block NE
uptake
Mixed Acting
Both Direct
and Indirect
Actions
Drugs that inhibit
enzymatic breakdown
of NE
23. Mechanism of action of adrenergic
agonists
• Direct-Acting Agonists - Mimic NE and EPI. They bind to the
adrenergic receptors without interacting with the prejunctional
neuron.
• (EPI, NE, ISO and Phenylephrine)
• Indirect-Acting Agonists:
• Displace norepinephrine from storage sites
(Amphetamine, hydroxyamphetamine, and tyramine)
• Block the uptake of norepinephrine at storage sites
(Cocaine, Tricylic Antidepressants, SNRI)
• Inhibit enzymatic breakdown of norepinephrine
(Monoamine Oxidase Inhibitors, i.e., phenelzine)
• Mixed-action agonists - Both stimulate receptors and
displace NE from storage sites.
• (Ephedrine, pseudoephedrine)
32. Adverse Effects:
1) Anxiety* reaction (hypertension,
tachycardia, sweating & paranoia)
2) Depression
3) Agitation*
4) Cardiac Arrhythmias
5) Seizures*
6) Incidence of MI unrelated to dose, duration
of use or route of administration (no marker)
* Can be treated with Benzodiazepines-Diazepam
Cocaine
33. SYMPATHOLYTICS:
Drugs that reduce or inhibit some or all of the
actions of the sympathetic nervous system.
β-adrenergic
antagonists
Adrenergic
neuronal
blocking drugs
Ganglionic
blocking drugs
α-adrenergic
antagonists
34. 38
Adrenergic Neuronal Blocking
Drug
• Reserpine – Discontinued in US
• MOA: Prevents uptake of biogenic amines (DA,
NE, EPI, 5HT) in both central and peripheral
neurons (also adrenal chromaffin granules)
Results in Biogenic amine depletion - denervation
• Indications : Hypertension .
• Adverse effects – Diarrhea, cramps, GI acid
secretion, postural hypotension, bradycardia,
sexual dysfunction, sedation, depression (suicide).
• Caution for Supersensitivity with Chronic use.
35. 39
Nonselective Alpha Adrenergic
Blocking Agents
• Phentolaminea (Regitine)
– reversible and competitive
• Phenoxybenzamineb (Dibenzyline)
– irreversible and non-competitive
• MOA – block both Alpha1 and Alpha2
• Indications : Diagnosisa and Treatmentb of
Pheochromocytoma
• Adverse effects – Orthostatic hypotension,
exaggerated reflex tachycardia (why), nasal
stuffiness, ejaculatory dysfunction
37. 41
Alpha-1 Selective Adrenergic
Blocking Agents
• Adverse effects :
• First Dose Effect - Exaggerated hypotension
that can lead to syncope especially when
patient stands after sitting or lying down
(orthostatic hypotension)
– less reflex tachycardia (why)
– sodium and water retention (prazosin) (limits
use in high blood pressure)
– nasal stuffiness
– ejaculatory dysfunction
38. 42
Beta Adrenergic Blocking
Agents
• Propranolol a (Inderal)
• Timolol a (Timoptic)
• Nadolol a (Corgard)
• Atenolol b (Tenormin)
• Metoprolol b (Lopressor)
• Esmolol b (Brevibloc)
• MOA :
a Nonselective - both beta-1 and 2
b “Cardioselective” Beta-1 specific
39. 43
Beta Blockers Indications cont.
• Indications :
– Prevention of migraines - May prevent catecholamine
vasodilation in the brain vasculature (Beta-2?)
– Hyperthyroidism – Thyroid storm
– Glaucoma – (Timolol)
– Arrhythmias, Angina pectoris, Myocardial Infarction, Heart
failure – Protective effect against sympathetic
overstimulation – improved survival !!
• Adverse reactions – Bradycardia, Heart block, Heart
failure, Raynaud’s (peripheral vasospasm), Vivid dreams,
depression, Bronchoconstriction in asthmatics/COPD, Sexual
dysfunction, Decreased glycogenolysis and glucagon
secretion
• Caution for Withdrawal Supersensitivity with Chronic use
40. 44
Alpha and Beta Adrenergic
Blocking Agents
• Labetalol a(Trandate, Normodyne)
• Carvedilol b(Coreg)
• MOA – block both Alpha1 and Beta Adrenoceptors.
– Result in peripheral vasodilation that lowers
blood pressure with reduced cardiac rate and
contraction
• Indications : Hypertension a and Congestive heart
failure b
• Adverse effects – Combines BOTH Alpha and
Beta adrenoceptor blocker adverse effects.
44. 48
Control of Blood Pressure
CF VR
mABP = CO x TPR
HR SV
Cardiac -
Chronotropy
Venous – Preload
Arterial - Afterload
Cardiac - Inotropy
Editor's Notes
* Quaternary ammonium compounds
** N = Nicotinic, M = Muscarinic
*Quaternary ammonium compounds
** MOA – Mechanism of actino
* Quaternary ammonium compounds
a Rivastigmine, but not its competitors, inhibits both acetylcholinesterase and butyrylcholinesterase by covalently binding to active sites on these enzymes, blocking their function. Breaking of these covalent bonds is the first and most important step in the degradation of rivastigmine, which is not metabolized in the liver
Quaternary ammonium compounds
**Competitive blocker - action can be reversed by increasing concentration of acetylcholine with cholinesterase inhibitors (edrophonium, neostigmine, and pyridostigmine)
Epi – Methylated NE
NE – lose the amino CH3
Dopamine – lose the Beta hydroxy from NE
ISO – Add isopropyl group on Nitrogen
Amphetamine – phenylisopropylamine
Epi – Methylated NE
NE – lose the amino CH3
Dopamine – lose the Beta hydroxy from NE
ISO – Add isopropyl group on Nitrogen
Amphetamine – phenylisopropylamine
Epi – Methylated NE
NE – lose the amino CH3
Dopamine – lose the Beta hydroxy from NE
ISO – Add isopropyl group on Nitrogen
Amphetamine – phenylisopropylamine
Epi – Methylated NE
NE – lose the amino CH3
Dopamine – lose the Beta hydroxy from NE
ISO – Add isopropyl group on Nitrogen
Amphetamine – phenylisopropylamine
Epi – Methylated NE
NE – lose the amino CH3
Dopamine – lose the Beta hydroxy from NE
ISO – Add isopropyl group on Nitrogen
Amphetamine – phenylisopropylamine
