Drug Listing: Autonomic Pharmacology
* Direct Muscarinic Agonists
o Choline Esters
o Alkaloids
* Direct Nicotinic Agonist
* Acetylcholinesterase Inhibitor (Reversible)
* Acetylcholinesterase Inhibitor (Irreversible)
* Muscarinic Antagonist
* 2-PAM
* Ganglionic Blockers
* Catecholamines
* Direct Adrenoceptor Agonists
* Indirect-Acting Sympathomimetics
* Alpha adrenoceptor Antagonists
* Beta-adrenoceptor Antagonists
* Adrenergic Neuron Blocking Drugs
Direct Muscarinic Agonists
Choline Esters
* Acetylcholine
* Bethanechol (Urecholine)
* Carbachol
* Methacholine (Provocholine)
Alkaloids
* Muscarine
* Pilocarpine (Pilocar)
Direct Nicotinic Agonist
Nicotine
Acetylcholinesterase Inhibitors
Acetylcholinesterase Inhibitors ("Reversible")
* Neostigmine (Prostigmin)
* Physostigmine (Antilirium)
* Edrophonium (Tensilon)
Acetylcholinesterase Inhibitors ("Irreversible")
* Soman
* Parathion
* Malathion
* Isoflurophate (Floropryl)
* (Diisopropylflurorphosphate DFP)
* Echothiophate (Phospholine)
Muscarinic Antagonists
* Atropine
* Scopolamine
* Ipratropium (Atrovent)
* Pirenzepine (M1 selective)
2-PAM: Acetylcholinesterase Reactivator
* Pralidoxime (Protopam) {2-PAM}:peripheral acetylcholinesterase reactivator for certain phosphoryl-enzyme complexes
Ganglionic Blockers
* Mecamylamine (Inversine)
* Hexamethonium
* Trimethaphan
Catecholamines
DRUG
Epinephrine
Norepinephrine (Levophed)
Isoproterenol (Isuprel)
Dobutamine (Dobutrex)
Dopamine (Intropin)
Receptor Classification
alpha-1, alpha-2, beta-1, beta-2
alpha-1, alpha-2, beta-1
beta-1, beta-2
beta-1 (alpha-1)
D-1 (alpha-1 and beta-1 at high doses)
Direct Adrenoceptor Agonists
Drug
Phenylephrine (Neo-Synephrine)
Methoxamine (Vasoxyl)
Oxymetazoline (Afrin)
Clonidine (Catapres)
Ritodrine (Yutopar)
Terbutaline (Brethine)
Albuterol (Ventolin,Proventil)
Salmeterol (Serevent)
Receptor Classification
alpha-1
alpha-1
alpha-1, alpha-2
alpha-2
beta-2
beta-2
beta-2
beta-2
Indirect-Acting Sympathomimetics
Drug
Ephedrine, Pseudoephedrine
Cocaine
Tyramine
Amphetamine
Mechanism of Action
Release & direct receptor activation
Uptake I inhibitor
Release
similar to ephedrine, but greater CNS actions
Alpha-Adrenoceptor Antagonists
Drug
Prazosin (Minipress)
Terazosin (Hytrin)
Trimazosin
Doxazosin (Cardura)
Phentolamine (Regitine)
Phenoxybenzamine (Dibenzyline)
Tolazoline (Priscoline)
Labetalol (Trandate, Normodyne)
Yohimbine (Yocon)
Receptor Selectivity(alpha1 vs. alpha2)
alpha-1
alpha-1
alpha-1
alpha-1
non-selective
only slightly selective for alpha-1 (non-competitive)
non-selective
alpha-1 (also non-selective beta-antagonist)
alpha-2
ß-Adrenoceptor antagonists
Drug
Propranolol (Inderal)
Metoprolol (Lopressor)
Esmolol (Brevibloc)
Atenolol (Tenormin)
Nadolol (Corgard)
Timolol (Blocadren)
Pindolol (Visken)
Labetalol (Trandate, Normodyne)
Butoxamine
Receptor Selectivity
non-selective
beta-1
beta-1
beta-1
non-selective
non-selective
non-selective (partial agonist)
non-selective (selective alpha-1-antagonist)
beta-2 (no clinical applications)
Adrenergic Neuron Blocking Drugs
Reserpine
Guanethidine (Ismelin)
* non-selective blockade of vesicular uptake and storage of biogenic amines
* similar to reserpine: Uptake I dependent
Return to top Menu
Sunday, August 30, 2009
DOBUTAMINE
More about dobutamine
*
Dobutamine is a racemate; the (+) isomer produces the beta-1 effect (positive-chronotropic), but minimal cardioacceleration occurs because the (-) isomer is an alpha agonist, which tends to prevent the chronotropic effect (cardioacceleration)
*
The result is that cardiac output is increased with minimal increase in heart rate.
*
Dobutamine is a racemate; the (+) isomer produces the beta-1 effect (positive-chronotropic), but minimal cardioacceleration occurs because the (-) isomer is an alpha agonist, which tends to prevent the chronotropic effect (cardioacceleration)
*
The result is that cardiac output is increased with minimal increase in heart rate.
Saturday, August 29, 2009
CATACHOLAMINE SYNTHESIS
Catecholamine Synthetic Pathway
Adrenergic Neurotransmission: Introduction to the Neurotransmitters
Norepinephrine: transmitter released at most postganglionic sympathetic terminals
Dopamine: major CNS neurotransmitter of mammalian extrapyramidal system and some mesocortical and mesolimbic neurononal pathways.
Epinephrine: most important hormone of the adrenal medulla
Catecholamine Synthesis, Storage, and Release
Aromatic L-amino acid decarboxylase (DOPA decarboxylase)
dopa leads to dopamine
methyldopa leads to a-methyldopamine (converted by dopamine ß hydroxylase to the "false transmitter" alpha-norepinephrine)
5-hydroxy-L-tryptophanleads to5-hydroxytryptamine (5-HT)
Tyrosine Hydroxylase
tyrosine leads to DOPA
rate limiting step in pathway
tyrosine hydroxylase is a substrate for cAMP-dependent and Ca2+ - calmodulin-sensitive protein kinase and protein kinase C
Increased hydroxylase activity is associated with the phosphorylated enzyme
Adrenergic Neurotransmission: Introduction to the Neurotransmitters
Norepinephrine: transmitter released at most postganglionic sympathetic terminals
Dopamine: major CNS neurotransmitter of mammalian extrapyramidal system and some mesocortical and mesolimbic neurononal pathways.
Epinephrine: most important hormone of the adrenal medulla
Catecholamine Synthesis, Storage, and Release
Aromatic L-amino acid decarboxylase (DOPA decarboxylase)
dopa leads to dopamine
methyldopa leads to a-methyldopamine (converted by dopamine ß hydroxylase to the "false transmitter" alpha-norepinephrine)
5-hydroxy-L-tryptophanleads to5-hydroxytryptamine (5-HT)
Tyrosine Hydroxylase
tyrosine leads to DOPA
rate limiting step in pathway
tyrosine hydroxylase is a substrate for cAMP-dependent and Ca2+ - calmodulin-sensitive protein kinase and protein kinase C
Increased hydroxylase activity is associated with the phosphorylated enzyme
SITES OF CHOLINERGIC ACTION
Cholinergic Transmission: Site Differences
Skeletal Muscle
Neurotransmitter: Acetylcholine
Receptor Type: Nicotinic
Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:
an enhanced post-synaptic responsiveness, denervation hypersensitivity.
Denervation hypersensivity in skeletal muscle is due to
increased expression of nicotinic cholinergic receptors
and their spread to regions aways from the endplate.
Autonomic Effectors
Neurotransmitter: Acetylcholine
Receptor type: Muscarinic
effector coupled to receptor by a G protein
In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.
Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.
Acetylcholine decreases heart rate by decreases SA nodal pacemaker phase 4 depolarization.
The cardiac action potential associated with HIS-purkinje fibers or ventricular muscle consists of five phases
Phase 0 corresponds to Na+ channel activation.
The maximum upstroke slope of phase 0 is proportional to the sodium current.
Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.
Phase 1 corresponds to an early repolarizing K+ current. This current like the Phase 0 sodium current is rapidly inactivated.
Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by an outward, repolarizing K+ current (delayed rectifier).
Phase 3 is also the combination of Ca2+ and K+ currents.
Phase 3 is repolarizing because the outward (repolarizing) K+ current increases while the inward (depolarizing) Ca2+ current is decreasing.
Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current. As a result, the membrane potential would normally be flat.
In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold. This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrthymogenesis.
Rate of phase 4 depolarization is decreased by an increase in K+ conductance--which leads to membrane hyperpolarization (takes longer to reach threshold)
Autonomic Ganglia
Neurotransmitter: Acetylcholine
Receptor type: Nicotinic
Generally similar to skeletal muscle site: initial depolarization is due to receptor activation. The receptor is a ligand-gated channel.
Blood vessels
Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).
In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.
Signal Transduction
Nicotinic Receptors
Ligand-gated ion channels
Agonist effects blocked by tubocurarine
Receptor activation results in:
rapid increases of Na+ and Ca2+ conductance
deplorization
excitation
Subtypes based on differing subunit composition: Muscle and Neuronal Classification
Muscarinic Receptors
G-protein coupled receptor system
Slower responses
Agonist effects blocked by atropine
At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities
Skeletal Muscle
Neurotransmitter: Acetylcholine
Receptor Type: Nicotinic
Sectioning and degeneration of motor and post-ganglionic nerve fibers results in:
an enhanced post-synaptic responsiveness, denervation hypersensitivity.
Denervation hypersensivity in skeletal muscle is due to
increased expression of nicotinic cholinergic receptors
and their spread to regions aways from the endplate.
Autonomic Effectors
Neurotransmitter: Acetylcholine
Receptor type: Muscarinic
effector coupled to receptor by a G protein
In smooth muscle and in the cardiac conduction system, intrinsic electrical activity and mechanism activity is present, modifiable by autonomic tone.
Activities include propagated slow waves of depolarization: Examples: intestinal motility and spontaneous depolarizations of cardiac SA nodal pacemakers.
Acetylcholine decreases heart rate by decreases SA nodal pacemaker phase 4 depolarization.
The cardiac action potential associated with HIS-purkinje fibers or ventricular muscle consists of five phases
Phase 0 corresponds to Na+ channel activation.
The maximum upstroke slope of phase 0 is proportional to the sodium current.
Phase 0 slope is related to the conduction velocity in that the more rapid the rate of depolarization the greater the rate of impulse propagation.
Phase 1 corresponds to an early repolarizing K+ current. This current like the Phase 0 sodium current is rapidly inactivated.
Phase 2 is the combination of an inward, depolarizing Ca2+ current balanced by an outward, repolarizing K+ current (delayed rectifier).
Phase 3 is also the combination of Ca2+ and K+ currents.
Phase 3 is repolarizing because the outward (repolarizing) K+ current increases while the inward (depolarizing) Ca2+ current is decreasing.
Phase 4 in normal His-Purkinje and ventricular muscle cells is characterized by a balance between outward Na+ current and inward K+ current. As a result, the membrane potential would normally be flat.
In disease states or for other cell types (SA nodal cells) the membrane potential drifts towards threshold. This phenomenon of spontaneous depolarization is termed automaticity and has an important role in arrthymogenesis.
Rate of phase 4 depolarization is decreased by an increase in K+ conductance--which leads to membrane hyperpolarization (takes longer to reach threshold)
Autonomic Ganglia
Neurotransmitter: Acetylcholine
Receptor type: Nicotinic
Generally similar to skeletal muscle site: initial depolarization is due to receptor activation. The receptor is a ligand-gated channel.
Blood vessels
Choline ester administration results in blood vessel dilatation as a result of effects on prejunctional inhibitory synapses of sympathetic fibers and inhibitory cholinergic (non-innervated receptors).
In isolated blood vessel preparations, acetycholine's vasodilator effects are mediated by activation of muscarinic receptors which cause release of nitric oxide, which produces relaxation.
Signal Transduction
Nicotinic Receptors
Ligand-gated ion channels
Agonist effects blocked by tubocurarine
Receptor activation results in:
rapid increases of Na+ and Ca2+ conductance
deplorization
excitation
Subtypes based on differing subunit composition: Muscle and Neuronal Classification
Muscarinic Receptors
G-protein coupled receptor system
Slower responses
Agonist effects blocked by atropine
At least five receptor subtypes have been described by molecular cloning. Variants have distinct anatomical locations and differing molecular specificities
CHOLINERGIC TRANSMISSION
Cholinergic Neurotransmission
Transmitter Synthesis and Degradation
Acetylcholine is synthesized from the immediate precursors acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase (choline acetylase).
Acetylcholinesterase
Rapid inactivation of acetylcholine is mediated by acetylcholinesterase.
Acetylcholinesterase is present at ganglia, visceral neuroeffector junctions, and neuromuscular junctional endplates.
Another type of cholinesterase, called pseudo-cholinesterase or butyrylcholinesterase has limited presence in neurons, but is present in glia. Most pseudocholinesterase activity is found in plasma and liver.
Pharmacological effects of anti-cholinesterase drugs are due to inhibition of acetylcholinesterase.
Acetylcholine Storage and Release
Small random release of acetylcholine-quanta, producing miniature end-plate potentials (mepps) , are released by presynaptic terminals.
These small currents were linked to ACh release since anticholinesterases (neostigmine) increased their effects, while cholinergic receptor antagonist (tubocurarine, a nicotinic receptor blocker) blocked.
Anatomical counterpart to the electrophysiological quanta is the synaptic vesicle.
The model is based on the nicotinic, skeletal neuromusclar junction.
Synchronous exocytotic release of many more quanta, dependent on Ca2+ occur when an action potential reaches the terminal.
Exocytotic release of acetylcholine and other neurotransmitters is inhibited by toxins elaborated by Clostridium botulinum.
Botulism
Botulism is caused by the most potent neurotoxins known. The neurotoxins are produced and liberated by Clostridium botulinum.
C. botulinum, ubiquitously found in soil and marine environments, is a group of gram positive anerobes that form spores.
Eight distinct toxins have been characterized, all but one being neurotoxic.
Botulinum neurotoxin affects cholinergic nerve terminals:
postganglionic parasympathetic endings
neuromuscular junctions
peripheral ganglia
CNS is not involved.
Botulinum neurotoxin prevents acetylcholine release:
binds presynaptically
internalized in vesicular form
released into the cytoplasm
the toxin(s), (zinc endopeptidases) causes proteolysis of components of the neuroexocytosis system.
Transmitter Synthesis and Degradation
Acetylcholine is synthesized from the immediate precursors acetyl coenzyme A and choline in a reaction catalyzed by choline acetyltransferase (choline acetylase).
Acetylcholinesterase
Rapid inactivation of acetylcholine is mediated by acetylcholinesterase.
Acetylcholinesterase is present at ganglia, visceral neuroeffector junctions, and neuromuscular junctional endplates.
Another type of cholinesterase, called pseudo-cholinesterase or butyrylcholinesterase has limited presence in neurons, but is present in glia. Most pseudocholinesterase activity is found in plasma and liver.
Pharmacological effects of anti-cholinesterase drugs are due to inhibition of acetylcholinesterase.
Acetylcholine Storage and Release
Small random release of acetylcholine-quanta, producing miniature end-plate potentials (mepps) , are released by presynaptic terminals.
These small currents were linked to ACh release since anticholinesterases (neostigmine) increased their effects, while cholinergic receptor antagonist (tubocurarine, a nicotinic receptor blocker) blocked.
Anatomical counterpart to the electrophysiological quanta is the synaptic vesicle.
The model is based on the nicotinic, skeletal neuromusclar junction.
Synchronous exocytotic release of many more quanta, dependent on Ca2+ occur when an action potential reaches the terminal.
Exocytotic release of acetylcholine and other neurotransmitters is inhibited by toxins elaborated by Clostridium botulinum.
Botulism
Botulism is caused by the most potent neurotoxins known. The neurotoxins are produced and liberated by Clostridium botulinum.
C. botulinum, ubiquitously found in soil and marine environments, is a group of gram positive anerobes that form spores.
Eight distinct toxins have been characterized, all but one being neurotoxic.
Botulinum neurotoxin affects cholinergic nerve terminals:
postganglionic parasympathetic endings
neuromuscular junctions
peripheral ganglia
CNS is not involved.
Botulinum neurotoxin prevents acetylcholine release:
binds presynaptically
internalized in vesicular form
released into the cytoplasm
the toxin(s), (zinc endopeptidases) causes proteolysis of components of the neuroexocytosis system.
function of ans
Fight or Flight: General Functions of the Autonomic Nervous System
ANS regulates organs/processes not under conscious control including:
circulation
digestion
respiration
temperature
sweating
metabolism
some endocrine gland secretions
Sympathetic system is most active when the body needs to react to changes in the internal or external environment: The requirement for sympathetic activity is most critical for:
temperature regulation
regulation of glucose levels
rapid vascular response to hemorrhage
reacting to oxygen deficiency
During rage or fright the sympathetic system can discharge as a unit--affecting multiorgan systems.
Sympathetic fibers show greater ramification.
Sympathetic preganglionic fibers may traverse through many ganglia before terminiating at its post-ganglionic cell. Synaptic terminal arborization results in a single preganglionic fiber terminating on many post-ganglionic cells.
This anatomical characteristic is the basis for the diffuse nature of sympathic response in the human and other species.
Sympathetic Responses
heart rate increases
blood pressure increases
blood is shunted to skeletal muscles
blood glucose increase
bronchioles dilate
pupils dilate
Parasympathetic responses
slows heart rate
protects retina from excessive light
lowers blood pressure
empties the bowel and bladder
increases gastrointestinal motility
promotes absorption of nutrients
ANS regulates organs/processes not under conscious control including:
circulation
digestion
respiration
temperature
sweating
metabolism
some endocrine gland secretions
Sympathetic system is most active when the body needs to react to changes in the internal or external environment: The requirement for sympathetic activity is most critical for:
temperature regulation
regulation of glucose levels
rapid vascular response to hemorrhage
reacting to oxygen deficiency
During rage or fright the sympathetic system can discharge as a unit--affecting multiorgan systems.
Sympathetic fibers show greater ramification.
Sympathetic preganglionic fibers may traverse through many ganglia before terminiating at its post-ganglionic cell. Synaptic terminal arborization results in a single preganglionic fiber terminating on many post-ganglionic cells.
This anatomical characteristic is the basis for the diffuse nature of sympathic response in the human and other species.
Sympathetic Responses
heart rate increases
blood pressure increases
blood is shunted to skeletal muscles
blood glucose increase
bronchioles dilate
pupils dilate
Parasympathetic responses
slows heart rate
protects retina from excessive light
lowers blood pressure
empties the bowel and bladder
increases gastrointestinal motility
promotes absorption of nutrients
parasympathetic nervous system
Comparisons between Sympathetic and Parasympathetic Nerves
Sympathetic system has a broader distribution, innervating effectors throughout the body
Sympathetic fibers show greater ramification.
Sympathetic preganglionic fibers may traverse through many ganglia before terminiating at its post-ganglionic cell.
Synaptic terminal arborization results in a single preganglionic fiber terminating on many post-ganglionic cells.
This anatomical characteristic is the basis for the diffuse nature of sympathic response in the human and other species.
Parasympathetic system is relatively limited
The parasympathetic system has its terminal ganglia near the end-organ.
Sometimes there is but a one-to-one ratio relationship between pre-and post-ganglionic fibers. The ratio between preganglionic vagal fibers and ganglion cells may be much higher, e.g. 1:8000 for Auerbach's plexus
Sympathetic system has a broader distribution, innervating effectors throughout the body
Sympathetic fibers show greater ramification.
Sympathetic preganglionic fibers may traverse through many ganglia before terminiating at its post-ganglionic cell.
Synaptic terminal arborization results in a single preganglionic fiber terminating on many post-ganglionic cells.
This anatomical characteristic is the basis for the diffuse nature of sympathic response in the human and other species.
Parasympathetic system is relatively limited
The parasympathetic system has its terminal ganglia near the end-organ.
Sometimes there is but a one-to-one ratio relationship between pre-and post-ganglionic fibers. The ratio between preganglionic vagal fibers and ganglion cells may be much higher, e.g. 1:8000 for Auerbach's plexus
Subscribe to:
Posts (Atom)