Autonomic Pharmacology Flashcards
Autonomic Nervous System
Controls subconscious or unconscious functions such as peristalsis, temperature, and heart rate. Functions that are necessary for life to be sustained. Two branches: parasympathetic and sympathetic.
Parasympathetic system
Long presynaptic fibers, often synapse with postsynaptic neuron right in the target tissue. Do not synapse in the ganglia.
Parasympathetic primary neurotransmitter
ACH.
Sympathetic system
Synapse in the ganglion, shorter fibers. Long postsynaptic going to end organs.
Sympathetic primary neurotransmitter
NE. Can have ACH or Dopamine as well. ACH in the ganglion, NE in target tissue.
Modified pathway
Neuron from the spinal cord to the adrenal gland, will release Epi or NE “fight or flight” response.
Somatic system
Volunatry muscle control. Long fibers run from spinal cord to muscle tissue, synapses in the neuromuscular junction. ACH is primary.
Enteric nervous system
GI tract. Motor and secretory function. Esophagus through the colon.
Neurotransmitter chemistry
Neurotransmitters synthesized in the neuron that releases them. Quantities vary. Some neurotransmitter functions will increase or decrease the function or the target tissue/organ.
Cholinergic junction
Cholinergic synapse, small vesicles containing ACH. Choline brought into neuron by transporter, combined with acetyl-CoA through certain enzymes, synthesizes ACH to be stored in a vesicle. Neuron has ACH receptor that serves as negative feedback to stop releasing ACH, we do not recycle ACH.
“-ase’s”
Enzymes. Acetylcholinesterase metabolizes ACH, very quick metabolism in synapse.
Drug actions affecting ACH synthesis
We can block choline entering the neuron, decreasing ACH production. We can block transporters that take drugs into the vesicle, decreasing ACH. Calcium is needed to bind vesicle to the receptor to release ACH, botox interferes with calcium aspect.
Release of ACH
Dependent on extracellular calcium. Action potential reaches the terminal and triggers opening of calcium channels, allowing influx of calcium.
Cholinoceptors
7 types of ACH receptors. 5 Muscarinic, 2 Nicotinic.
M1 receptor
CNS neurons, sympathetic postganglionic neurons, some presynaptic sites
M2 receptor
Myocardium, smooth muscle, some presynaptic sites, CNS neurons
M3 receptor
Exocrine glands, vessels (smooth muscle and endothelium), CNS neurons
M4 receptor
CNS neurons, possibly vagal nerve endings
M5 receptor
Vascular endothelium, especially cerebral vessels, CNS neurons
Catecholamines
Neurotransmitters in sympathetic or adrenergic system. All come from tyrosine. Tyrosine transported into cell, tyrosine hydroxylase enzyme converts it to dopamine or NE (adrenal gland further metabolizes to Epi), transported into storage vesicle. Receptors on postsynaptic membrane and neuron, negative feedback.
Catecholamine metablism
REUPTAKE. NE is taken back into neuron and stored away, or MAO (lives in synapse) will metabolize NE, Epi, Dopamine.
Indirect sympathomimetics
Mimic sympathetic function. Displaces NE in synapse. Example: amphetamine gets taken up by storage vesicle, so NE is pushed out of synapse (cannot be stored) and will see increased effects.
Adrenoceptors
- 2 alpha, 3 beta.
NANC
Nonadrenergic, noncholinergic neurons. Autonomic effector tissue containing nerve fibers that have no adrenergic or cholinergic fibers. Both motor and sensory. Peptides are the most common transmitter substances. Poorly understood, most studied in Enteric NS.
Muscarinic agonists
Different ways they work. Either increase second messengers, or open ion channels.
Nicotonic agonists
Prolonged agonist receptor occupancy: Contraction in skeletal muscle due to opening of ion channels and depolarization. Not in cardiac muscle. Example: succinylcholine, paralyzes because it over stimulates the receptor until it can no longer respond.
Cholinergic agonists CNS effects
M1 receptors richly expressed in brain areas involving cognition.
Nicotine stimulates ACH receptors on dopamine-containing neurons: Mesolimbic system, reward system, pleasure/positive feedback. (Tobacco nicotine, highly lipid soluble, crosses BBB)
Indirect acting cholinomimetics
Mimic ACH activity in the body, do not stimulate the receptor. Some have direct actions at nicotine receptors. Block acetylcholinesterase.
“-mine’s”, donepezil, edrophonium. Irreversible: “-phate’s” echothiophate, organophosphates
Glaucoma
Aqueous humor is secreted by the epithelium of the ciliary body, flows into space in front of iris, exits via the canal of Schlemm.
Glaucoma: Iris circular muscle
contracts, m3
Glaucoma: Cilliary muscle
contracts, m3
Myasthenia Gravis
An autoimmune disease affecting skeletal muscle neuromuscular junctions. Autoantibodies against a1 at nicotinic receptor, bind to receptor and ACH cannot bind. Competitive receptor interaction. Ptosis, diplopia, difficulty speaking and swallowing, extremity weakness.
Diagnosis of MG
Edrophonium administered after baseline muscle strength measured, if no reaction occurs after 45 sedconds, an additional dose is given. If patient has MG, an improvement in muscle strength lasts about 5 minutes. Edrophonium inhibits metabolism of ACH, increasing activity.
Treatment of MG
Ocular may be treated with cholinesterase inhibitors alone. Pyridostigmine or neostigmine used for long term. Additional therapy of immunosuppresssants for widespread muscle weakness. Immunoglobulins, plasmapharesis and thymus removal for severe disease.
MG treatment side effects
Can have muscarinic side effects, treat with antimuscarinics (atropine). Bradycardia, diarrhea.
Donepezil
Reversible indirect-acting cholinomimetic. Used for dementia, mild to moderate Alzheimer’s.
Edrophonium
Reversible indirect-acting cholinomimetic. Diagnosis of MG, reversal of nondepolarizing neuromuscular blockade.
Neostigmine
Reversible indirect-acting cholinomimetic. Reversal of nondepolarizing neuromuscular blockade.
Oxybutynin
M1-4. First line for OAB. Also for bladder spasm after urologic surgery, reducing involuntary voiding in neuro disease.
Undergoes 1st pass metabolism. Metabolized by liver. 6% bioavailability. t1/2: IR 2 h, ER 13.2 +- 6.2 h.
Cross BBB more than other OAB drugs. Lipophilic, small, neutral.
Multiple forms.
Oxybutynin metabolite
DEO. N-desethyloxybutynin. Responsible for unwanted SE.
ER released slowly over 24h, decreasing first pass metabolism and DEO production. Transdermal patch further decrease DEO, decrease dry mouth, associated with local skin rash/pruritus.
Transdermal Oxybutinin
Up to 96 hours, steady state reached within 1 week. Significantly reduces urge incontinence, frequency.
Toletrodine
OAB. Tertiary-amine (BUT low lipophilic). Nonselective M1-3, 5. First pass metabolism, hepatic metabolism. 77% bioavailability. t1/2: 2-3 h.
Limited ability to cross BBB. Efficacy similar to oxybutynin, but less SE (dry mouth).
Trospium
OAB. Quaternary-amine, non selective. M1-5. First pass, RENAL excretion. (may be good for poly-pharmacy). 4-16% bioavailability. IR, ER.
60% excreted unchanged in the urine.
P-gp substrate, actively transported out of the brain
Fesoterodine
OAB. Tertiary-amine. Non selective. M1-3, 5. First pass metabolism, hepatic. 50% bioavailability.
Active metabolite 5-hydroxymethyl tolterodine. 70% RENAL excretion as active/inactive metabolites. CrCl <30 adjust dose. Fine for 30-80.
Low lipophilic, limited crossing BBB. P-gp substrate, transported out of brain
Darifenacin
OAB. Tertiary-amine. M3 SELECTIVE ANTAGONIST.
First pass, 15-20% bioavailability.
98% protein bound.
60% renal excretion, 3% unchanged.
High lipophilicity, substrate for P-gp out of brain.
Solifenacin
OAB. Quaternary-amine. Non-selective M2-3. First pass, hepatic. 90% bioavailability.
Active metabolite 4R-hydroxy solifenacin.
LONG HALF LIFE, longer in elderly. 45-68 hours.
Only 3-6% excreted unchanged renally.
Low lipophilicity, P-gp substrate.
