What is the peripheral nervous system?
1. Everything but the brain
2. Includes the AUTONOMIC NS and SOMATIC NS
Autonomic Nervous System
- 1) Cardiac and smooth muscle contraction
- 2) Glandular secretion
- 1) Sympathtic NS
- 2) Parasympathetic NS
- --> These two generally oppose each other
Sympathetic Nervous System
1) Catabolic (Expends energy)
3) When under stress, SNS predominates diverting energy to functions supporting "fight or flight"
4) > tissue oxygenation and cardiac output
- 2) > HR, dilates bronchi, decreases secretions
- "Speed up"
What are the major neurotransmitters in the sympathetic NS?
1) Dopamine --> Norepinephrine
2) epiniphrine (adrenaline)
Parasympathetic Nervous System
1) Anabolic (conserves energy)
- 2) < HR, stimulates GI function
- "Slow Down" or "Poke Along"
3) When in a resting state, PNS predominates
4) Relative slowing of heart rate, adequate secretions, normal gut motility
What are the major neurotransmitters in the parasympathetic NS?
How is the autonomic NS pathway organized?
2 neurons: presynaptic and postsynaptic
extend from the brain to autonomic ganglia where they transmit NS signals to postsynaptic neurons by releasing acetylcholine into the synaptic cleft
transmit impulses to end organs (heart, gut, etc.) by releasing norepinephrine (NE) from sympathetic neurons or acetylcholine (ACh) from parasympathetic neurons
What is the mechanism by which impulses are transmitted in the sympathetic division?
NE and EPI (epinephrine) transmit most impulses of the SNS
On release from the presynaptic neurons, NE diffuses across the synaptic cleft and binds to postsynaptic adrenergic receptors ( a1, a2, β1, β2 )
a1 receptor location?**
- 1) arterioles
- 2) veins
- 3) glands
- 4) eye
- 5) intestine
- 6) myocardium
a1 receptor effects when stimulated?**
- 1) vasoconstriction
- 2) decreased glandular secretion
- 3) constriction of radial muscle
- 4) decreased motility
a2 receptor location?**
- 1) CNS post and postynaptic terminals
- 2) Beta islet cells in the pancreas
- 3) larger vessels
- 4) skin
- 5) mucosa
- 6) kidney
a2 receptor effects when stimulated?**
- 1) Decreased sympathetic outflow from brain
- 2) Decreased NE release
- 3) Decreased islet cell secretion
β1 receptor location?**
Heart: myocardial tissue and electrical conduction system
β1 receptor effects when stimulated?**
- 1) > HR
- + chronotropicity = increased HR
- - chronotropicity = decreased HR
- 2) > contractility (force of contraction)
- + ionotropicity = increased cardiac output, strength of contraction
- - Beta blockers can give cardiac effects)
- 3) > conduction velocity
- 4) > automaticity (ability to beat on its own)
β2 receptor location?**
- 1) Trachea
- 2) Bronchioles
- 3) Bronchi
- 4) Uterus
- 5) Arterioles (except brain and skin)
- 6) Veins
- 7) Vascular smooth muscle
- 8) Liver
β2 receptor effects when stimulated?**
- 1) tracheal/bronchial relaxation
- 2) uterine relaxation
- 3) circulatory dilation
During times of stress, the adrenal gland releases ___ and where? What is the action?
EPI directly into the blood
Like NE, circulating EPI is an agonist at adrenergic (sympathetic) receptors (A1, A2, B1, B2) --ALL receptors
What is the mechanism by which impulses are transmitted in the parasympathetic division?
ACh transmits all parasympathetic signals to end organs such as the heart and lungs by binding to muscarinic receptors.
What does ACh do? (what type of impulses and where)
1) Transmits both sympathetic and parasympathetic impulses from preganglionic neurons in brain and spinal cord to nicotinic ganglionic receptors on postganglioninc neurons of ANS
2) occurs in sympathetic ganglia in the spinal cord and parasympathetic ganglia near end organs
All ganglionic transmission is ______? Drugs which block ganglionic transmission does what?**
- Drugs which block ganglionic transmission inhibits either sympathetic or parasympathetic signals, depending on which system is predominant at the moment
When ACh is released from neurons, what is its mechanism of action?
Causes muscle contraction by binding to nicotinic receptors on muscle cells, causing Ca++ influx
Can ACh be considered as a neurotransmitter?
Yes, acts as a nt in the brain
Acts predominantly via muscarinic receptors
How is NE synthesized? What broad category of nt is NE under?
- NE is a catecholamine
1) Synthesized from TYROSINE
2) Tyrosine hydroxylated to dopa --> decarboxylated to dopamine in presynaptic neurons
3) Dopamine diffuses into synaptic vesicles --> hydroxylated into NE
4) When a nerve is stimulated --> Ca++ enters the presynaptic neuron --> vesicles fuse with plasma membrane and release NE into synaptic cleft
NE can bind with what kind of receptors?**
a1, B1, B2 adrenergic receptors
- Direct sympathomimetic drugs such as EPI can bind to to these receptors as well, w/o interacting with the presynaptic neuron
a2 adrenergic receptors on presynaptic neurons, when stimulated by NE, will inhibit subsequent NE release from the terminal
Catechol-o-methyl transferase (COM-T) does what?
COM-T degrades catecholamines such as NE
More commonly NE is transported back into the presynaptic neuron where it is restored or degraded by mitochondrial monoamine oxidase (MAO)
What is an indirect sympathomimetic?
Drugs that work by entering the presynaptic terminal and displacing NE
1) Choline acetyltransferase catalyzes the acetylation of choline by acetyl CoA to form ACh
2) ACh is stored in storage vesicles
3) When a nerve is stimulated, the action potential travels down the neuron and causes Ca++ influx into the nerve terminal. This causes vesicles to fuse with the plasma membrane and release ACh. ACh diffuses through the synaptic cleft and may bind to nicotinic receptors on muscle cells, nicotinic receptors on ganglionic synapses of the ANS, or on muscarinic receptors
4) ACh is cleared from the synaptic cleft by active reuptake. ACh breakdown products are recycled into ACh.
What are adrenergic receptors?**
- autonomic receptors
- 1) Alpha receptors
- 2) Beta receptors
Note: Dopaminergic receptors are located mainly in the renal and mesenteric vasculature. Stimulating dopaminergic receptors can lead to different responses based on degree of stimulation
(For CV medications)
- present in the neurons in the vascular smooth tissue
- a1 receptors are found in the myocardium
- a2 receptors are found in larger blood vessels (skin, mucosa, gut, kidney)
- stimulation leads to arteriolar VASOCONSTRICTION
(For CV medications)
- 1) B1 receptors
- - located in myocardial tissue and in the cardiac conduction system
- - Stimulation results in increased cardiac contractility and heart rate
- 2) B2 receptors
- - located in vascular smooth muscle tissue, bronchi, and liver
- - stimulation leads to coronary and peripheral VASODILATION and BRONCHODILATION
What are muscarinic receptors?
- a cholinergic receptor
- mediate postganglionic parasympathetic and CNS functions of ACh
- can be M1, M2, or M3
- a muscarinic receptor
- - Organs:
- stomache, ganglion, CNS
- - Cholinergic Action:
- increase acid/pepsin secretion, stimulate ganglia, facilitate neurotransmission
- a muscarinic receptor
- - Organs:
- heart, lung, stomach, bladder
- - Cholinergic Actions:
- slows heart rate, decreases contractility and conduction velocity, causes bronchoconstriction, increases secretions, increases GI motility, relaxes sphincter (both urinary and fecal)
- a muscarinic receptor
- - Cholinergic Actions:
- increases glandular secretions. In the eye, causes miosis and accommodation
Nicotinic Receptors (won't be tested)
located in the ganglia and at the neuromuscular junction
N1: contraction of skeletal muscle
N2: stimulation of ganglia
N3: neurotransmission in CNS
Mechanisms by which autonomic activities are increased?
1) Direct receptor stimulation
- 2) Promotion of neurotransmitter release
- - stimulate postganglionic fibers, for example with nicotine
- - promote NE release, for example with amphetamines
- 3) Inhibition of neuronal neurotransmitter uptake
- -inhibit uptake of NE, for example with cocaine
- 4) Inhibition of neurotransmitter biotransformation
- - inhibit biotransformation of NE, eeg with phenelzine
- - Inhibit biotransformation of SCh with pyridostigmine
Mechanisms by which autonomic activities are decreased?
- 1) Ganglionic receptor blockade, eg with mecamylamine
- -Transmission to cholinergic and adrenergic postganglionic fibers will be inhibted --> RARE (won't be tested)
- 2) Neurotransmitter synthesis inhibition
- 3) Inhibition of neurotransmitter release
- - eg botulinum toxin, which inhibits ACh release
- 4) Inhibition of neurotransmitter storage-inhibit reuptake of NE into vesicles, eg with reserpine (rarely used)
- 5) Peripheral Receptor Blockade
- - Can be Adrenergic or Cholinergic (details on other slides)
Adrenergic Peripheral receptor blockade
- a mechanism by which autonomic activities are decreased
phenoxybenzamine, a1 - specific blockers such as prazosin and terazosin are available
- β: beta adrenergic blockers such as propranolol and timolol
- - β1 specific agents include metoprolol (Lopressor), esmolol, atenolol, betaxolol, etc are available.
- - at high doses, β1 selectivity can be lost and some β2 effects can be seen
Cholinergic Peripheral receptor blockade
- Muscarinic: atropine
- Nicotinic: atracurium, vecuronium and other similar neuromuscular blocking agents, and mecamylamine for severe hypertension
Cholinergic stimulants are called ______.
Cholinergic blocking agents are called ______.
stimulates: PARASYMPATHOMIMETIC AGENTS
blocking: PARASYMPATHOLYTIC AGENTS
Autonomic Nicotinic Receptors
1) Endogenous ACh
- 2) Nicotine
- -used in decreasing amounts to overcome nicotine additcion. Adverse effects can include HTN. Nicotine overdose can result in respiratory arrest (due to ganglionic blockade) and seizures
Muscarinic Receptors - Parasympathomimetic
- Parasympathomimetic (stimulant)
- - Direct Stimulants:
- 1) ACh
- 2) Pilocarpine
- 3) Carbachol
- - Cholinesterase Inhibitor:
- 1) Pyridostigmine
- 2) Ectothiophate
Muscarinic Receptor: ACh
- - used as a surgical miotic agent
- - ADEs are rare but can cause complications in patients with PUD (peptic ulcer disease) (secondary to increase in acid/pepsin secretion), bronchial asthma, hyperthryroidism, Parkinson's disease, etc.
Muscarinic Receptor: Pilocarpine
- used for treating open angle glaucoma, causes miosis and changes aqueous outflow
- common ADEs in the eye include local irritation/conjunctivitis, burning, ciliary spasm, lacrimation, etc.
- Caution in patients with Parkinson's dz, asthma, PUD, hyperthyroidism, abnormal blood pressure, epilepsy, tachycardia
- usual dose for glaucoma is 1-2 drops up to 6 times a day, depending on concentration of solution use
Muscarinic Receptor: Carbachol
- used as a surgical miotic agent and for open angle glaucoma (lowers IOP)
- usual dose for glaucoma is 1-2 drops up to three times a day
- ADEs similar to pilocarpine
not really Rx'd but on NBEO
Muscarinic Receptor: Pyridostigmine
- used for myasthenia gravis and reversal of non-depolarizing muscle relaxants
- available in PO, IM, IV dosage forms
(prob not on test)
Muscarinic receptor: Echothiophate
- Used for treatment of open-angle glaucoma
- Occasionally used for accommodative esotropia in children
- Possible ADEs include miosis, excessive salivation, rhinorrhea, Nausea/Vomiting/Diarrhea, convulsions, respiratory depression
- Effects of the drug can be reversed with atropine or pralidoxime (2-PAM)
Autonomic Nicotinic receptors
- 1) Mecamylamine
- - used for control of moderately severe to severe HTN
- - not commonly used
- - Potential ADEs can include urinary retention, cycloplegia, xerostomia, orthostatic hypotension
(Prob won't ask, never see this dispensed)
Muscarinic Receptors - Parasympatholytic
Other medications in this class include oxybutinin, flavoxate, tolterodine, trihexyphenidyl, benztropine, etc.
Muscarinic Receptor: Atropine**
- Produces mydriasis and cyclopegia for examintion of the retina and optic disc, refraction
- used for amblyopia, to treat anterior uveitis, and decrease secretions pre-operatively
- also used in the treatment of GI spasms, symptomaitc bradycardia, pulseless electrical activity in the heart and asystole
- used also in the treatment of organophosphate poisoning/overdose of cholinergic stimulants
- ADEs can include excessive mydriasis,cycloplegia, facial flushing, xerostomia (dry mouth), confusion (irritation, delerium), urinary retention, tachycardia.
- Contraindicated in narrow angle glaucoma
Muscarinic Receptos: Scopolamine
- Produces cyclopegia and mydriasis
- used transdermally to prevent N/V associated with motion sickness
- potential ADEs include xerotomia, confusion/disorientation, increased body temperature, facial flushing, urinary retention, tachycardia
- contraindicated in narrow angle glaucoma
Muscarinic Receptor: Homatropine
- used as a cycloplegic/mydriatic agent for refraction, also for treatment of acute inflammatory conditions of the uveal tract
- ADEs can include blurred vision, photophobia, local irritation, increased IOP
Adrenergic stimulants are called ___________. Adrenergic blockers are called ___________.
stimulant: SYMPATHOMIMETIC DRUGS
Sympathomimetic drugs acting on α1 adrenergic receptors
- 1) Phenylephrine**
- - used for eye exams
- - includes mydriasis but not cycloplegia
- - also used to produce mydirasis prior to ocular surgery
- - Non-Rx strength available to relieve redness of the eye, but should not be used for longer than a 72 hour period
- - caution if used within 21 days of an MAO-inhibitor
- - many potential ADEs including increases in blood pressure, headache, dizziness, etc.
- 2) Pseudoephedrine
- - see respiratory section
Sympathomimetic drugs acting on α2 adrenergic receptors
meds include those used for their ability to inhibit NE release in the CNS (ie clonidine, guanfacine and guanabenz) and those agents used for local vasoconstrictive effects (ie naphazoline and oxymetazolone)
- also reviewed in the cardiac section and opiate withdrawal
Sympathomimetic drugs acting non-selectively on α adrenergic receptors
key example: norepinephrine (see cardiac section)
Sympathomimetic drugs acting on β1 adrenergic receptors
this group includes pressor agents such as dobutamine, dopamine, (and norepinephrine).
- see cardiac section
Sympathomimetic drugs acting β2 adrenergic receptors
this group includes albuterol and terbutaline, and will be reviewed in the respiratory section
Sympathomimetic drugs acting non-selectively on β adrenergic receptors
Doesn't matter if β1 or β2
a key example is isoproterenol, which will be reviewed in cardiac section (won't ask, it is rare)
Sympathomimetic drugs acting non-selectively on all adrenergic receptors
epinephrine and ephedrine are key examples
reviewed in the cardiac section
Sympathomimetic indirect acting agents
1) Amphetamines (facilitate NE release)
2) Cocaine (prevents NE uptake)
3) Tricyclic antidepressants (prevent NE reuptake, see Psych section)
4) Monoamine oxidase (MAO) Inhibitors (Prevent NE biotransformation)
Sympatholytic drugs acting on α1 adrenergic receptors
prazocin and terazocin
- see HTN section
Sympatholytic drugs acting on α2 adrenergic receptors
None currently in use!
Sympatholytic drugs acting non-selectively on α adrenergic receptors
key example: phentolamine
discussed in the cardiac section as an epinephrine reversal agent
Sympatholytic drugs acting on β1 adrenergic receptors
the "beta blockers" that are "cardioselective" such as atenolol
will be reviewed in the HTN/cardiac sections
Sympatholytic drugs acting on β2 adrenergic receptors
none currently in use
Sympatholytic drugs acting non-selectively on β adrenergic receptors
the "beta blockers" that are "non-cardioselective" such as propranolol
Will be reviewed in HTN/cardiac sections
Propylthiouracil (PTU) and Methimazole
Mechanism of Action: Inhibits synthesis of thyroid hormone within the thyroid gland
Adverse Effects: Fever, blood dyscrasias, skin rash/itch, arthralgia (joint pain), peripheral neuropathy, dizziness, loss of taste, N/V, stomach pain, renal and hepatic complications, etc.
Admin/PK: (won't ask bc we don't Rx) Usually given in divided doses every 8 hours. Doses will be lowered in elderly patients in PTU.
Comments: No specific ocular side effects reported, but watch for bleeding episodes. Many possible DD interactions
- Mechanism of Action: Supplemental thyroxine (T4)
- - T4 is converted in the PERIPHERAL TISSUES to T3 (Tri-iodothyronine)
usually dose related. Chest pain, diarrhea, leg cramps, apetitc changes, fast/irregular heart rate, termor, headache, irritiability, insomnia, change in sensitivity to heat, etc.
- Admin/PK: Slow increasein dosage helps to prevent adverse effects
- - Dosage will be reduced for elderly patients
: Preferred agent to use in the treatment of hypothyroidism. Effects more predictable because of standard hormone content. Effects of therapy may not be evident for months
What factors are involved in good blood glucose control vs loss of control?
- 1) Diet
- 2) Exercise
- 3) Drugs
+ Basic state of health/other stressors
Insulins: MOA, Uses, ADE, DD Interactions
MOA: Hormone that controls the storage and metabolism of carbohydrates, proteins, and fats. Substitutes for endogenous insulin in patients with Type I DM.
Uses: Type 1 DM, possible Type 2 DM
ADE: Hypoglycemia, weight gain, and (rarely) edema and lipohypertrophy
Possible Drug Interactions: Ethanol (increases potential for hypoglycemia), Beta adrenergic blocking agents--including opthalmic formulations (may modify carbohydrate metabolism and lead to hyperglycemia, but may also cause hypoglycemia and block physiologic responses to hypoglycemia). Corticosteroids antagonize insulin effects
Rapid Acting Insulin includes:**
- 1) Insulin Aspart*
- 2) Insulin Lispro*
- 3) Insulin Glulisine*
- 4) Regular
(They are very short acting)
Intermediate-acting Insulin includes:**
Long-acting Insulin includes:**
- 1) Insulin Glargine
- 2) Insulin Detemir
Mixtures of intermediate/short acting insulin includes:
- 1) Humulin 70/30
- 2) Novolin 70/30
Mixtures of intermediate/rapid acting insulin includes:
- 1) Humalog Mix 75/25
- 2) Novolog 70/30
The only insulin that can be givne intravenously is...
no insulin should ever be given IM
Type 2 Diabetes
- MOA: Sulfonylurea agent
- - stimulates acute release of insulin from functional Beta cells
- - may increase insulin sensitivity in target cells
Hypoglycemia, weight gain, hepatic and renal complications, blood dyscrasias, GI disturbances, headache, increased cardiac risk in those with CV disease
- Admin/PK: Patient monitored for hepatic and renal function
- - doses are reduced in elderly patients
- Comments: ocular side effects include blurred vision and changes in accommodation
- - best effect as monotherapy is approx. 1.5% reduction in A1c
- - D:D interaction with some SOP meds
Type 2 Diabetes
inhibits breakdown of complex starches to glucose, slows absorption of glucose into the bloodstream
- ADE: Flatulence, diarrhea, abdominal pain.
- - Should not cause hypoglycemia when used as monotherapy
- - if occurs, treat with oral glucose instead of table sugar (sucrose)
caution is used when the drug is administered with other meds that lower blood glucose due to increased risk of hypoglycemia
- Comments: Best effect as an adjunct is approx 0.5-0.8% recution in A1c.
- - Not used as montherapy
- Renal function should be monitored in MIGLITOL
Type 2 diabetes
potentiates the effect of endogenous insulin. May work by decreasing hepatic glucose production and improving insulin sensitivity
N/V/D, flatulence, rash, weakness, HA, hypoglycemia, lactic acidosis, myalgia, blood dyscrasias, chest discomfort, etc.
Caution is used when the drug is administered with other meds that lower blood glucose due to increased risk of hypoglycemia.
- Comments: renal function should be monitored. The drug may be discontinued in renal dysfunction.
- - Medication is held before surgeries and use of contrast media.
- - Best effect is 1-2% reduction in A1c
- - D:D interactions with some SOP meds (ie Trimethoprim and oral fluoroquinolones)