Autonomic Pharmacology Flashcards
1
Q
the autonomic NS (ANS) regulates…
A
ANS regulates visceral functions that occur w/out conscious control.
all visceral organs are innervated by ANS except skeletal muscles, being under the control of the somatic NS (SNS)
cardiovascular respiratory digestive urinary reproductive **key role in the body's response to stress
2
Q
the ANS originates from?
A
from the CNS (brain & SC)
3
Q
what are the 2 divisions of the ANS?
A
sympathetic and parasympathetic
based on the type of efferent nerves
4
Q
sympathetic vs. parasympathetic systems
A
constant opposition to each other
SYMPATHETIC:
allows body to function under stress
fight or flight
short neuron pathways- quick
PARASYMPATHETIC:
controls vegetative functions
main regulator of automatic functions
neuron pathways are much longer- slower system
5
Q
effects of stimulating the sympathetic system..
A
dilates pupils
inhibits salivation
relaxes bronchi
accelerates heart
inhibits digestive activity
stimulates glucose release by liver
secretion of epinephrine & norepinephrine form kidney
relaxes bladder
contracts rectum
6
Q
effects of stimulating the parasympathetic system…
A
constricts pupil
stimulates salivation
inhibits heart
constricts bronchi
stimulates digestive activity
stimulates gallbladder
contracts bladder
relaxes rectum
7
Q
anatomically the sympathetic fibers originate from?
A
the first thoracic to the second/third lumbar segments of the SC
8
Q
anatomically the parasympathetic fibers originate from?
A
the midbrain, medulla oblongata, and the sacral part of the SC
9
Q
what is autonomic ganglia?
A
specialized complex structures residing outside the SC that contain axodendritic synapses between pre-ganglionic and post-ganglionic neurons
10
Q
what is a neurotransmitter?
A
a chemical substance which travels across a synaptic junction to act on a target cell
11
Q
what are 2 types of neurotransmitters?
A
1- acetylcholine (Ach)
2- norepinephrine (NE)
12
Q
what is acetylcholine (Ach)?
A
the neurotransmitter in the autonomic ganglia (pre-ganglionic neurotransmitter) of both the sympathetic and parasympathetic divisions
the neurotransmitter at the neuro-effector junction (post-ganglionic neurotransmitter) of the parasympathetic system
13
Q
acetylcholine (Ach) is synthesized in the neurons from:
A
acetyl CoA and choline by choline actyltransferase
14
Q
acetylcholine (Ach) is broken down in:
A
the ganglionic junction or the neuro-effector junction by acetylcholine esterase
15
Q
what is norepinephrine (NE)?
A
the neurotransmitter at the neuro-effector junction (post-ganglionic neurotransmitter) of the sympathetic division
NE does not get broken down but rather is re-uptaken by the pre-synaptic fiber- a process mediated by pre-synaptic a2 receptors
16
Q
NE belongs to a group of endogenous chemicals called:
A
catecholamines
include dopamine and epinephrine
17
Q
SLIDE 9
A
???
18
Q
Ach’s effects are mediated through 2 subtypes of receptors:
A
1- muscarinic (M)
2- nicotinic (N)
19
Q
muscarinic (M) receptors are present in..
A
in the neuro-effector junction (post-ganglia) of the parasympathetic division
7 different receptors- if you stimulate 1 you automatically stimulate all the others
20
Q
nicotinic (N) receptors are present in..
A
the autonomic ganglia (pre-ganglia) of BOTH sympathetic and parasympathetic divisions of the ANS and in the neuromuscular junction
21
Q
NE and epinephrine’s effects are mediated by 2 receptor subtypes:
A
alpha and beta
22
Q
alpha receptors are either:
A
alpha1
or
alpha2
23
Q
alpha1 receptors are present in the:
A
arteriolar smooth muscles
24
Q
activation of a1 receptors leads to:
A
vasoconstriction
25
alpha2 receptors are found:
pre-ganglionically and in the CNS
26
activation of a2 receptors leads to:
decrease in the sympathetic flow from CNS
27
beta receptors are either:
beta1
or
beta2
28
beta1 receptors are found in:
the heart and kidney
29
activation of B1 receptors leads to:
increase HR (chronotropic), force of contraction (inotrophic), and release of renin from kidney (increases BP)
30
beta2 receptors are found in:
smooth muscles of blood vessels and bronchi
31
activation of B2 leads to:
vasodilation and bronchodilation
32
adrenergic impulses from the
sympathetic system
33
cholinergic impulses from the
parasympathetic system
34
adrenergic vs cholinergic impulses on effector organs
slides 13-18
35
parasympathomimetics:
mimic the effects of parasympathetic nerve stimulation
muscarinic receptor agonists
36
direct acting parasympathomimetics:
directly stimulates the muscarinic receptor
mechanism of action: stimulation of M receptors at the neuro-effector junction w/ no or little N receptor stimulation
ACh is not commonly used because it is hydrolyzed rapidly by plasma pseudocholine esterase (broken down right away in the blood)
ex: methacholine, carbachol, bethanchol, pilocarpine
37
4 therapeutic uses for muscarinic receptor agonists
1- GI disorders
bethanchol can be of value in post-op abdominal distention & gastric atony
2-urinary bladder disorders
muscarinic agonists can be useful in combating urinary retention & inadequate emptying of the bladder when organic obstruction is absent, as in post-op and postpartum urinary retention
3-Xerostomia
pilocarpine can be administered orally for the tx of dry mouth that follows head & neck radiation txs or that is associated w/ Sjorgen syndrome, an autoimmine disorder in women associated w/ dryness of lacrimal and salivary secretions are compromised
4-Opthalmological
pilocarpine is also used in tx of glaucoma, it is able to reverse an acute narrow angle glaucoma and overcoming mydriasis produced by atropine
38
what is ACh esterase?
the enzyme that breaks down ACh
39
Indirect-acting parasympathomimetrics
these agents do not stimulate the M receptors but prolong the duration of action of endogenous Ach by inhibiting ACh esterase- the enzyme that breaks down ACh
(prevents breakdown of acetylcoline by blocking th enzyme response)
40
reversible inhibitors of ACh esterase:
carbamates
physostigmine
neostigmine
pyridostigmine
41
therapeutic uses for indirect acting parasympathomimetics:
similar to direct acting agents
in addition, they are used in myasthenia gravis, and paralytic ileum
Donepezil (Aricept) is used to manage the dementia associated w/ Alzheimer disease
42
irreversible ACh esterase inhibitors include:
organophosphorous insecticides:
paraxon
malaoxon
nerve gas sarin
these agents have no therapeutic uses: intoxication symptoms can vary from increased secretions to tremors and respiratory collapse.
To counteract the effects of these agents, atropine (M receptor blocker) and pralidoxime (2-PAM) is usually given. 2-PAM salvages the ACh esterase before the binding of the organophosorous to the enzyme becomes permanent.
43
precautions, toxicity and contra-indications of muscarinic agonists:
serious toxic reactions to muscarinic agonists can be treated with ATROPINE SULFATE either subcutaneously or intravenously.
Epinephrine can also be of value in overcoming severe cardiovascular or bronchoconstrictor responses
44
mechanism of action of muscarinic receptor antagonists?
competitive blocking of muscarinic receptors at the neuro-effector sites on smooth muscle, cardiac muscle, gland cells, in the CNS with little blockade of the effects of ACh at nicotinic receptor sites
muscarinic receptor blockers show little or no selectivity towards the different muscarinic receptor subtypes (M1, M2, M3) with the exception of Pirenzepine that possess relative selectivity towards M1 receptors
45
muscarinic receptor antagonists pharmacological properties on cardiovascular system:
```
HEART:
increases HR (tachycardia) by blocking the vagal nerve effects on M2 receptors on the SA nodal pacemaker
```
BLOOD VESSELS:
when given alone, muscarinic receptor antagonists do not affect the vascular smooth muscle contractility due to the absence of parasympathetic control of the vascular system.
** but if choline esters are administered, muscarinic blockers can block vasodilation induced by choline esters effects on endothelial M3 receptors
46
muscarinic receptor antagonists pharmacological properties on the respiratory tract:
parasympathetic nerve stimulation plays a major role in regulating broncomotor tone. stimulation of M3 receptor causes bronchoconstriction.
muscarinic receptor blockers induce BRONCHODILATION.
futhermore, muscarinic blockers inhibit secretions of the nose, pharynx and bronchi- thus drying mucous membrane of the respiratory tract
47
muscarinic receptor antagonists pharmacological properties on the GI tract:
inhibit GI motility and secretions
inhibit gastric acid secretion induced by parasympathetic nerve stimulation
48
muscarinic receptor antagonists pharmacological properties on the urinary tract:
decreases the tone and amplitude of contractions of ureter and bladder
49
muscarinic receptor antagonists pharmacological properties on the sweat glands:
inhibition of sweating leading to skin becoming hot and dry
high doses may raise the body temperature in response to inhibition of sweating
50
muscarinic receptor antagonists pharmacological properties on the CNS:
effects on the CNS depend on the ability of the drug to cross the BBB
at higher than therapeutic doses, atropine causes central excitation, leading to restlessness, hallucinations, and delirium. This excitation is followed by CNS depression.
Scopolamine, in therapeutic doses, causes CNS depression manifested as drowsiness, amnesia, fatigue
51
muscarinic receptor antagonists pharmacological properties on the eye:
mydriasis- dilation of the pupil
cycloplegia- paralysis of the ciliary eye muscle
52
what is atropine?
medication used to decrease saliva and phlegm to control stomach/intestinal spasms.
works by blocking ACh
53
effects of 0.5mg of atropine
inhibition of sweating, some dryness of mouth
54
effects of 1mg of atropine
definite dryness of mouth, heart acceleration, mild pupil dilation
55
effects of 2 mg of atropine
rapid heart rate, palpitations, marked dilation of pupils
56
effects of 5 mg of atropine
all of the above symptoms +
| inhibition of parasympathetic control of GI, urinary bladder, inhibition of gastric secretions and motility
57
effects of >10mg of atropine
in addition to above symptoms,
| CNS involvement is evident: restlessness, excitement, hallucinations, delirium, coma
58
therapeutic uses for muscarinic receptor antagonists
Ipratropium bromide (atrovent):
a muscarinic receptor blocker devoid of CNS activity
principal use is a bronchodilator in chronic obstructive pulmonary disease (COPD) and to a lesser extent in asthma
homatropine, hydrobromide, cyclopentolate, tropicamide
These drugs are used as mydriatic agents necessary for thorough examination of retina and optic discs. These drugs are preferred over atropine because of the duration of action
overactive bladder
59
scopolamine (transderm scop) is?
owing to its ability to cross the BBB
has been used prophylactically to control motion sickness for durations up to 72 hours.
common side effects include:
dry mouth
loss of visual accommodation
60
what is atropine?
used as xerostomic in conditions of salivary hyper secretions
pre-operatively to reduce mucus membrane secretions
protect against reflex bradycardia
can be used as an antidote for mushroom poisoning
61
muscarinic receptor antagonists used for overactive bladder:
tolterodine tartrate (detrol): approved for symptoms associated with overactive bladder
fesoterodine fumarate (Toviaz): recently approved pro-drug for the tx of overactive bladder
62
parasympatholytics=
receptor antagonists
63
parasympathomimetics=
receptor agonists
64
side effects and toxicity of muscarinic receptor antagonists
```
dryness of mouth
urinary retention
anhydrosis- absence of sweat
tachycardia
palpitations
constipation
```
65
sympathomimetic agents
these drugs exert their effects via direct stimulation of the adrenergic receptors (a1, a2, B1, B2) leading to a widerange of pharmacological effects
66
endogenous sympathomimetric drugs include:
epinephrine (adrenaline)
norepinephrine (nonadrenaline)
dopamine
67
cardiac effects of epinephrine
through stimulation of B1 receptors, epinephrine has a positive chronotropic and positive inotropic effects
68
respiratory effects of epinephrine
through stimulation of B2 receptors, epinephrine has a potent bronchodilator effect (relaxation of bronchial smooth muscles)
69
epinephrine has a short duration of action because..
it is rapidly metabolized by enzymes
monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
70
routes of administering epinephrine:
epinephrine is not active when given orally because it is rapidly metabolized by enzymes
rapid intravenous injection of epinephrine may result in cerebral hemorrhage from the sharp rise in BP
```
other serious effects include:
tremors
palpitations
anxiety
restlessness
```
71
therapeutic uses for epinephrine?
provide rapid relief of hypersensitivity reactions including anaphylaxis to drugs and allergens
restore cardiac rhythm in patients with cardiac arrest due to various causes
72
epinephrine has a higher affinity for?
beta receptors
73
norepinephrine has a higher affinity for?
alpha receptors
specifically a1
74
pharmacological effects of norepinephrine?
NE is a more powerful activator of a1 receptors than epinephrine is, but a much weaker activator of B2 receptors.
therefore, NE increases BP more than epinephrine. The net effect of epinephrine on BP would be a balance between its a1 and B2 effects.
NE is not useful as a bronchodilator
75
therapeutic uses of epinephrine
can be titrated to the desired pressor effect in treatment of hypotension
76
route of administrating NE
NE is not active orally and is subject to the same metabolic pathways as that of epinephrine
77
what receptor does dopamine use? and what are the pharmacological effects of dopamine?
dopamine is in the synthetic pathway to NE and epinephrine. It is a central neurotransmitter and has the ability to act as an agonist on its own receptor- DOPAMINE RECEPTOR
at low doses, activation of D1 receptors in the renal, coronary, and mesenteric beds leads to VASODILATION
at higher doses, dopamine can stimulate cardiac B2 RECEPTORS leading to positive inotropic and chronotropic effects
78
therapeutic uses of dopamine?
used in treatment of severe CHF, particularly in patients with oligurea and with low or normal peripheral vascular resistance
79
what is CHF?
decreased CO that leads to fluid retention and an increase in peripheral resistance
80
how does dopamine act to treat CHF?
by dilating renal arteries (D1 vasodilates, B2 bronchodilates)--> increases renal profusion --> increase urine output --> alleviates the fluid retention problem in CHF
81
what are dopamine related drugs?
Fenoldopam (Corlopam, A synthetic D-1-selective agonist with no effect towards a or B receptors
indicated for short term management of severe HTN where rapid reduction of BP is clinically indicated
82
2 non-selective B agonists:
ISOPRETRENOL
isuprel
83
what is isoprotrenol?
a potent NON-SELECTIVE B AGONIST with no a agonist effects
cardiac effects include:
increased CO do to positive inotropic & chronotropic effects
dilation of muscle and mesenteric arteries
84
therapeutic uses for non-selective B agonists-Isoprotrenol
in emergencies to stimulate HR in patients with bradycardia or heart block
85
B2 selective agonists
higher preferential affinity towards B2 receptors with little or no effects on B1 receptors.
ex: treatment of asthma, B2 is ideal
this selectivity has been realized although at high doses of these drugs, the selectivity is lost!!
86
short-acting B2 agonists:
albuterol (venotolin)
terbutaline (Brethine)
these drugs have a rapid onset of action (15 min)
short duration of action (4-6 hours)
87
alpha adrenergic receptor agonists work by stimulating...
either a1 or a2 receptors
88
uses for a1 selective agonists
NASAL DECONGESTANTS: in patients with allergic rhinitis. The effect is through constriction of blood vessels in nasal tissues leading to decreased BF --> decreased fluid accumulation in nasal tissues
ex: Oxymetazoline (Afrin), Phenylephrine, Mephentermine
chronic use of nasal decongestants leads to loss of efficacy and worsening of congestion symptoms. This is due to RECEPTOR DESENSITIZATION
89
what is receptor desensitization?
chronic use leads to loss of efficacy and worsening of symptoms
90
a2 selective agonists?
Clonidine (Catapres)
this drug selectively stimulates a2 adrenergic receptor in the CNS. This effect results in a decrease in central sympathetic outflow (decreased norepinephrine -->decreased BP)
91
therapeutic uses of a2 selective agonists?
treatment of hypertension (a2 decreases NE; NE increases a1- increases HR and force)
92
miscellaneous adrenergic agonists
Amphetamine, dextroamphetamine (Dexedrine), methylphenidate (Ritalin)
Pharmalogical effects:
CNS stimulant effect: this effect is mediated by the ability of these drugs to release NE in the CNS
Uses: dextroamphetemine and methylphenidate are used in tx of ADHD
93
adrenergic receptor antagonists:
this class of drugs exhibit its effects via competitive blockade of a and/or B adrenergic receptors
94
alpha adrenoceptor blockers:
Phenoxybenzamine (Dibezyline)
irreversible blocker of a1 and a2 receptors with a slight selectivity towards a1 receptors
Used to treat pheocromocytoma
Phentolamine (regitine): non-selective reversible
Tolazoline (Priscoline): non-selective reversible
used in newborns to treat persistent pulmonary HTN
95
name 2 non-selective reversible alpha blockers
phentolamine (regitine)
tolazoline (priscoline)
96
what is phentolamine?
non-selective reversible alpha-blocker
used in the short term to control HTN in patients with pheocromocytoma (benign adrenal gland cancer that produces too many hormones- increases HR and BP)
97
a1 selective blockers examples:
Prazosin (Minipress)
Terazosin (Hytrin)
Doxazosin (Cardura)
98
pharmacological effects of a1 selective blockers:
blocking of a1 receptors in vascular smooth muscles of arterioles and veins
decreases peripheral resistance
tachycardia is less observed with these drugs compared to non-selective alpha blockers
99
2 adverse effects of a1 selective blockers:
1- First-dose phenomenon: marked postural hypotension and syncope observed 60-90 minutes after first dose
2- these drugs, owning to their vasodilating effect, can promote water retention
100
therapeutic uses of a1 selective blockers:
treatment of primary systemic hypertension
101
what is the effect on the heart from B adrenergic receptor blockers?
blocking of B1 receptors leads to slowing of HR and decreasing myocardial contractility
102
what is the effect on the pulmonary system from B adrenergic receptor blockers?
blocking of B2 receptors has little effects on pulmonary function in normal individuals.
In patients with asthma or COPD, this can lead to life-threatening bronchoconstriction
103
what is the effect on peripheral vascular resistance from B adrenergic receptor blockers?
blocking of B2 receptors in the arteriolar smooth muscle can lead to an increase in vascular resistance.
long term effect of B1 blocker use in HTN patients with high circulating renin levels is a reduction in peripheral vascular resistance
104
non-selective B blockers examples:
these drugs reversibly block B1 and B2 receptors with no selectivity towards either
ex:
PROPRANOLOL (Inderal)
Nadolol (Corgard)
Timolol (Blocadren)
Pindolol (Viskin) also has the ability to produce a partial stimulation of the B receptor
Labetalol (Normodyne) and Carvedilol (Coreg): also posses a1 blocking activity. The a1 blocking activity would lead to some degree of decreased peripheral resistance beneficial in tx of HTN
105
B1 selective blockers
at therapeutic doses show a higher selectivity towards B1 receptors more than B2
```
ex:
Metoprolol (Lopressor)
Atenolol (Tenormin)
Esmolol (Brevibloc)
Acebutolol: also some agonist properties
```
106
therapeutic uses for B1 selective blockers:
HTN
CHF
Angina and MI
107
adverse effects of B1 selective blockers:
in patients with AV conduction defects, B1 blockers may cause life threatening bradyarrhythmias
abrupt discontinuation of long term B1 blockers use in angina can exacerbate angina and may increase risk of sudden MI
B2 receptor blockade can worsen bronchoconstriction in asthmatic populations.
*B1 selective blockers or non-selective B blockers w/ partial B2 agonism produce less bronchoconstriction than non-selective B blockers.
108
what is clonidine?
alpha2 selective agonist
by means of CNS decreases NE--> decreases BP
109
what is succinylcholine?
the only depolarizing skeletal muscle relaxant. It blocks reach ACh from going to the receptor. It works on the neuromuscular junction therefore has no effect on cardiac or smooth muscle
110
increased renin leads to?
increased vasoconstriction --> increased BP
