Exam 1: ANS Drugs Flashcards
1
Q
SNS neurons (location and length)
A
o Preganglionic thoracolumbar (short) o Postganglionic (long)
2
Q
PSNS
A
o “around the SNS” above/below the thoracolumbar area - Cranial/sacral areas o Preganglionic (long) o Postganglionic (short)
3
Q
key characteristics of ANS
A
o Regulates involuntary response—sm m, glands, heart
o 2-neuron pathways
o Diffuse vs. Discrete responses
o Dual Innervation–Opposing, antagonistic effects
Will see reflex response that will oppose your drugs given
o Reflex responses
o Predominant, basal activity/control
Basal activity = which system controls that tissue at the basal level (mostly PSNS)
4
Q
exceptions to dual innervation
A
• Exceptions to Dual Innervation
o Adrenal Medulla
Sympathetic only
o Most sweat glands
Sympathetic only
o Blood vessels
Sympathetic only
• But have cholinergic RECEPTORS on blood vessels (no PSNS innervation to the blood vessels)
Basal tone – some vasoconstriction (SNS basal tone)
Receptor distribution determines response
• Vessels in skeletal m, heart
o beta2 mediated vasodilation
o need more blood flow during fight or flight
• Vessels in skin, viscera
o alpha1 mediated vasoconstriction
o Most _______ in the body (missed this factoid)
• EPI stimulates both
other: piloerector muscle
5
Q
unique glands: adrenal medulla
A
Sympathetic innervation Only 1 neuron Postsynaptic neuroendocrine cells Secrete Epi/norepi into blood Mimics sympathetic stimulation
6
Q
unique glands: sweat glands
A
Sympathetic innervation
Post-ganglionic neuron is cholinergic (not adrenergic)
Acetylcholine is NT
Receptor at effector tissue is muscarinic (a cholinergic receptor)
7
Q
nicotinic cholinergic receptor
A
o Ligand-gated, Na+ , K+ depolarizing channel
o 2 major subtypes
-NicN
-NicM
o Location -Autonomic ganglia -Skel muscle innervated by somatic n -CNS o ACh binds → Conformational changes; Channel opens and+ chgd ions pulled thru channel o Depolarization of post-synaptic cell
8
Q
M1, M4, M5 receptor location
A
CNS
9
Q
M2 receptor location
A
heart
10
Q
M3 receptor location
A
SEEG.
Also M1 = CNS, M2 = heart, so M3 = everything else!
smooth muscle, glands, endothelium, eye (circular, ciliary muscle)
11
Q
Nic N receptor location
A
ANS ganglia (all of them), adrenal medulla, CNS
12
Q
Nic M receptor location
A
skeletal muscle NMJ
13
Q
3 subtypes of alpha adrenergic receptors
A
a1 - smooth muscle, eye
o a1 → excitatory - ^Ca++ → calmodulin activation → ^ actin-myosin interaction → sm muscle contraction (VSMC contr)
a2 - mainly presynaptic
o a2 → inhibitory - decrease cAMP → decrease norepinephrine release
-Eg. Clonidine is agonist for this receptor
ligands: NE, EPI, DA (in large doses)
14
Q
beta adrenergic receptors
A
o β1 β2 β3
o GPCR, Gs
o Activation of adenyl cyclase → ^ cAMP → ^ kinase activation & phosphorylation
o Autonomic effector tissues
-heart, kidney, liver, smooth m, skel m; fat cells, B3
-receptor subtypes will cluster at certain tissues
15
Q
a1 adrenergic receptor locations
A
alpha 1 - SEV
- Smooth muscle: G-U sphincters (esp. bladder)
- Most vascular (skin, splanchnic)
- Eye –radial m
- Heart, liver
16
Q
a2 adrenergic receptor locations
A
(inhibitory)
- Pre-synaptic nerve terminal Platelets, pancreatic beta cell
17
Q
B1 adrenergic receptor locations
A
- Heart
- Kidney - juxtaglomerular cells Renin release *ppl usually forget this one
“you beta know that the heart and the kidney think they’re the most important 1”
18
Q
B2 adrenergic receptor locations
A
Smooth m: bronchiolar, uterine, etc. Vascular sm muscle: Skel m beds Liver Skeletal muscle Heart (albuterol)
19
Q
B3 adrenergic receptor locations
A
adipose tissue
20
Q
adrenergic receptors -general info
A
o Adrenergic Receptors:
GPCR (different signal transduction pathways)
Alpha2 – inhibitory
NT: Norepinephrine
Other Ligands include -Epi, DA
**Tip about smooth muscle receptors: alpha1 contracts; beta2 relaxes
**Tip about beta receptors: 1 heart, 2 lungs
o Heart’s main receptor is B1, but has some B2
21
Q
NE in the peripheral NS
A
o Roles in peripheral and CNS (excitatory) o Catecholamine NT aka noradrenaline o Termination of action reuptake back into presynaptic neuron diffusion Metabolism – minor role • Monoamine oxidase (MAO) • COMT
22
Q
DA in the peripheral NS
A
o Roles in peripheral and CNS o Catecholamine NT Precursor of norepi, epi At effector jxn –sympathetic, renal vascular sm m o Termination of action neuronal reuptake by DA transporter MAO breakdown (remember that MAO breaks down DA also) • MAO-A – periphery • MAO-B – CNS • COMT – minor role
23
Q
DA receptor
A
GPCR, cAMP 2nd messenger
D1 class (D1 , D5 ) - ^ cAMP
D2 class (D2 , D3 , D4 ) - decrease cAMP
o Periphery
D1 – Vasodilation in renal, mesenteric, coronary vasculature
D2 – presynaptic; modulates NT release
24
Q
DA drug effects (low, intermediate, high dose)
A
- Low dose – vasodilation (D1 ) in renal, mesenteric, and coronary vascular beds
- Intermediate - + inotrope (B1 )
- High dose – vasoconstriction (a1)
Uses: shock, HF, increase blood flow to kidneys
25
- Other Transmitters in autonomic, enteric, and NANC neurons
```
o Neurotransmitter and/or Co-transmitters in PNS – many postganglionic parasympathetic neurons utilize other transmitters, including
Nitric Oxide (NO)
Vasoactive intestinal peptide (VIP)
Calcitonin Gene Related Peptide (CGRP)
Neuropeptide Y (NPY)
Substance P
Serotonin
Others
```
26
Nitro-based vasodilators, PDE5 inhibitors, combined effect
o Nitro-based vasodilators
Isosorbide
NO
NTG
Nitroprusside
(NTG and nitroprusside act in the same way)
o PDE5: phosphodiesterase 5; the enzyme that breaks down the 2nd messenger (cGMP)
-sildenafil/Viagra
-tadalafil/Cialis
o Nitro-based vasodilators + PDE5 inhibitor → pronounced vasodilation →
DEATH
27
ACh vs. other cholinergic agonists
o Ach
- Quaternary ammonium
- Short duration
- Less therapeutic value
- Both Nic & Musc activity
o Other drugs
- ↑ muscarinic selectivity
- Lack acetate ester fxn
- AChE does not hydrolyze
28
Reversible AChE Inhibitor Drugs
- Alcohol: edrophonium, short duration
- Carbamate
• neostigmine (quaternary) - medium-duration
• also pyridostigmine, physostigmine, & donepezil
-Enzyme active site is carbamylated (when its stuck on there, the ACh cannot bind)
• can be insecticides as well
29
Irreversible AChE Inhibitor Drugs
organophosphates; long duration
- Echothiophate
- Think covalent bond to the enzyme, NONcompetitive
requires synthesis of new AChE to overcome
30
AChE inhibitor drug effects
o Autonomic
- ↑ secretions (salivary, lacrimal, bronchial, GI)
- ↑ GI motility
- Bronchoconstriction
- Bradycardia
- Hypotension
- Miosis; accommodation for near vision
o Neuromuscular junction
- Reverses NM block by nondepolarizing blocker
- Improves transmission – myasthenia gravis
- Large doses—depolarizing block
```
o CNS (if it can get into the CNS system)
-Therapeutic – dementia tx/Alzheimer’s
-Toxicity
• Excitation (possible convulsion)
• Depression follows (unconsciousness)
```
31
Toxicity mnemonic: Cholinergic crisis “DuMBBELLS”
```
o Diarrhea, Diaphoresis
o Urination
o Miosis
o Bradycardia
o Bronchoconstriction
o Excitation (skel m; CNS)* + Emesis
o Lacrimation
o Salivation Sweating
o *paralysis of skel m/depression of CNS follows initial excitation
```
o Examples - pesticide, Sarin nerve gas
o Muscarinic toxicity
-Antidote: atropine
o AChE Inhibitor toxicity
- Antidote
• Atropine (prototype muscarinic receptor antagonist)
• Pralidoxime – regenerates active AChE enzyme (PAM?)
32
Muscarinic agonist drug effects “parasympathomimetic”
o Think about where you have muscarinic receptors in the body – these drugs are still going to have broad effects in the body
o Cardiovascular
- ↓ HR
- ↓ CO & arterial pressure
- vasodilation (via NO – stimulated by endothelium musc receptors)
o GI - ↑ motility
o Bladder - contracts
o Lungs – bronchoconstriction
o ↑ Secretions
-sweat, lacrimation, salivation, bronchial
o Eye
-miosis, accommodation for near vision, ↓ intraocular pressure
33
SLUDGE mnemonic
o Salivation
o Lacrimation
o Urination
o Diarrhea
o GI Upset
o Emesis
o Limited list bc skeletal muscle part
o Note: this mnemonic is good for GI-GU effects, but does not include effects on: heart, lungs, eye effects from muscarinic receptor activation.
o What effects would you expect on these organs?
o What drug could be used to oppose toxicity of muscarinic agonists? ATROPINE
34
drugs affecting the nAChR
o Different nicotinic subunits – so that’s how you target certain receptor types despite them being nicotinic receptors
o Ganglionic stimulators are not particularly useful, bc then you just excite all those cells
o Mecamylamine, trimetaphan, hexamethonium, a-conotoxin more useful for lab than medical use
35
muscarinic blockers, in general
Most muscarinic blockers are non-selective – so you’ll just be blocking ALL muscarinic receptors.
Some newer ones are selective for M3 receptor – for incontinence
36
muscarinic ANTAGONIST effects on systems
```
Heart - ↑
Bronchi – broncodilate
GI – decrease
GU – decrease
Glands – decrease
Sweat glands – decrease
Eye – mydriasis, paralysis of accommodation, atropine can ↑ IOP in pts with glaucoma
CNS – sedation (receptors in the brain are excitatory), cycloplegia
```
No effects on blood vessels, or skeletal muscles (uses NAchR)
Parkinsons – imbalance between DA and ACh, so they’ll block muscarinic receptors and increase the DA [ ]
37
Muscarinic antagonists: atropine
tertiary amine, lipophilic, CROSSES BBB
half-life: 4 hrs (10 hrs in elderly), eye effects last days
IV, IM, or opthalmic
Uses:
opthalmic, CV - for bradycardias, antidoe vs cholinergic agonists, preop - to inhibit secretions, adjunct for NMBD reversal
38
Muscarinic antagonists: scopolamine
tertiary amine, CROSSES BBB, ++++CNS effects, such as amnesia and sedation
half-life: 1-4 hrs
onset: 10 minutes
duration: IV, 2 hrs
Transdermal patch, IV, or IM
Uses:
motion-sickness, PONV, preop - for amnesia, sedation, antiemetic, or to decrease secretions
39
Muscarinic antagonists: glycopyrrulate
**quaternary amine, less CNS SEs. (charged, so won't cross BBB)
half-life: 1 hr
onset: 1 min (IV)
duration: 7 hrs
IV, PO
Uses:
preop, cardiac dysrhythmias (vagal reflex association), and as an adjunct to reverse NMBD blockade
40
anticholinergic mnemonic:
| “Dry as a bone, hot as a pistol, red as a beet, blind as a bat, mad as a hatter”
Dry as a bone = urine retention
hot as a pistol, red as a beet = hyperthermic/no sweating
Mad = confusion/delirium from CNS effects
41
antimuscarinic concerns
o Hyperthermia risk (esp. infants, children)
o Glaucoma – relative contraindication, esp. closed-angle (antimuscarinics ↑ IOP)
o GU obstruction
o Prostatic hypertrophy – relative contraindication
o CV – esp myocardial ischemia, HF, certain arrhythmias, HTN, etc.
o GI-ileus, ulcerative colitis, etc.
think about what muscarinic receptors do, then the opposite
42
meds with anticholinergic activity
o Antihistamines (e.g., diphenhydramine, hydroxyzine)
o Antispasmodics
o Antiparkinson drugs (e.g., benztropine)
o Skeletal muscle relaxants
o Antipsychotics
o Antidepressants (e.g., tricyclic class) – replaced by SSRIs, sometimes they block adrenergic receptors too, “they’re just really dirty drugs”
o Antimuscarinics for urinary incontinence
o Note: elderly are especially susceptible to anticholinergic toxicity – often on (Beers?) list to avoid in elderly
- 1st gen antihistamines – Benadryl, _____,
43
Nicotinic M antagonists: effects and clinical use
effects:
competitive antagonism at skeletal muscle
"non-depolarizing"
clinical uses include:
skeletal muscle relaxation for surgical, intubation, ventilation control
44
Nicotinic N antagonists: effects and clinical use
effects:
blocks ganglionic output
uses:
historically used for HTN emergency
45
endogenous catecholamines, and when they're administered as drugs
Dopamine
Epinephrine
norepinephrine
o When catecholamines are administered as drugs:
- Rapid onset
- Brief duration (MAO, COMT metabolism)
- No oral admin – why??
- Poor CNS penetration– why??
o Most adrenergic drugs are NON-catecholamines:
- Longer acting
- Oral administration
46
Ephedrine, pseudoephedrine - indirect or mixed action?
MIXED
- Displaces/releases stored catecholamine NT
- Some agonist activity - alpha and B- adrenergic receptors
- Non-catecholamine – extended duration (won’t be readily metabolized)
- Herbal source - ma huang
47
amphetamine
Displaces/ releases stored catecholamine NT
Secondary--Inhibits catecholamine reuptake (NET, DAT)
Uses in ADHD, narcolepsy, appetite suppression (not as much used for this anymore bc of potential for abuse)
48
cocaine
Blocks NE reuptake (inhibits NET & DAT transporters) into presynaptic neuron
Blocks sodium channels – local anesthetic actions
49
tyramine
Displaces/releases stored catecholamines
Not a drug, in fermented foods (red wine, aged cheese, pickled things); role in drug-food interactions of MAO inhibitors
-Can be taken up by storage vesicles and pushes NE out. And when they take MAOI inhibitors, can have massive NE response – hypertensive crisis
50
indirect acting:
o Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors
- Block NE reuptake (inhibits NET transporter)
51
indirect acting:
```
o Monamine oxidase inhibitors (MAOIs)
- Prevents breakdown of catecholamines in presynaptic terminal— catecholamine accumulates in vesicles
• MAO-A – metabolizes NE
• MAO-B –metabolizes DA
- Nonselective – inhibits MAO-A & MAO-B
• Tranylcypromine, phenelzine, etc.
Selective MAO-B inhibitors
• Selegiline, rasagiline
```
52
Adrenergic receptor agonists predominant effects, uses, adverse effects - alpha 1
• Vasoconstriction (skin/splanchnic beds)
• Smooth muscle
o contracts (except GI)
o Trophic effect - BPH
• GI/GU sphincters-contract
• Eye- mydriasis
My dry eyes DILATE with the radial muscle, uses alpha 1 receptors.
* increases vasc tone, PVR (peripheral vasc resistance), BP, EYE - mydriasis (redness also disappears bc of vasoconstriction)
* phenylephrine
Uses:
shock
(OTC) decongestant, opthalmic hyperemia
53
Adrenergic receptor agonists predominant effects, uses, adverse effects - alpha 2
* Decrease NE release (presynaptic) – mostly found pre-synaptic
* CNS- inhibit sympathetic outflow from the brain to lower BP (clonidine)
* Platelet aggregation
* Pancreas- ↓ insulin
- ↓ sympathetic outflow from brain
- AE: in the brain, will have high degree of sedation bc decreasing NE which is stimulatory in the brain. So those drugs would be given at nighttime.
*clonidine
Uses:
HTN (central effects)
54
Adrenergic receptor agonists predominant effects, uses, adverse effects - B1
* ↑ HR, contractility
* Effects on rhythm - AV node conduction force
* Kidney – renin
* Trophic effect- hypertrophy (another reason why we use B-blockers in CHF)
Uses:
acute CHF
55
Adrenergic receptor agonists predominant effects, uses, adverse effects - B2
- Bronchodilation
- Vasodilation (esp skel m beds)
- Most sm muscle - relaxes
- Skeletal m contracts-tremor
• Hypokalemia/Incr K+ uptake
- GI/GU-relaxation
- Uterine sm muscle relaxation
- Glycogenolysis (raise BG)
- Think about fight or flight responses
Uses:
asthma, COPD, preterm labor
AE: increased glucose, cardiac stimulation
56
(NE vs. Epi vs. ISO) - NE
o NE will induce reflex bradycardia
- Causes ↑ SBP and DBP bc of alpha activation
- Increases peripheral vasc resistance
Receptors: a1, B1 (little effect on B2).
Use: shock
57
(NE vs. Epi vs. ISO) - EPI
- Increase HR – all alphas and betas
- B2 receptors in skeletal muscle/liver – dilate - decreases DBP
- Α1, partially B1 - increased SBP
- Mix effects – net decrease in peripheral vasc resistance
ALL adrenergic receptors: a1, a2, B1, B2, B3
Low doses: B effects
High doses: alpha effects
Uses: anaphylaxis, use with local anesth's (vasoconstricts locally, keeps LA in that area to extend DOA, and prevent systemic effects), cardiac arrest
58
(NE vs. Epi vs. ISO) - ISO
- Nonselective B-agonist - B1, B2
- Increase force (B1) – increase SBP
- vascular size – vasodilate (B2) – decrease DBP
- Net decrease in peripheral vasc resistance
Use: acute asthma (obsolete), cardiac stimulant
59
dexmedetomidine
“agonist that shuts off NE”
o Selective alpha2 receptor agonist – CNS actions
- Suppresses sympathetic NS activity
- Sedative effects (locus coeruleus); activates endogenous sleep pathways
- Analgesic effects (spinal cord)
- CV—infusion decrease HR (up to 42%), decrease SVR, hypotension (up to 56%); transient HTN (28%) with bolus dose; bradycardia may be significant (fatal cases reported); elderly may be more sensitive
- Respiratory—less decrease in resp rate; some decr in tidal vol; some resp flr
- Tolerance, tachyphylaxis, withdrawal symptoms
- Uses include ICU sedation, premed, adjunct to general anesthesia (decreases dose requirements)
60
• Adrenergic Agonists Some potential concerns
o CV disease
o Cerebrovascular disease
o Other vasoconstriction related
o Diabetes (incr blood glucose)
o IV extravasation risks
o Thyroid disease – general SNS stimulation
o *depending on receptor activity profile of drug
61
beta receptor antagonists effects, clinical SEs, adverse effects
decreased HR/force of contraction, renin release by kidneys, anti-dysrhythmic effects (some)
Uses:
HTN, angina, MI, arrhythmia, thyrotoxicosis, CHF (only for chronic and stable, and only select agents. Decreases morbidity and mortality)
Other uses: infantile hemangioma, glaucoma topical, migraine prophylaxis/anxiety - propanolol
```
AEs:
R- bronchoconstriction
CV - bradycardia
CNS - sedation
decreased sexual fn
DM - nonselective blocks B2 response of glycogenolysis, and blocks typical sx's of hypoglycemia (tachycardia and anxiety)
```
62
Comparison of AChE inhibitors: edrophonium
chemical structure
onset, DOA, dose
only alcohol chemical structure of the 3. Quaternary amine, VERY polar (won't cross BBB).
reversible blockade
IV, IM
Use: reversal of nondepolarizing block
Onset 30-60 sec, DOA 10 minutes
Dosage 1-1.5 mg/kg (from pharm 1)
63
Comparison of AChE inhibitors: neostigmine
chemical structure
onset, DOA, dose
carbamate, quaternary amine, moderately polar (won't cross BBB).
Hydrolyzed by AChE; labile covalent bond
IV, "orally active"
Use: reversal of nondepolarizing block
Onset 10-30 minutes, DOA 2-4 hours
64
Comparison of AChE inhibitors: physostigmine
chemical structure
onset, DOA, dose
carbamate, tertiary amine**
(Crosses BBB!)
Hydrolyzed by AChE; labile covalent bond
PO, IM, IV
use for tx of anticholinergic toxicity
Onset 3-8 minutes, DOA 1 hr
65
DBA receptor/use
B1 primarily
use: acute HF
66
MYDRIASIS
My dry eyes DILATE - SNS response - iris radial muscle - alpha 1 ARs
alpha 1 AR also causes ciliary eye muscle to constrict
67
MIOSIS
My, OH the circle CONSTRICTs, sis - PSNS response -iris circular - M3 muscarinic
M3 also causes ciliary eye muscle to accommodate for "near vision"
68
ejaculation
"AAAAH - alpha 1"
| SNS - alpha 1 receptor
69
erection
PSNS - M3 (if not CNS or heart, is going to be the M3 muscarinic receptor)
70
B3 cells cause
glycolysis (glucose broken down into pyruvate/pyruvic acid)
71
ciliary body - SNS and PSNS effects
SNS - ↑ IOP by ↑ secretion of aqueous humor, B2 receptors
PSNS - ↓ IOP by ↑ outflow of aqueous humor (unknown receptor)
