Exam 1: ANS Drugs Flashcards
SNS neurons (location and length)
o Preganglionic thoracolumbar (short) o Postganglionic (long)
PSNS
o “around the SNS” above/below the thoracolumbar area - Cranial/sacral areas o Preganglionic (long) o Postganglionic (short)
key characteristics of ANS
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)
exceptions to dual innervation
• 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
unique glands: adrenal medulla
Sympathetic innervation Only 1 neuron Postsynaptic neuroendocrine cells Secrete Epi/norepi into blood Mimics sympathetic stimulation
unique glands: sweat glands
Sympathetic innervation
Post-ganglionic neuron is cholinergic (not adrenergic)
Acetylcholine is NT
Receptor at effector tissue is muscarinic (a cholinergic receptor)
nicotinic cholinergic receptor
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
M1, M4, M5 receptor location
CNS
M2 receptor location
heart
M3 receptor location
SEEG.
Also M1 = CNS, M2 = heart, so M3 = everything else!
smooth muscle, glands, endothelium, eye (circular, ciliary muscle)
Nic N receptor location
ANS ganglia (all of them), adrenal medulla, CNS
Nic M receptor location
skeletal muscle NMJ
3 subtypes of alpha adrenergic receptors
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)
beta adrenergic receptors
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
a1 adrenergic receptor locations
alpha 1 - SEV
- Smooth muscle: G-U sphincters (esp. bladder)
- Most vascular (skin, splanchnic)
- Eye –radial m
- Heart, liver
a2 adrenergic receptor locations
(inhibitory)
- Pre-synaptic nerve terminal Platelets, pancreatic beta cell
B1 adrenergic receptor locations
- 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”
B2 adrenergic receptor locations
Smooth m: bronchiolar, uterine, etc. Vascular sm muscle: Skel m beds Liver Skeletal muscle Heart (albuterol)
B3 adrenergic receptor locations
adipose tissue
adrenergic receptors -general info
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
NE in the peripheral NS
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
DA in the peripheral NS
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
DA receptor
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
DA drug effects (low, intermediate, high dose)
- 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
- 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
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
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
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
Irreversible AChE Inhibitor Drugs
organophosphates; long duration
- Echothiophate
- Think covalent bond to the enzyme, NONcompetitive
requires synthesis of new AChE to overcome
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)
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?)
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
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
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
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
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 [ ]
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
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
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
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
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
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, _____,
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
Nicotinic N antagonists: effects and clinical use
effects:
blocks ganglionic output
uses:
historically used for HTN emergency
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
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
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)
cocaine
Blocks NE reuptake (inhibits NET & DAT transporters) into presynaptic neuron
Blocks sodium channels – local anesthetic actions
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
indirect acting:
o Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors
- Block NE reuptake (inhibits NET transporter)
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
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
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)
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
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
(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
(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
(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
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)
• 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
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)
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)
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
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
DBA receptor/use
B1 primarily
use: acute HF
MYDRIASIS
My dry eyes DILATE - SNS response - iris radial muscle - alpha 1 ARs
alpha 1 AR also causes ciliary eye muscle to constrict
MIOSIS
My, OH the circle CONSTRICTs, sis - PSNS response -iris circular - M3 muscarinic
M3 also causes ciliary eye muscle to accommodate for “near vision”
ejaculation
“AAAAH - alpha 1”
SNS - alpha 1 receptor
erection
PSNS - M3 (if not CNS or heart, is going to be the M3 muscarinic receptor)
B3 cells cause
glycolysis (glucose broken down into pyruvate/pyruvic acid)
ciliary body - SNS and PSNS effects
SNS - ↑ IOP by ↑ secretion of aqueous humor, B2 receptors
PSNS - ↓ IOP by ↑ outflow of aqueous humor (unknown receptor)
