7. Somatic/Autonomic Pharmacology Flashcards
Divisions of Efferent Nervous System
• Voluntary or somatic nervous system
– End organ of single nerve from CNS is always ____ muscle
– Typically must think about it before it is activated
– Neurotransmitter = ____
– End Organ Receptor = ____
• Autonomic nervous system
– Totally “automatic” – is always working
– ____ neuron outflow from CNS to smooth muscle, glandular tissue or heart
– End Organ Receptors = ____ and ____
• Acetylcholine ○ Permanently \_\_\_\_ molecule - do not move throughout the body § Does not have good \_\_\_\_ solubility • Nicotinic M (muscle) receptor on skeletal muscle ○ \_\_\_\_ can cause skeletal muscle contraction, in addition to ACh • Two neuron outflow: one neuron out of CNS, synapses with another neuron, which then synapses with an end organ (smooth muscle, glandular tissue or cardiac tissue) • Autonomic: \_\_\_\_ (keeps us more in a relaxed stage), and \_\_\_\_ (fight or flight) ○ Cholinergic receptor, but not the same as the one on skeletal ○ \_\_\_\_ can stimulate both, but different drugs activate each • Adrenergic - \_\_\_\_
skeletal
acetylcholine
nicotinic M cholinergic
two
muscarinic cholinergic
adrenergic
charged lipid nicotine parasympathetic sympathetic
Ach
adrenaline/epinephrine
• Voluntary: single nerve fiber out of CNS (spinal cord here)
○ ____ - nodes of Ranvier (where most Na+ are located)
○ Release of Ach, muscle contraction
• Autonomic (para or symp)
○ Two neuron outflow
○ ____ released onto post-ganglion from pre-ganglion
§ ____ receptor, but different from skeletal
§ ____ (nerve) receptor
□ Exists in both para and symp divisions - why it becomes messy when playing around with this site
○ Releases onto bronchi, glandular tissue (sweat gland, salivary gland), or smooth muscle
§ Depends on what NT/drug is released, and whether it stimlulates or blocks the receptor
• Most organs are ____ innervated (both symp and para) - can block and/or stimulate specific divisions
○ Propranolol - antagonist on ____ receptor on heart - heart is also innervated by parasymp, so now this predominates thereby slowing HR and contraction force
myelinated
Ach
nicotinic
nicotinic N
dually
B1 adrenergic receptor
The Neuromuscular Junction
• Muscle will fatigue if this process continues on for a while and will enter \_\_\_\_ ○ Excitation following by blockage • Nerve gas - permanently binds \_\_\_\_
depolarizing block
acetylcholinesterase
Acetylcholine
• Chemical can move in and out of synapse, but cannot travel throughout the \_\_\_\_ ○ Permanent \_\_\_\_ • Reuptakes \_\_\_\_ and used to make more acetylcholine ○ \_\_\_\_ - blocks the reuptake of choline back into the nerve terminal - creates paralysis
body
charge
choline
hemicollineum
Some Pharmacological Manipulations of Voluntary Nervous Systems
- Blocking skeletal muscle contraction with ____ or ____ for intubation - a nicotinic M cholinergic receptor antagonist (neuromuscular blocker). Non-depolarizing ____ blocker. Can be reversed by increasing ____. Drugs called ____ (physostigmine) can do this.
- Blocking skeletal muscle contraction with succinylcholiine for intubation - a ____ receptor antagonist (neuromuscular blocker). Depolarizing ____ blocker. No ____. Must ____ for drug to be enzymatically degraded by cholinesterases. Issue in patients with ____.
- Using anticholinesterases (neostigmine) to symptomatically treat myasthenia gravis, an autoimmune disease where ____ receptors are being destroyed. ____ again increase ACH at neuromuscular junction. However they also do it all over the ____ where there are other neurons releasing ACH.
- Anticholinesterases that cross the blood brain barrier also shown to improve memory in ____ patients. Drugs like ____ and ____ (Aricept®). DO YOU WANT INCREASED MUSCLE CONTRACTION IN THESE PATIENTS????
curare gallamine competitive Ach anticholinesterases
nicotinic M cholinergic non-competitive reversal agent wait "atypical cholinesterases"
nicotinic M cholinergic
anticholinesterases
body
alzheimers
physostigmine
donepezil
Some Pharmacological Manipulations of Voluntary Nervous Systems
• Drugs that work on nicotinic M cholinergic receptors are all \_\_\_\_ ○ Blockers have higher \_\_\_\_ for receptors, and slowly comes off; \_\_\_\_ have the opposite effect (on-off-on-off constantly) • Breathing machine for 24-48 hours - \_\_\_\_ • Neostigmine ○ Used in myasthenia gravis, where nicotinic M cholinergic receptors are being destroyed ○ Eventually, the receptors get \_\_\_\_ and these drugs will have no effect • Neostigmine won't work for Alzheimer's patients - it is permanently \_\_\_\_ and it cannot cross the BBB ○ Amyloid leads to destruction of cholinergic receptors ○ Doesn't slow down progression, but it improves symptoms (physostigmine and donepezil [Aricept]) § Affects Ach wherever it is: unwanted muscular contraction (\_\_\_\_), diarrhea and increased salivation (affecting the \_\_\_\_ also)
blockers/antagonists affinity agonists "atypical cholinesterases" destroyed charged symp parasymp
Competitive and Non-Competitive Blockade of NMJ
• With \_\_\_\_, because its competitive antagonist, effects of curare can be reversed by increasing acetylcholine at the site ○ Muscle is flaccid and paralyzed • With succ (non-competitive), with \_\_\_\_, cannot reverse the effect
curare
atypical cholinesterases
Other Drugs in Treatment of Alzheimer’s Disease
• Anticholinesterases: ____ (Aricept®), ____ (Exelon®), ____ (Razadyne®)
– Adverse Events predictable by mechanism of actions: muscle ____ and contracting, bradycardia, ____, diarrhea, increased ____, tremors/seizures
• Excitatory amino acid antagonist (i.e. ____, n-methyl-d-aspartate) ____ (Namenda®)
• All 3 can cross the \_\_\_\_ • Can increase response at \_\_\_\_ (nicotinic and cholinergic), and at \_\_\_\_ receptor effects (end organs innervated by parasymp nervous system) ○ \_\_\_\_ are exception (sweating is symp); but anatomically, innervated by sympathetic outflow (first is short, second is long), the NT is acetylcholine • Add-on to anticholinesterase - memantine ○ Too much excitatory AA - \_\_\_\_, and alzheimer's - destroy neurons ○ Blocks the action of \_\_\_\_ (glutamate, aspartate)
donepezil rivastigmine galantamine twitching drooling sweating glutamate memantine
BBB NMJ muscarinic cholinergic sweat glands stroke excitatory NT
Divisions of Autonomic Nervous System 1
• Parasympathetic Division
– Fine control of ____ body systems
– End organs again are ____ muscle, ____ tissue and ____ tissue
– Body is kind of in ____ state
– Pupils constricted (____), salivation is copious, heart rate ____, digestion of food (stomach acid secretion) and ____ turned on, good blood flow to skin and stomach, ____somewhat constricted
• \_\_\_\_ neuron outflow • \_\_\_\_ relationship between first neuron and synapsing on the second neuron ○ \_\_\_\_: first neuron (pre-gang) can synapse on 20 post-gang nerve fibers
individual smooth glandular cardiac relaxed miosis slow peristalsis bronchi
two
1:1
sympathetic
Divisions of Autonomic Nervous System 2
• Sympathetic Division
– Fight, fright, flight system.
– Simultaneous energizing of ____ body organs
– pupils dilate (____), mouth becomes dry, ____, bronchi open, blood flow to brain and skeletal muscle increases, blood flow to skin/stomach ____, heart rate and contraction force ____.
• \_\_\_\_ neuron outflow • Same organs stimulated as para, but the effects are opposite • Drops at eye office - \_\_\_\_, or alpha norepinephrine stimulating receptors - stimulates sympathetic system • Sweat glands - anatomically: sympathetic, but uses \_\_\_\_ ○ Drugs that affect sweating, are the ones that stimulate or block the end organs of the \_\_\_\_ system • Different receptor types: ○ B2 for brain, when stimulated, dilation of BV ○ A1 for skin and stomach, when stimulated, constriction of BV
multiple mydriasis sweating decreases increase
two
alpha adrenergic
acetylcholine
parasymp
IMPORTANT CONCEPT CONCERNING AUTONOMIC NERVOUS SYSTEM 1
• Most organs are dually innervated by both systems so…………
– If u give a drug that stimulates (an agonist) ____ nervous system that system’s effects predominate
– If u give a drug that blocks (an antagonist) the parasympathetic nervous system the ____ nervous system’s effects predominate
parasympathetic
sympathetic
IMPORTANT CONCEPT CONCERNING AUTONOMIC NERVOUS SYSTEM 2
• Most organs are dually innervated by both systems so…………
– If u give a drug that stimulates (an agonist) ____ nervous system that system’s effects predominate
– If u give a drug that blocks (an antagonist) the sympathetic nervous system the ____ nervous systems effects predominate
sympathetic
parasympathetic
Parasympathetic anatomy
end organ receptor = ____
ganglionic receptor = ____
* Parasymp nerve fibers come of \_\_\_\_ and \_\_\_\_ regions of spinal cord * 1:1 (one pregang to one postgang) * Pregang is \_\_\_\_, and postgang is \_\_\_\_ * Not talking about skeletal muscle anymore - smooth muscle in eye, salivary gland, etc. * GI ulcers - nicotine is hitting the \_\_\_\_ receptors on the end of pre-gang - driving acid in the stomach
muscarinic cholinergic
nicotinic N cholinergic
cranial sacral long short nicotinic
Divisions of Autonomic Nervous System 1
• Parasympathetic Division
– Fine control of individual body systems
– Typically one long preganglionic nerves synapses on one very short postganglionic nerve which then synapses on end organ
– Neurotransmitter at both preganglionic and postganglionic sites is ____
– Receptor at ganglionic site = ____
– Receptor at end organ =____ (M1, M2, M3, M4, M5).
• Do not have any drugs that selectively stimulate/block the different \_\_\_\_
acetylcholine
nicotinic N cholinergic
muscarinic cholinergic
muscarinic subtypes
Some Effects of Parasympathetic (Muscarinic) Stimulation
- Increased ____ (watery saliva)
- Pupillary constriction (____)
- Bronchoconstriction and ____ respiratory secretions
- Decreased heart rate (negative ____) and contraction force (negative ____)
- Increased GI peristalsis and acid secretion
- A few blood vessels dilate but most only have ____ innervation
ACTIONS ARE GENERALLY OPPOSITE THE SYMPATHETIC SYSTEM
salivary flow miosis increased chonotropic inotropic sympathetic
Drug strategies effecting muscarinic receptors 1
• Treating dry mouth (xerostomia) from Sjogren’s syndrome or radiation treatment
– Prescribe muscarinic cholinergic receptor agonist like ____ (Salagen®)
– What are potential side effects of pilocarpine??
– Pupillary ____, bradycardia, diarrhea, increased ____, increased sweating – WHY ?? All these organs also contain muscarinic receptors. ____ muscarinic receptors most sensitive to drug.
Why not employ anticholinesterase to treat xerostomia???
pilocarpine
constriction
stomach acid
salivary gland
Drug strategies effecting
muscarinic receptors 2
• Want to dry patient’s mouth before impression for 7 crowns which will make you a lot of money!!
– Prescribe muscarinic cholinergic receptor antagonist like ____.
– What are possible side effects of atropine?
– ____, increased heart rated, decreased ____, constipation, drowsiness. These organs also have muscarinic receptors and now ____ nervous system predominates except for the decreased sweating.
• Atropine extremely effective in drying the mouth • \_\_\_\_-soluble - can get into the brain, etc • Unpredictable effects in \_\_\_\_; chemical structure similar to cocaine ○ May end up getting stimulation
atropine
mydriasis
sweating
sympathetic
lipid
brain
Related drugs to atropine
(antimuscarinics)
• \_\_\_\_ (Pro-Banthine®) • \_\_\_\_ (Robinal) – Both can dry the mouth and have other peripheral anticholinegic effects – Permanently \_\_\_\_ so they stay out of the brain, i.e. minimal sedation with these drugs • \_\_\_\_ (Transderm Scop®) • \_\_\_\_ – also an antihistamine – Both readily penetrate \_\_\_\_ – Highly \_\_\_\_
• These drugs are permanently charged - requires a big dose for it to be absorbed • Stays out of eye chamber and away from the brain, minimal side effects like you get from atropine • To get through skin, need a lipophilic vehcile • Diphenyhydramine - benedryl acts only on \_\_\_\_ ○ Most common: H1 antagonists - classic antihistamines, used as an adjunct for anaphylaxis (helps somewhat) - on bronchi ○ (\_\_\_\_ receptors - on parietal cells - acid secreting cells in the stomach) § Used to treat \_\_\_\_ ○ Also blocks muscarinic cholinergic receptors - \_\_\_\_, can be a side effect (from antihistamine) or good effect depending on what you're taking it for
propantheline glycopyrollate charged scopolamine diphenydramine CNS sedating
H1
H2
GI ulcers
dry mouth
Blocking ____ receptors in CNS to prevent motion sickness. Drugs like diphenhydramine
(Benadryl®) or scopolamine patch. Why won’t they work for nausea caused by opioids (narcotics) or cancer chemotherapy????
* \_\_\_\_ drugs (muscarinic cholinergic antagonists) * +++ - NT stimulates the vomiting center * The above drugs block the +++ - why they're good motion sickness drugs * The drug needs to get into the \_\_\_\_ (\_\_\_\_ isn't good) * Drug-induced vomiting (opioids/chemo) involves NT different from motion sickness; need \_\_\_\_ and \_\_\_\_ receptors
muscarinic cholinergic
anticholinergic brain glycopyrollate dopamine serotonin
Geopolitical Concerns With Irreversible Anti Cholinesterases
- Drugs like neostigmine used in myasthenia gravis and donepezil in Alzheimer’s ____ bind cholinesterase –IN OTHER WORDS THEY LET GO
- Certain types of nerve gases with names like ____, Sarin and ____ are irreversible binders and extremely ____ soluble. They will penetrate body right through ____ and mucous membranes.
reversibly Soman Tabun lipid skin
Physiological Effects of Nerve Gases
• SLUDGE SYNDROME Ø S = Excess \_\_\_\_ Ø L = Excess \_\_\_\_ Ø U = Excess \_\_\_\_ Ø D = Excess \_\_\_\_(diarrhea) Ø G = \_\_\_\_ (convulsions) v \_\_\_\_ excitatory neurotransmitter in brain Ø E = \_\_\_\_ (vomiting) v Remember vomiting center schematic Ø \_\_\_\_
salivation lacrimation urination defecation grand mal like seizures Ach emesis depolarizing neuromuscular blockade
Sympathetic System
• \_\_\_\_ preganglion, \_\_\_\_ postganglion • Same \_\_\_\_ end site on the preganglion for both para and symp • Different NT, except for the \_\_\_\_ • Can be \_\_\_\_ (preganglion:postganglion) • The nerve cell bodies are all \_\_\_\_ ○ \_\_\_\_ rami ○ Excite one and you excite them all • \_\_\_\_ glands act as post-ganglionic nerve fibers ○ Right: \_\_\_\_ shape ○ Left: \_\_\_\_ shape ○ End organ: blood, \_\_\_\_ and some \_\_\_\_ and some \_\_\_\_ • Epinephrine/NE/DA can travel far - not highly \_\_\_\_ molecules
short long nicotinic sweat glands 1:20 connected grey adrenal pyramid crescent epinephrine norepinephrine dopamine charged
Receptors of Sympathetic Division and Some Clinical Significance 1
• Alpha one–stimulate these and see ____. One key location is ____ under skin and mucous membranes. Clinical importance of adding ____ to local anesthetic solutions. Increases ____, efficacy of lidocaine. Decreases local ____ and slows ____ absorption of lidocaine. Block alpha one receptors with alpha one adrenergic antagonist like ____ (Minipres®) get ____ and lowers ____. Side effect is ____.
Blood Pressure = PVR X CO
* End organs - alpha-adrenergic - respond to NE/EP; and beta-adrenergic, and subtypes of both * Epinephrine and lidocaine combined * Prazosin - gold-standard drug; \_\_\_\_ - alpha1 adrenergic receptor blocker
constriction blood vessels epinephrine duration bleeding systemic prazosin vasodilation blood pressure postural (orthostatic) hypotension
azosin
Other alpha -1 receptor blockers
• ____ – blocks both alpha 1 and alpha 2 receptors, so non-selective
– See more reflex ____ with these because of alpha-2 blockade
– Currently available in small dose in local anesthetic cartridge marketed as ____®. Essentially when injected in same spot as local anesthetic at end of procedure speeds up ____ from numbness and loss of function.
* First drugs that were developed were non-selective * Drugs that work by vasodilation > orthostatic opostural hypotension > BV in legs are staying open, and by gravity there is leess blood to brain > \_\_\_\_ out * Reflexively speeds up the heart > reflex tachycardia with older alpha blockers (both 1 and 2) vs. the pure ones (\_\_\_\_, less likely to occur) * Oraverse - increases numbing recovery 50-60% quicker
phentolamine
tachycardia
oraverse
recovery
passes
asozins
Other alpha -1 receptor blockers
• ____ (Cardura), ____ (Hytrin)
– Alpha 1 ____ like prazosin
– Major drugs in treatment of ____ and congestive heart failure (like prazosin) because they ____.
– ____ again a possibility
• Tamsulosin (Flomax®)
– Selective for ____receptor blockade
– ____ drug
• These are selective - asozin • CHF - short of breath, retaining fluid • Prostrate, urethra and bladder neck have \_\_\_\_ receptors ○ Doesn't cure the disease, but treats the symptoms ○ 1A doesn’t hit as hard on BV - selective, do not see \_\_\_\_ etc.
doxazosin terazosin selective hypertension vasodilate postural hypotension
alpha1A
benign prostatic hypertrophy
alpha1
postural hypotension
Receptors of Sympathetic Division and Some Clinical Significance 2
• Alpha two –post synaptic alpha two similar to ____ on blood vessels. However presynaptic alpha-2 receptors on nerve terminals when stimulated ____ neurotransmitter release. Sort of an auto receptor or ____ on system. Drug called ____ (Catapres®) stimulates alpha 2 receptors, decreases ____ release and lower blood pressure. Mainly works in ____.
* Two types: pre-synaptic and post-synaptic * Post-synaptic - work just like post-synaptic alpha 1 * Pre-synap > stimulate > decrease NT release > \_\_\_\_ mechanism * NE causes vasoconstriction and accelerates HR * Lots of symptoms - \_\_\_\_, limp * Used in \_\_\_\_ withdrawal - CNS excitation and sympatihetic sympathetic effects - worst case of flu, heart is pounding - clonidine dampens these effects
alpha one decreases break clonidine norepinephrine central nervous system
feedback
drowsiness
opioid
- Nts of sympathetic NS there are precursors
- Tyr into nerve terminal -> ____ -> ____ -> NE within a vesicle; adrenal medulla can take the NE to ____
- Stimulate ____ > decrease effect on NE release
- Excessive ____ is supposed to feedback on this
- Cocaine also accels release of ____, and ____ reuptake as well, and increases release of ____ (euophoric NT), also sensitizes receptors in brain to ____
- ____ don’t cross BBB (DOPA, DA, NE); won’t work for parkinson’s (____)
DOPA dopamine alpha 2 NE NE blocks dopamine DA catecholamines L-DOPA
Receptors of Sympathetic Division and Some Clinical Significance 3
• Beta one – One key place these are found is the ____. Stimulate these you ____ heart rate and contraction force. Too much epinephrine will do this because it is an agonist (stimulator) at both ____ and ____ receptors. Or u accidentally shoot that lidocaine with epinephrine right into a blood vessel. Now if u block beta 1 receptors with drug like ____ (Inderal®) you slow heart rate and contraction force. Propranolol use to treat high blood pressure, angina and rapid heart beats – tachy-arrhythmias.
* Proproanol - \_\_\_\_ takes over, acetylcholine takes over [???] * Also used in \_\_\_\_ headache sufferers - non-\_\_\_\_; vasodilatory phase first in migraine, contain mainly beta2 receptors, so this is effective in treating that
heart increase alpha1 beta1 propranolol para-symp migraine selective
Clinical consequences of dual innervation of the heart
• M - muscarinic cholinergic receptor (heart doesn't have any nicotinic) ○ Vagus drops \_\_\_\_ and stimulates, and breaks on the heart • B1 - beta 1 adrenergic receptor ○ \_\_\_\_ from adrenal medulla, drives the heart • \_\_\_\_ > used in xerostomia, dry-mouth > salivary glands are more sensitive to these receptor; MCR agonist, if enough gets to heart > \_\_\_\_ the heart, and may begin to retaining fluid • Atropine > blocking MC action of Ach > speeds up the \_\_\_\_, \_\_\_\_ • Too much epi > heart rate speeds up > \_\_\_\_ • Propranolol > sits and blocks > slows the heart down, slows contraction force
Ach
Epi
pilocarpine
slows
heart
tachycardia
palpitations
Receptors of Sympathetic Division and Some Clinical Significance 4
• Beta 2 adrenergic – key places they are found are ____ located in skeletal muscle and certain organs (the ____) and the ____ tree.
Stimulate these and you get ____. Typical inhaler asthmatic uses for an acute attack is a beta-2 adrenergic agonist like ____ (Proventil®). What type of drug on the muscarinic cholinergic side might also be useful in asthma??
Muscarinic cholinergic antagonist = ____ (Atrovent®)
• Asthma + non-selective beta blockers > death • Asthma is a chronic inflam disease • All beta drugs end in ol • Reserve these drugs for acute attacks, but using drugs with \_\_\_\_ properties to prevent attacks (these are taken chronically) • Attack astham via cholinergic/muscarinic > attack via antagonist > ibatropium ○ Looks like atropine from name - in inhaler, took atropine and \_\_\_\_ it, penetrate less, but placing it down your airway so doesn't need to travel ○ To reach peak it takes 15 mins, lasts 8-10 hours, so they combiend with \_\_\_\_ (proventil) > combination of both, albuterol comes on quick § Combovent
blood vessels
brain
bronchial
dilation
albuterol
ipatropium
anti-inflam
charged
b2 agonist
• Do not need to know enzyme
• Synthethic pathway of catecholamines
• Important points:
○ AA - precursors can cross ____
○ Catecholamines are excluded from ____
§ Benzene ring, 2 OH, amine end
• Major drug > L-DOPA > more powerful than R; but issues: some L-DOPA before getting to brain, ____ degrades it; also can be prescribed a ____ blocker (entocapone, camtom), there’s dopa d-carboxy in periphery, so a lot of L-DOPA that survives COMT gets converted to dopamine before it gets into the brain, can add ____ (dopa d-carboxy antagonist, and only blocks the peripheral ones)
BBB brain catechole o-methyl transferase COMT carbydopa
Parkinson’s Disease
Too much muscarinic stimulation in CNS?
Too little dopaminergic
stimulation in CNS?
• Balance of \_\_\_\_ and \_\_\_\_ in normal individuals • With PD > Ach is the fat guy, and DA is the skinny - too much Ach, too little DA ○ What are way s to treat: give \_\_\_\_ receptor blockers (antihistimines have anti-chhlinergic effects), give \_\_\_\_, MAO inhibitors (blocks dopamine metabolism), enhance DA release (will fail, the neurons are destroyed; \_\_\_\_ - precursor of tamiflu > action in PD); stimulate DA receptors
Ach DA muscarinic cholinergic L-DOPA simitrel
Drugs Directly Stimulating Nicotinic Cholinergic Receptors
- We’ve already spoke about how curare and succinylcholine can block the ____ receptors leading to muscle paralysis.
- What about nicotine itself – it’s an agonist at ____ and ____ receptors (on autonomic ganglia and the brain).
- Most popular delivery system is ____.• On para and symp - ganglia, the autonomic ganglia
nicotinic M cholinergic
nicotinic M
nicotinic N
cigarettes
Nicotine continued
- Cigarette (tobacco) smoke contains other materials including carbon monoxide and ____ such as benzpyrene. Deaths directly attributable to smoking, account for 20% of all deaths and 30% of cancer deaths in the USA. It is estimated that about 90% of cases of chronic obstructive lung disease in the USA are due to smoking.
- CO - obstructive lung diseases
carcinogens
Nicotine continued
• When inhaled or injected, nicotine can also activate ____ receptors (remember Nicotinic N receptors) on both sympathetic and parasympathetic ganglia inducing a multitude of sympathetic and parasympathetic effects.
In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic. ____ blood pressure and ____ predominate, although vagally mediated ____ may follow.
In the GI and urinary tracts the effects are primarily parasympathomimetic, leading to increased ____ secretion, nausea, diarrhea and increase ____ of urine. Tolerance to some of these effects does develop, but it is fairly well established that nicotine use is a major contributor to both recurrent ____ disease and ____ disease.
• Nicotine, the ganglionic sites are symp and para - can stimulate both • If can affect both, it will affect most what is predominant in that system ○ Cardio - \_\_\_\_ - nicotine drives it up ○ Stomach/GI - \_\_\_\_ - GI ulcers, excessive acid secretion, working not dircrtly on stomach but on nerve cell body at the ganglia, that innervate parietal cells in the stomach
nicotinic
increased
tachycardia
bradycardia
acid
voiding
peptic ulcer
cardiovascular
Nicotine Continued
• Nicotine activates receptors in the CNS inducing feelings of ____, alertness with a rapid development of tolerance, physical dependence and often psychological dependence (addiction). The cravings induced by nicotine withdrawal are intense and long lasting.
* Nicotine receptors in brain - hook us on nicotine and drugs * \_\_\_\_ - more drug to get same effect * \_\_\_\_ - go cold turkey or take antagonist - withdrawal
well-being
tolerance
physical dependence
Some Drugs Used for Smoking Cessation
• Nicotine transdermal systems (skin patch) – ____ (McNeil Consumer) –Indicated > ____ cigarettes per day
–____ mg/nicotine per 16 hours
–____ week course of therapy
–Includes ____ modification literature on insert
* Dosing is based upon the number of cigarettes you smoke; not on \_\_\_\_ * Wear patch for 24 hours - \_\_\_\_
nicotrol 10 15 6 behavior
body weight
sleep disturbances
Smoking Cessation Systems 2
____ Patch (Smith Kline Beecham)
–Step 1: ____ mg/24 hours (weeks 1-6)
–Step 2: 14 mg/24 hours (weeks 7-8)
–Step 3: ____ mg/24 hours (weeks 9-10)
– If < 10 cigarettes/day
–Step 2: ____ mg/24 hours (weeks 1-6)
–Step 3: 7 mg/24 hours (weeks 7-8)
– Wear ____ hours if craving on awakening
– Wear ____ hours if sleep disturbances
– Includes ____ modification literature
nicoderm CQ
21
7
14
24
16
behavioral
Smoking Cessation Systems 3
____ (chewing gum)
____ (Smith Kline Beecham)
– Up to 24 cigarettes/day – ____ mg strength
– > 25 cigarettes/day – ____ mg strength
– Instructions: 15 chews, then “park” between cheeks and gums (buccal mucosal absorption)
– Weeks 1-6: one piece every one to ____ hours
– Weeks 7-9: one piece every ____ to four hours
– Weeks 10-12: one piece every four to ____ hours
– ____ modification literatur
nicotine polacrilex nicorette gum 2 4 two two eight behavior
Other Approved Drugs in Smoking Cessation
• Bupropion–an ____ antidepressant that is a weak inhibitor of ____, serotonin and ____ reuptake. Marketed as ____® as an antidepressant and ____® for smoking cessation. Some patients overdosed on the drug when they didn’t realize the Wellbutrin® they were taking for depression and the Zyban® for smoking was in fact the same thing. More alarmingly some of the physicians prescribing the drug didn’t realize this either.
* Doesn't fit in the four different categories that are antidepressants (tricycl antidepress, SNRIs, MAOIs, SSRIs) * Overdose because two brand names are the same
atypical dopamine norepinephrine wellbutrin zyban
Other Approved Drugs for Smoking Cessation 2
• ____ (Chantix®) - Varenicline is an FDA-approved medication that binds to and partially activates ____ receptors (partial agonist at the ____ ____ nicotinic acetylcholine receptor) in the brain.
The drug seems to both diminish the pleasure associated with smoking (possibly by decreasing ____ release) and also prevents relapse of smoking behavior once an individual has quit.
One study published in JAMA compared use of varenicline to placebo or bupropion. It was a 12 week study which enrolled roughly 1,000 generally healthy smokers between the ages of 18 and 75 years. Study subjects who took varenicline were more ____ to quit smoking than study subjects who took buproprion or placebo. The proportion of study subjects who did not smoke during the third month of the study was 44% among study subjects taking varenicline, 29.5% among study subjects taking buproprion, and 17.7% among subjects taking placebo. Reports of ____ symptoms and ____ ideation are concerning.
varenicline
nicotinic
alpha-4 beta-2
dopamine
likely
depressive
suicidal
To Add to the Confusion…..
• Ganglionic Blockers
– ____ (Inversine®), ____ (Afronad)
– Block ____ receptors on both sympathetic and parasympathetic autonomic ganglia
– Main use is ____ crisis
– Lots of parasympathetic and sympathetic ____ side effects
mecamylamine trimethaphan nicotinic N hypertensive blockade
Ganglionic Blockers 2
• Generally speaking side effects show up in system (parasympathetic or sympathetic) that usually predominate those end organs.
• So on parasympathetic side see a lot of ____ and constipation.
• On sympathetic side see a lot of ____ and hypotension
xerostomia
bradycardia
Important concept: Neurotransmitters and drugs can activate and inhibit multiple receptor subtypes at same time producing multiple effects if they can get to all those receptors. Many examples.
Epinephrine: Agonist at ____, ____ and ____ adrenergic receptors. So if it can get
to all of these what can happen?? Will there also be CNS effects??
alpha 1
beta 1
beta 2
Epinephrine Receptor Actions
Alpha-1 Adrenergic: ____ skin and mucous membranes
Beta-1 Adrenergic: increased ____ and increased contraction force
Beta-2 Adrenergic: ____; ____ skeletal muscle and internal organs
vasoconstriction
heart rate
bronchodilation
vasodilation
LOOK AT TABLE FOR LIDO TIMES
YAY
Related drugs to epinephrine 1
• ____ and ____ (Pseudophed®)
– Available as pills for nasal decongestion and asthma
– Directly stimulate ____, ____ and ____ receptors but also act indirectly by releasing neurotransmitter (____)
– ____ can occur
– Cross ____ where action is stimulatory. They are not ____!
ephedrine pseudophedrine alpha-1 beta-1 beta-2 norepinephrine tachphylaxis BBB catecholamines
Related drugs to epinephrine 2
• ____ (Afrin®)
– Major ingredient in nasal decongestants
– Pure ____ agonist so if you push dose can see hypertension (increases in blood pressure)
– Also if you push dose you can see a reflex ____
– Vasoconstrictor in recently FDA-approved 3% tetracaine/0.05% ____ (Kovanaze®) local anesthetic nasal spray –NO NEEDLES
– Gets teeth #s 4-13 (2nd ____ to 2nd ____ numb)
* Extremely expensive * Used for severe nose bleeds, makes them constrict * Post synaptic alpha-2 receptor that is stimulated * Doesn't number all the teeth
oxymetazoline alpha bradycardia oxymetazoline premolar premolar
Oxymetazoline
* Anterior superior and ???? alveolar nerves * Cannot do the mandibular nerves - the nerve is not located in the maxillary sinus
NEED TO UPDATE MY BOY
Mixed receptor action continued
- Norepinephrine - ____ and ____ agonist. What are its effects?
- Dopamine - ____ and ____ agonist. Dopamine receptor stimulation on renal vasculature induces ____. Remember can’t cross ____ if swallowed or injected.• NE doesn’t hit ____
alpha-1 beta-1 dopamine beta-1 vasodilation BBB
B2
Mixed receptor action continued
• ____ (Isuprel®) - An old anti- asthmatic drug. Stimulates beta-1 and beta- 2 adrenergic receptors. What’s the potential problem here in treating an acute asthmatic attack? Last thing you want to do in asthmatic is also stimulate ____ receptors and increase ____ demand.
isoproterenol
beta-1
myocardial oxygen
Selective Beta -2 Adrenergic Agonists
• ____ (Proventil®), ____ (Brethaire®), ____ (Servent®)
– Lack beta-1 adrenergic activity if dosed properly
– Get ____ without cardiac stimulation
– These are now the major ____ inhalers
* Problem of long-acting drugs: Salmeterol - takes a while for it to activate, the others activate quickly * Terbutaline - \_\_\_\_ labor - stimulate B2 receptors in uterus - premature delivery
albuterol terbutaline salmeterol bronchodilation antiasthmatic premature
Mixed receptor action continued
• Propranolol (Inderal) - An antagonist (or blocks) ____ and ____ adrenergic receptors. Still widely used in treatment of ____, cardiac arrhythmias and ____. Therapeutic effect in these disorders is the beta-1 receptor blockade. What’s the potential problem in some people (like those that have high blood pressure and asthma) of also blocking beta-2 receptors??
____
beta-1
beta-2
angina
hypertension
bronchoconstriction
Cardioselective Beta-1 Adrenergic Antagonists
• ____ (Lopressor®), ____ (Tenormin®)
– If dosed properly get negative ____ and negative ____ effect without bronchoconstriction
– Both in Top 25 selling prescribed drugs
– Same indications as ____
metoprolol atenolol inotropic chronotropic propranolol
Haloperidol (Haldol®) in Schizophrenia 1
- Schizophrenia is a brain disorder characterized by disorganized thoughts, flat effect, loss of executive function, paranoia, auditory (hearing voices) and sometimes visual hallucinations. There is ____ matter loss.
- Onset age typically 15 – 18 years old in males, 19 – 23 years old in females.
- 80% of it is ____ predisposition plus there are some unknown “2nd environmental hits”.
- It is typically “a career ender” and no ____.
gray
genetic
cure
Haloperidol (Haldol®) in Schizophrenia 2
- Haloperidol is a ____ receptor antagonist and some of the disease is due to an overactive dopaminergic system in the brain. Improves some of the symptoms (the ____, the flat effect etc)
- However by blocking dopamine receptors in the brain some people develop a ____ syndrome (extrapyramidal effects). To treat this some people take anticholinergics like ____ (Cogentin®) – look at see-saw picture
- Haloperidol also blocks alpha – 1 receptors so ____ a possibility.
dopamine voices parkinson's-like anticholinergics orthostatic hypotension
§ Block alpha-1 – lower ____, treat ____
• Stimulate ____ - increase local anesthetic duration
• Stimulate alpha -2 –lower ____
• Block beta-1 – lower ____, slow heart in angina and arrhythmias
• Stimulate beta -2 -treat ____
• Block MAO – treat ____ and ____
• Block COMT – treat ____
• Give L-Dopa – Treat ____
• Block reuptake 1 (presynaptic nerve terminal) – treat ____
BP benign prostatic hypertrophy alpha 1 BP BP asthma depression Parkinson's Parkinson's Parkinson's depression
