some innervated by either PNS or SNS; some innervated by BOTH (PNS effect is usu opposite SNS);
Innervation of end organs: discharge pattern
PNS - "discrete" 1pre to 1 post; SNS - "diffuse" 1pre to many post
ANS Receptors: cholinergic
mucarinic, nicotinic
ANS Receptors: adrenergic
alpha, beta
Muscarinic Cholinergic Receptors: M1
CNS, ANS ganglia
Muscarinic Cholinergic Receptors: M2
heart
Muscarinic Cholinergic Receptors: M3
smooth muscle, glands
Muscarinic Cholinergic Receptors: M4 and M5
CNS
Nicotinic Cholinergic Receptors: Nn
CNS, ANS ganglia
Nicotinic Cholinergic Receptors: Nm
skeletal muscle
Neurotransmission
most NTs don't cross membranes; each binds to specific ptn receptors: Ion channels (change membrane pot/ion conc); Adenyl cyclase (inc ptn phosphorylation); DAG/IP3 (inc ptn phosph and intracellular Ca)
NT Release: Ca-dependent Exocytosis
AP --> depolarization --> enhanced Ca entry to nerve terminal; Ca enables fusion of storage granule ptns (synapsin/synaptobrevin) w/nerve terminal membrane followed by NT release
ACH Release - Quantal
Storage (one granule has <50K ACH molec); Release (ACH released from several hundred quanta)
Presynaptic Regulation of Transmitter Release: Autoreceptors
respond to NT released from its own nerve terminal; usu inhibits release of more NT
Presynaptic Regulation of Transmitter Release: Heteroreceptors
respond to NTs released from other nerve terminals or substances from nearby tissue or blood
Presynaptic Regulation of ACH Release: Dec ACH release from PNS - M2, M4 presynaptic receptors
stimulated by ACH released from PNS nerve terminals
Presynaptic Regulation of ACH Release: Dec ACH release from PNS - a2a, a2c presynaptic receptors
stimulated by NE released from SNS nerve terminals
Presynaptic Regulation of ACH Release: Inc ACH release from spinal nerves - Nn receptors
stimulated by ACH released from spinal nerves to skeletal muscle; prolongs NMJ fxn during prolonged high-frequency contraction of skeletal muscle
Stress Reaction: SNS in action - "Fight or Flight"
Parasympathomimetic Amines: adverse drug reactions (ADRs)
avoid IM or IV injections: hypotension (reflex tachycardia); miosis; hypersalivation/sweating; bronchoconstriction; GI discomfort; impaired cognition (pilocarpine)
Parasympathomimetic Amines: Treatment of Glaucoma - Closed Angle
Medical emergency; lense position blocks access of aqueous humor to trabecular network; indication - short term prior to surgery; caution: Rx may inc IOP (miosis --> iris presses against lens and blocks anterior chamber)
relatively specific for M3 receptors of GI and GU; post-op urinary retention; GERD - inc LES pressure; Caution w/IM or IV injection --- circulatory collapse/cardiac arrest
Direct Acting Parasympathomimetic Amines: Muscarine alkaloids/Amanita muscaria ADRs
phosphorylated ACHE enzyme is extremely stable; restoration of normal ACH fxn requires synthesis of new ACHE molecules (days); good absorption across body membranes ==> widespread distribution thru body and CNS
Antinicotinic Decreased ACH Release - Botulinum toxin (Botox)
decreases ACH release from spinal nerves into NMJ, temporary paralysis of skeletal muscle
Antinicotinic Decreased ACH Release: Botulinum toxin (Botox) Indications - Cosmetic
facial wrinkles (red facial mm contraction); hyperhydrosis, blepharospasm; skeletal muscle spasticity; multiple sclerosis (bladder and bowel symptoms)
Neuromuscular Junction Blockers Non-Depolarizing: Curare (d-tubocurarine) Indications - Adjunct to general anesthesia
Reversible competitive blockade of nicotinic receptors of neuromuscular junction --> flaccid paralysis
Neuromuscular Junction Blockers Non-Depolarizing: Similar Drugs - Mivacurium (Mivacron)
short acting; 10-20min
Neuromuscular Junction Blockers Non-Depolarizing: Similar Drugs - Vecuronium (Norcuron)
intermediate acting; 20-35min
Neuromuscular Junction Blockers Non-Depolarizing: Similar Drugs - Doxacurium (Nuromax)
long acting; >35min
Neuromuscular Junction Blockers Depolarizing: Succinylcholine (Anectine) Indications - Adjunct to general anesthesia
persistent opening of nicotinic receptor channel --> prolonged depolarization of motor endplate --> loss of electrical excitability; duration ~5-10min
Indirect Acting ACE Inhibitors: Ambenonium
treats myasthenia gravis
Indirect Acting ACE Inhibitors: Pyridostigmine
Reverses NM blockade
ACHE Inhibitors: Role in Alzheimers
40-90% dec in choline acetyltransferase in cortex/hippocampus b/f sx; correlation w/ dec ACH, mental status score & sx; Nerves passing thru plaques are damaged and have disrupted NTs; the axons project to cortex/hippocampus for memory/cognition
ACHE Inhibitors: Role in Alzheimers - IV physostigmine
significant improvement of visual recognition
ACHE Inhibitors: Role in Alzheimers - Butyl-cholinesterase
may have role in plaque development
Cholinergic role in Alzheimers - The Flaws
function of other NTs also decrease (seratonin, NE); cholinergic dysfunction may be a result not a cause of Alzheimers
ACHE Inhibitor Role in Alzheimers: Tacrine (Cognex) - additional MOA
blocks neuronal K channels prolonging APs to increase amount of ACH released
ACHE Inhibitor Role in Alzheimers: Tacrine (Cognex) - Indications
mild to moderate conditions; dose-related improvement of cognition and attention tasks; slow decline may occur
ACHE Inhibitor Role in Alzheimers: Tacrine (Cognex) - ADRs
ACHE Inhibitors Role in Alzheimers: Donepezil (Aricept)
selective for CNS ACHE; few effects on peripheral ACHE (less effect on GI pseudocholinesterase)!! Long half-life = once daily dosing; mild to moderate improvement of cognitive testing/caregiver impression scale; efficacy dec w/continued therapy
NMDA Antagonists Role in Alzheimers: Memanthine (Namenda)
dose-dependent blockade of glutamine receptors; efficacy reduces rate of clinical deterioration; ADRs - HA, dizziness (mild, reversible)
ACHE Inhibitor Role in Alzheimers: Rivastigmine (Exelon)
efficacy, ADRs similar to donepezil
ACHE Inhibitor Role in Alzheimers: Galantamine (Razadyne)
efficacy and ADRs similar to donepezil and rivastigmine
Adrenergic Receptor Typical Effects: alpha1
stimulates
Adrenergic Receptor Typical Effects: alpha2
inhibits
Adrenergic Receptor Typical Effects: beta1
stimulates (heart)
Adrenergic Receptor Typical Effects: beta2
inhibits (bronchi of lung; dilation)
Adrenergic Receptor Typical Effects: beta3
stimulates lipolysis in fat cells (beta1 and beta2 have minor role)
Sympathomimetic: Direct acting
receptor agonist
Sympathomimetic: Indirect acting
increases synaptic NE
Sypatholytic: Direct acting
receptor antagonist
Sympatholytic: Indirect acting
decrease synaptic NE
Adrenergic Agonists: Structure/Activity Relationship: Non-catechol Amines (phenylephrine and amphetamine)
remove OH at benzene ring position 4; Less a and b receptor affinity than EPI; Poor substrates for MAO and COMT (won't be catalyzed as fast; last longer than NE); Oral absorption, long duration of action; Penetrates BBB (lipid soluble)
Agonist of a and b receptors (both OH needed for max binding); Do NOT cross BBB; Metabolized by neuronal MAO and COMTof liver/GI; Not orally active; Short duration; Readily oxidized (light/pH sensitive)
a1, a2, b1, b2: slight inc in HR; slight drop in peripheral resistance; systolic inc/diastolic dec slightly
Norepinephrine
a1, a2, b1; baroreceptor reflex; HR slows; great inc in peripheral resistance; systolic rises/diastolic inc slightly
Isoproterenol
b1, b2; HR rises; big drop in peripheral resistance b/c no alpha constriction; systolic slight inc/diastolic drops
Miosis drugs
contraction of circular muscle fibers in iris; stimulated and iris goes towards center of pupil
Mydriasis drugs
alpha1 are dilator fibers; pulls iris muscle back to get dilation of pupil
Oxymetazoline (afrin): a1 selective agonist
nasal decongestant, OTC
Metaraminol (aramine): a1 selective agonist
shock-induced hypotension; prescritpion
Clonidine (catapres): a2 selective agonist
stimulates a2 presynaptic receptors to dec NE release; used for withdrawal from dependece-producing drugs (nicotine and opiate withdrawal inc NE release)
Clonidine (catapres): Hypertension
stimulates a2 receptors of vasomotor ctr to decreases SNS discharge and increase PNS discharge; Decreases HR, CO, and TPR
increases release and inhibits uptake of NE in limbic system (d-isomer > l-isomer) as well as DA and Seratonin possibly by stimulating inhibitory pathways leading to frontal cortex and limbic system)
Amphetamine (Dexedrine, Dextrostat): Indications
Narcolepsy (65-85% efficacy); ADHD (impulsivity, hyperactivity, inability to focus, hypofxn of frontal cortex/limbic system?)
loss of DA uptake; gray matter structure abnormalities, impaired memory and verbal learning, motor slowing, phsycosis
Methamphetamine "speed": Treatment
HT(a-antagonist/Na nitroprusside); NH4Cl (acidify urine to enhance clearance); Anxiety (benzodiazepine); Phychosis (haloperidol may inc meth serum concentration)
MDMA "Ecstasy" (d- and dl-amphetamine, Adderall): Increases Transmitter Release MOA in CNS
Releases and inhibits reuptake of seratonin; (3, 4-methylendedioxymethamphetamine)
MDMA "Ecstasy" (d- and dl-amphetamine, Adderall): Adverse Drug Reactions
LSD-like; hallucinations, perceptual disorders
Cocaine "crack": Indications
local anesthetic blockade of neuronal Na+ binding sites to prevent depolarization
Cocaine "crack": Adverse Drug Reactions
CNS effects dt inhibition of NE, DA, and serotonin reuptake; Tachyphylaxis (25mg line - 9g)
d- and dl-amphetamine (Adderall): Adverse Drug Reactions
this drug is abused; sudden cardiac death in children (family Hx of SVT, near drowning, cardiac structure abnormalities, heat exhaustion, heart attack); FDA prohibits use in cardiac defect pts; suspended in Canada
similar to methamphetamine; must by capsules behind pharmacy counter now so sales are logged to prevent misuse
Ephedrine (ephedra, ma-huong): Increase NE release/a1b1 agonist: Indications
nasal decongestant, appetite suppression
Ephedrine (ephedra, ma-huong): Adverse Drug Reactions
seizure, troke, MI; withdrawn from market by FDA
Monoamine Oxidase (MAO) Inhibitors
located in nerve terminals, liver, GI mucosa, platelets; regulates degradation of catecholamines and serotonin in CNS/periphery
Hepatic MAO
metabolizes circulating monoamines such as indirect-acting sympathomimetic amines (dietary tyramine (tyrosine?))
MAO Inhibitors: MAO-A
role in adrenergic nerve terminals (ANS, CNS); preferentially deaminates NE, EPI and serotonin, Inhibited by Clorgyline
MAO Inhibitors: MAO-B
found in serotonin and histaminergic nerve terminals; deaminates Phenethylamine; Inhibited by Selegiline (eldepryl)
MAO-A and MAO-B
metabolize tyramine and DA; Inhibited by Phenelzine (Nardil) and Tranylcypromine (Partate)
MAO Inhibition Onset
occurs w/in few days but onset of clinical efficacy is several weeks; down-regulation of adrenergic and/or serotonin receptors
MAO Inhibitors: Caution
Irreversible Inhibition: it takes several weeks to regenerate MAO; 2wk washout of MAOI prior to start of sympathomimetic Rx (ex: many OTC cold products); Risk of fatal intracranial bleeds!!
MAO Inhibitors: Indications
treatment of resistant depression (2nd or 3rd line Rx); MAOI-A is more effective than MAOI-B for treating major depression (clinical efficacy occurs w/80% inhibition to enhance availabe dopamine)
MAO Inhibitors: Parkinsons Disease
degeneration of DA neurons that project from S. nigra to basal ganglia and striatum; DA deficit corrected by Levodopa; efficacy "wears off" after several years; Adjunct to L-dopa to increase available DA
MAO Inhibitors: Other Indications
phobias, social anxiety (phenylzine 77% effic; seligiline 32% effic); Refractory migraine, Panic disorder? (poorly designed trials/adequate dose/duration?)
MAO Inhibitors: Adverse Drug Reactions
Hepatotoxicity (Pheylzine-Nardil >> Tranylcypromine-Parnate); Hyperprolactinema; postural hypotension (mc); anti-ACh; sexual dysfunction-dose related
dietary tyramine increases release of catecholamine and 5-HT causing a HYPERTENSIVE Crisis (10mg - HT, 25mg - HTCrisis)
Selegiline (eldepryl): MAO Inhibitor
selective inhibitor of MAO-B; less risk for "cheese rxn;" dietary tyramine is metabolized by MAO-A (less tyramine to release NE and 5-HT)
Selegiline (eldepryl): MOA
metabolized to L-amphetamine + L-methamphetamine; Neuroprotection; prevents peroxide formation a/w oxidative deamination of DA?
a-Methyltyrosine (desmer): Decreases NE synthesis
inhibits tyrosine dydroxylase (rate limiting); depletes catecholamines in SNS nerve terminals, adrenal medulla, and CNS
a-Methyltyrosine (desmer): Indications
pheochromocytoma (tumor of adrenal medulla that secretes excessive EPI and NE
a-Methyltyrosine (desmer): Adverse Drug Reactions
Nasal stuffiness, diarrhea, impotence, hallucinations, depression, Parkinsonism (no NE to constrict a1 in nasal mucosa); exaggerated cholinergics = diarrhea (adronergics slow it down but they're blocked); no dopamine = hypercholinergic = muscle rigidity
Reserpine (serpasil): decrease NE storage
irriversibly blocks CCA uptake into nerve terminal storage granules (several day duration)
Reserpine (serpasil): Indications
hypertension (outdated)
Guanethidine (ismelin): inhibit NE release
displaces NE from storage granules = gradual long-term depletion; Irreversible damage of nerve terminal = sympathectomy
Guanethidine (ismelin): Indication
severe HT (outdated) vasodilation increases venous capacity
a1 >>>>a2; 1. Benign prostatic hypertrophy (blocks a1a receptors [70% of receptors] relaxes prostate capsule, intern sphincter of bladder/urethra); 2. Hypertension (not monotherapy; block arteriole/vein a1b to dec venous return, TPR, CO/BP)
Prazosin (minipress): MOA acute and long-terem
1. Acute: baroreceptor reflex inc HR + renin (Na/H2O retention); 2. Long-term: HR and renin return to normal; Lack of a2 blockade = no increased release of NE
Prazosin (minipress): Adverse Drug Reactions
1. "first dose effect" Orthostatic Hypotension (OH) dt blockade of 1b receptors; possible CNS effect to dec SNS outflow; 2. 50% incidence of concomitant diuretic Rx (a1b blockade, CNS effect?)
Prazosin (minipress): "First Dose Effect"
OH after first dose (90min onset) - 1% incidence at >2mg; low dose 1mg at HS; HS dose titration; May also occur during rapid dose increase (after first few days of Rx or resumption of Rx after few days w/o drug)
indicated for: Benign Prostatic Hypertrophy; selective block of a1a receptors (inhibits contraction of prostate vascular smooth muscle; less affinity for a1b receptors in arterioles/veins so less OH (less need for dose titration); not studied for HT
Tamsulosin (Flomax): Adverse Drug Reactions
Priapism (prolnged and painful erection)
Tamsulosin (flomax): Advantages
initial Rx at lowest maintenance dose; dose anytime during day, no dose titration (shorter ~2wk onset of peak effect); OK to add to selective anti-hypertensives (altenolol, furosemide, enalapril, nifedipine)
b1-selective; partial agonist effects at b2 receptors
Esmolol
b1-selective;
Labetalol
non-selective; partial agonist, local anesthetic (also causes a1 adenoceptor blockade)
Metoprolol
b1-selective; local anesthetic
Nadolol
non-selective
Penbutolol
non-selective; partial agonist
Pindolol
non-selective; partial agonist; local anesthetic
Propranolol
non-selective; local anesthetic
Sotalol
non-selective
Timolol
non-selective
b-Receptor Antagonists: b1-cardioselective
b1>b2: heart and kidney (vs. b2>b1: lungs/liver/pancreas/arterioles); less likely to provoke broncospasm/vasoconstriction; safer for asthmatics, COPD, peripheral vascular dx, diabetes; preferred in ischemic heart disease to prevent second MI
b-Receptor Antagonists: Effects on Heart
At Rest: modest reduction of HR and force of contraction; Stress Rxn: attenuate typical positive inotropic and chronotropic effects
b-Receptor Antagonists: Effects on Eye
reduce formation of aqueous humor
b-Receptor Antagonists: Effects on Kidney
antagonize release of renin
b-Receptor Antagonists: Member stabilizing ("Quinidine-like" Effect)
blocks Na channels of nerve, heart, skeletal muscle; dose-dependent
b-Receptor Antagonists: Effects on Serum Lipids
Non-selective (reduce HDL, increase LDL and TGs); b1-Selective (improve lipid profile of dyslipidemic pts)
b-Receptor Antagonists: Adverse Drug Reactions
Reduce insulin secretion mostly in insulin-dependent diabetics (hyperglycemia, hampers recovery from hypoglycemia, masks warning signs of hypoglycemia/hyperthyroidism (tachycardia)); Exacerbates Hypoglycemia (inc SNS tone, unopposed a1 vasoconstriction)
b-Receptor Antagonists: Adverse Drug Reactions
Hypotension, Cardiac Failure (usu high dose; a/w prior LV dysfxn, neg inotropics); Bradycardia, heart block, Exacerbate bronchospasm in asthma/COPD; Exacerbate Raynaud's disease; Erectile Dysfxn (dec flow to corpora); CNS (depression, fatigue, no libido)
b-Receptor Antagonists: Warnings - Exercise
attenuates the following: cardiac stimulation, bronchodilation, glycogenolysis and lipolysis
prevents tachycardia seen in hypoglycemia; reduced insulin response to hyperglycemia; may need to adjust antidiabetic Rx
b-Receptor Antagonists: Warnings - Abrupt Cessation of Rx
For pts predisposed to myocardial ischemia (MI, arrhythmia, death, inc sensitivity of b-receptors to EPI and NE; failure to dec physical activity); Uncompromised pts (tachycardia, inc sweating, malaise); **Taper dose over 2wks
b-Receptor Antagonists: Contraindications
Bronchial asthma (non-selective, lacking ISA); Cardiac Failure (use w/caution in pts w/well-compensated cardiac failure); Cardiogenic shock; Severe bradycardia; Severe prolonged hypotension
long-term Rx reduces peripheral resistance (inc NO, a1 antagonist, block Ca-channels, b2 agonist, antioxidant, open K-channels; Combined effect of reduced CO and reduced peripheral resistance
indicated for: Preclampsia HT (IV); HT of pregnancy (doesn't aggravate peripheral vascular disease as much as pure b-blockers); HT emergency (decreases peripheral vascular resistance w/no effect on HR or CO)
b-Receptor Antagonists: Migraine Prophylaxis
unknown MOA; most widely used (atenolol, metoprolol, nadolol, propranolol); drugs w/ISA are ineffective
b-Receptor Antagonists: Alcohol Withdrawal and Social Anxiety
blocks peripheral SNS effects
b-Receptor Antagonists: Anxiety
useful for pts w/palpitations or tremor; for non-responders to benzodiazepine (ex: Valium); Typical onset = 1wk (take ahead of time); Taper to avoid rebound anxiety
b-Receptor Antagonists: Hyperthyroidism
palpitations, anxiety, tremor, heat intolerance; inhibits conversion of T4 to T3; minor effect unrelated to b-blockade
b-Receptor Antagonists: Role in Ischemic Heart Disease
dec HR and contractility, slight BP dec myocardial O2 demand; countered slightly by inc ventricular vol and ejection time; Net Effect: Reduced Myocardial O2 Demand; (a1 stimulation in presence of b-blockade may constrict coronary aa)
b-Receptor Antagonists: Role in Ischemic Heart Disease - b-blocker of choice
no evidence to ID a b-blocker; Cardioselectives may be preferred in pts w/COPD, asthma or intermittent claudication; Labetolol = possible less coronary artery constriction (useful in pts w/little LV reserve)
b-Receptor Antagonists: MI
recuce ventricular arrhythmias, recurrent ischemia and re-infarction; reduced workload dt reduced HR, systolic BP, and myocardial contractility
b-Receptor Antagonists: Acute MI
n = 16,000; Atenolol IV, oral; 15% reduction in vascular mortality OR n = 6,000; Metoprolol 13% reduction in mortality in 1 month
b-Receptor Antagonists: Post MI
short term dose of various b-blockers after MI are more beneficial; n = 1,884 pts for 12-33 mo, Timolol 39% red mortality and 28% red re-infarct; OR n = 3,837 for 27 months Propranolol 26% red mortality;
b-Receptor Antagonists: Angina
reduces frequency and severity of exertional angina
b-Receptor Antagonists: Angina Pectoris
neg inotropic/chronotropic effects; red myocardial O2 demand; inc diastolic coronary perfusion time; Atenolol (reduced hospitalization for angina, need for revascularlization, death); Chronic/stable w/preserved LV fxn (question red in mortality; MI Hx pt)
b-Receptor Antagonists: Perioperative
CABG after MI; 1yr mortality red from 12 to 4%; Non-cardiac surgery in pts w/coronary risk factors; fewer perioperative CV events
b-Receptor Antagonists: Heart Failure
Bisoprolol w/pts with LVEF 34% red in mortality; significantly fewer CV deaths
b-Receptor Antagonists: Heart Failure
Metoprolol extended release in pts w/LV ejection fraction; red mortality, sudden death and death dt worsening CHF
b1-Cardioselective Receptor Antagonists
dose-dependent (high dose also blocks b2); patient-specific
dec BP w/o reflex tachycardia and w/o red in HR; BP is lowered more in standing than supine position; OH First Dose Effect can occur (usu w/in 2-4hrs of large initial dose or on change of dose)
Labetolol (normodyne, trandate): Indications
Oral (Hypertension); IV for hospitalized pts (severe HT dt risk of OH, pt must be supine during injection; must be able to tolerate upright posture b/f ambulating)
Carvedilol (coreg): mixed b + a1 antagonist
compared to other b-blockers: produces more hypotension and dizziness; possible greater anti-hypertensive effect
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