| ANS drugs |
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|
| Features |
|
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| Autonomic Nervous System |
Enteric (semiautonomous), Parasympathetic (CN III, VII, IX, X and S2-S4), Sympathetic (T1-12, L1-L5) |
| Cholinomimetic (cholinergic) Drug Breakdown: Direct Acting |
Muscarinic (choline esters, alkaloids) and Nicotinic |
| Cholinomimetic (Cholinergic) Drug Breakdown: Indirect Acting |
Edrophonium (short-acting), Carbamates (intermed-long acting), Organophosphates (very long-acting) |
| Adrenergic Agonists: Adrenoceptors |
alpha1, alpha2, beta1, beta2 |
| Adrenoceptors: alpha1 |
vasoconstriction, inc peripheral resistance, inc BP, inc closure of internal bladder sphincter, mydriasis |
| Adrenoceptors: alpha2 |
inhibition of NorEpi release, inhibition of insulin release |
| Adrenoceptors: beta1 |
tachycardia, inc lipolysis, inc myocardial contractility, inc release of renin |
| Adrenoceptors: beta2 |
vasodilation, slight dec peripheral resistance, bronchodilation, inc release of glucagon, relaxed uterine smooth muscle |
| ANS Direct-acting drugs |
muscarine, carbachol, bethenachol, pilocarpine, nicotine, succinylcholine |
| ANS Indirect-acting drugs |
echotiphate (irreversible), edrophonium, neostigmine, pyridostigmine, physostigmine, parathion, malathion, dichlorvos |
| Other ANS drugs |
Acetylcholine, botulinum toxin, cocaine, dopamine, epinephrine, metanephrine, norepinephrine, saxitoxin, tetrodotoxin |
| Neurotransmitters: Parasympathetic NS |
pre - ACH, post - ACH |
| Neurotransmitters: Sympathetic NS |
pre - ACH, post - NE |
| Innervation of end organs: |
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" |
inc flow of oxygenated blood; inc skeletal muscle contractility; inc blood glucose; inc platelet aggregation; inc pupil diameter (mydriasis) |
| Stress Reaction: Increased flow of oxygenated blood - b2 |
dilate bronchi and vessels to skeletal muscle |
| Stress Reaction: Increased flow of oxygenated blood - b1 |
positive chronotropic (rate) and inotropic (force of contraction) cardiac effects |
| Stress Reaction: Increased flow of oxygenated blood - a1 |
constrict arteries to skin, GI, kidney and shunt blood to skeletal muscles; contracts spleen to inc RBCs in blood |
| Stress Reaction: Increase skeletal muscle contractility - b2 |
EPI increases rate and force of contraction |
| Stress Reaction: Increase/Maintain Blood Glucose - a1, b2 |
increase glycogenolysis |
| Stress Reaction: Increase/Maintain Blood Glucose - b2 |
increase glucagon secretion |
| Stress Reaction: Increase/Maintain Blood Glucose - a2 |
decrease insulin secretion |
| Stress Reaction: Platelet aggregation - a2 |
increases |
| Stress Reaction: eye - a1 |
contracts radial muscle of iris ==> mydriasis |
| Stress Reaction: eye - b2 |
relaxes ciliary muscle for far vision |
| Stress Reaction: sweat glands - a1 |
increase activity |
| Stress Reaction: sweat glands - M3 |
increases sympathetic cholinergic |
| Visual Accomodation - SNS |
distant vision accomodation: relaxes ciliary body, tension on lens, flattens lens |
| Visual Accomodation - PNS |
near vision accomodation; contract ciliary body, lessen tension on lens, thickens lens |
| Visual Accomodation - cycloplegia |
loss of accomodation d/t antimuscarinic drugs (atropine) |
| Enteric Nervous System: myenteric and submucosal plexuses |
contain interneurons w/transmitters ACH, NE, Substance P, enkephalins, vasoactive intestinal peptide (VIP); local reflexes maintain peristalsis/secretion; innervated by PNS, SNS and sensory nerves |
| Enteric Nervous System: ANS |
modulates neural regulation |
| Enteric Nervous System: PNS |
directly innervates smooth muscle and glands of gut |
| Enteric Nervous System: SNS |
inhibits gut motility and secretions; synaps w/ PNS cells w/in intramural plexuses inhibits ACH release from PNS nerve terminals |
| Direct Acting: Muscarinic Agonists - Pilocarpine |
Glaucoma |
| Direct Acting: Muscarinic Agonists - Carbachol |
Glaucoma |
| Direct Acting: Muscarinic Agonists - Behanechol |
postoperative ileus, megacolon, urinary retention |
| Indirect Acting: ACHE Inhibitors - Physostigmine |
glaucoma |
| Indirect Acting: ACHE Inhibitors - Echothiophate |
glaucoma |
| Indirect Acting: ACHE Inhibitors - Isoflurophate |
glaucoma |
| Indirect Acting: ACHE Inhibitors - Decamerium |
glaucoma, treats myasthenia gravis |
| Indirect Acting: ACHE Inhibitors - Edrophonium |
diagnose myasthenia gravis; reverses NM blockade; supraventricular tachyarrhythmia |
| Indirect Acting: ACHE Inhibitors - Neostigmine |
glaucoma, post-op ileus, megacolon, urinary retention, reverse NM blockade |
| Neurotransmission: Muscarinic Receptor Agonists |
inc cGMP; inhibits cAMP activity; attenuate inc cAMP induced by EPI, NE; stimulates DAG and IP3 to inc phosphorylation and intracellular Ca |
| The Plan: Parasympathomimetic |
Direct: Muscarinic receptor agonists; Indirect: Inhibits ACHI |
| The Plan: Parasympatholytic |
Direct: Receptor antagonists; Indirect: Decrease ACH release |
| Parasympathomimetic Therapy Overview: Muscarinic Agonists |
glaucoma, post-op ileus, congenital megacolon, urinary retention |
| Parasympathomimetic Therapy Overview: ACHE inhibitors |
glaucoma, post-op ileus, congenital megacolon, urinary retention, diagnose/treat myasthenia gravis; reverse neuromuscular blockade; Alzheimer's disease |
| Parasympathetic Therapy Overview: Muscarinic Antagonists |
antsecretory; examin retina/measure refraction; hypermotility of GI and urinary tract; urinary incontinence; IBS; COPD; Parkinson's Disease |
| Parasympathetic Therapy Overview: Ganglionic Blockers |
hypertensive emergency |
| 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: Contraindications |
Asthma, CAD, bradycardia, peptic ulcer, GI/GU hypermotility or obstruction, COPD, HYPOtension |
| Parasympathomimetic Amines: Treatment of Glaucoma - Open Angle Primary |
ocular angle is open; abnormal trabecular network impedes drainage of aqueous humor |
| Parasympathomimetic Amines: Treatment of Glaucoma - Open Angle Secondary |
d/t inflammation, trauma, or ocular disease |
| Parasympathomimetic Amines: Treatment of Glaucoma - Mechanism and Caution |
contract longitudinal ciliary muscle --> stretch/open trabecular network; Miosis --> iris moves away from ocular angle; Caution: Reduced accomodation |
| 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) |
| Parasympathomimetic Amines: Pilocarpine, Pilocar, Pilopine HS Gel, Ocsert (time release); tertiary amine; lipophilic; pure muscarinic agonist |
open-angle glaucoma - parasympathomimetic amine of choice; Xerostomia d/t radiation or Sjogren's syndrome (Cevimeline, Evoxac) |
| Parasympathomimetic Amines: Bethenechol (Urecholine) |
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 |
mushroom poisoning onset 15-30min; N&V, diarrhea; bronchial constriction; cutaneous vasodilation |
| Indirect Acting Parasymathomimetic Drugs: Reversible ACHE Inhibitors |
broader use than muscarinic agonists; Reversible (Neostigmine, Prostigmin) and Irreversible (Organophosphates) |
| ACHE Inhibitor duration of action: Edrophonium |
5-15 min |
| ACHE Inhibitor duration of action: Neostigmine |
30min - 2hr |
| ACHE Inhibitor duration of action: Physostigmine |
30min - 2hr |
| ACHE Inhibitor duration of action: Pyridostigmine |
3 - 6hrs |
| ACHE Inhibitor duration of action: Ambenonium |
4 - 8hrs |
| ACHE Inhibitor duration of action: Demacarium |
4 - 6hrs |
| ACHE Inhibitor duration of action: Echothiophate |
100hrs |
| Indirect Acting Parasympathomimetic Drugs: Reversible ACHE Inhibitors - Neostigmine (prostigmin) |
urinary retention (contract bladder wall/relax internal sphincter); Parylitic Ileus; Open-angle glaucoma; Myasthenia gravis (skeletal muscle weakness d/t dec nicotinic receptors at NMJ; ACHE inhibitors inc ACH to stim available receptors |
| Parasympathomimetic "Irreversible" ACHE Inhibitors: organophosphates |
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 |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Echothiophate (phospholine) |
open angle glaucoma (100hr duration) |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Diazinon, Malathion, Malaoxon, Parathion |
insecticides |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Abuse |
nerve gas (ricin, sarin, soman, tabun); symptoms occur w/in 6hrs w/50% inhibition; hypotension, miosis, bronchospasm, abdominal cramps, incontinence, arrhythmias, hypertension, respiratory paralysis, tremor, weakness, seizures, coma |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Treatment of Nicotinic Effects - Pralidoxime (2-PAM, Protopam) |
regenerates ACHE - breaks ACHE-organophosphate bond; IV q 5-30min; repeat in 30min PRN; Rapid injection --> laryngospasm, muscle rigididy, weakness |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Aging |
breaking one oxygen-phosphorous bond of inhibitor further strengthens phosphorous-enzyme bond |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Treatment of Muscarini Effects - Atropine generic |
blocks muscarinic receptors; IV q 5-15min to dry bronchial secretions; repeat or constant IV infusion; questionable efficacy to treat CNS toxicity |
| Indirect Acting Parasympathomimetic "Irreversible" ACHE Inhibitors: Treatment of Seizures |
benzodiazepines |
| Parasympatholytic Muscarinic Receptor Antagonist: Atropine Indications - adjunct to general anesthesia |
reduce bronchial secretion; prevent vagal reflex d/t organ manipulation |
| Parasympatholytic Muscarinic Receptor Antagonist: Atropine Indications - Myocardial Infarction |
prevent reflex bradycardia; AV block |
| Parasympatholytic Muscarinic Receptor Antagonist: Atropine Indications - Mushroom poisoning |
some mushrooms contain muscarininc alkaloids |
| Parasympatholytic Muscarinic Receptor Antagonist: Atropine Indications - Ophthalmic Examination |
ciliary paralysis, mydriasis - facilitates examination of fundus |
| Parasympatholytic Muscarinic Receptor Antagonist: Tolerodyne (Detrol), Oxybutynin (Ditropan) Indications - Urinary incontinence |
relax urinary bladder wall; contract internal sphincter |
| 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 |
rate limitins/decreased use; liver toxicity; N&V, loose stools, dizziness, HA; tolerance develops to peripehral cholinergic effects |
| 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) |
| Adrenergic Agonists: Structure/Activity Relationship: Catecholamines (EPI, NE, Isoproterenol) |
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) |
| Adrenergic Agonists: Structure/Activity Relationship: alpha Carbon Substitution |
poor substrates for MAO; prolongs duration of action of catecholamines and non-catecholamines |
| Adrenergic Agonists: Structure/Activity Relationship: beta OH |
required for storage in nerve terminal granules |
| Adrenergic Agonists: Structure/Activity Relationship: Amine Nitrogen Substitution |
beta receptor affinity increases as group on amine nitrogen increases in size (EPI > NE) |
| Adrenergic Agonists: Examples of Non-catecholamines |
Amphetamine, Ephedrine, Dobutamine, Methyphenidate, Albuterol, Phenylephrine |
| Synthesis of Catecholamines |
Tyrosine --> DOPA --> Dopamine --> NE --> EPI (bulkier amines stimulate beta receptors) |
| Cocaine |
blocks reuptake of NE into nerve terminal |
| Alpha 2 receptors stimulated on nerve terminal has: |
negative feedback on NE release |
| Radial m. of eye: SNS effect, adrenergic receptor |
contracts (mydriasis); alpha1 |
| Circular m. of eye: PNS effect; cholinergic receptor |
Contract (miosis); M3 |
| Trabecular network of eye: SNS Effect; Adrenergic Receptor |
Increases outflow of aqueous humor; alpha2 |
| Trabecular Network of eye: PNS effect; Cholinergic Receptor |
Increases outflow of aqueous humor; M3 |
| Ciliary Process (epithelium) of Eye: SNS Effect, Adrenergic Receptor |
Increased synthesis of aqueous humor; Beta2 OR Decreases synthesis of aqueous humor; alpha2 |
| Lungs: SNS Effect, Adronergic Receptor |
Dilates; beta2 |
| Lungs: PNS Effect; Cholinergic Receptor |
Contract; M3 |
| Heart Rate: SNS Effect: Adrenergic Receptor |
increases; beta1 |
| Heart Rate: PNS Effect: Cholinergic Receptor |
Decreases; M2 |
| Heart Force: SNS Effect: Adrenergic Receptor |
Increases; beta1 |
| Heart Force: PNS Effect: Cholinergic Receptor |
Decreases; M2 |
| Blood Vessels: SNS Effect; Adrenergic Receptor |
constrict; alpha1 |
| Coronary Arteries: SNS Effect; Adrenergic Receptor |
dilate; inc work of heart increases synthesis of adenosine (vasodilator) |
| Coronary Arteries: PNS Effect; Cholinergic Receptor |
Dilate; M2 |
| Blood Vessels in Skeletal Muscle: SNS Effect; Adrenergic Receptor |
Dilate; beta2 |
| Skeletal Muscle Contractility: SNS Effect; Adrenergic Receptor |
increases; beta2 |
| Spleen: SNS Effect: Adrenergic Receptor |
contracts; alpha1 |
| Platelet aggregation: SNS effect; adrenergic receptor |
increases; alpha2 |
| Apocrine sweat glands (stress): SNS effect; adrenergic receptor |
increases; alpha1 |
| Sweat gland temperature regulation: SNS effect; Adrenergic Receptor |
increases; M3 sympathetic cholinergic |
| Liver Glycongenolysis: SNS Effect; Adrenergic Receptor |
Increases; alpha1, beta2 |
| Fat Cell Lipolysis: SNS Effect; Adrenergic Receptor |
increases; beta3 (small role of b1/b2) |
| Pancreas Insulin secretion: SNS Effects; Adrenergic Receptor |
Decreases; alpha2 OR Increases; beta2 |
| Pancreas Glucagon Secretion: SNS Effects; Adrenergic Receptor |
Increases; beta |
| GI tract wall: SNS Effect; Adrenergic Receptor |
relaxes; alpha2, beta2 |
| GI tract wall: PNS Effect; Cholinergic Receptor |
contracts; M3 |
| GI tract secretion: PNS Effect; Cholinergic Receptor |
Increases; M3 |
| Kidney Renin Secretion: SNS Effect; Adrenergic Receptor |
increases; beta1 |
| Nasal, salivary, gastric secretory glands: SNS Effect; Adrenergic Receptor |
decrease; alpha1 |
| Nasal, salivary, gastric secretory glands: PNS Effect; Cholinergic Receptor |
Increases; M3 |
| Bladder Wall: SNS Effect; Adrenergic Receptor |
relaxes; beta3 |
| Bladder wall: PNS effect; cholinergic receptor |
contracts; m3 |
| Bladder internal sphincter: SNS effect; adrenergic receptor |
contracts; alpha1 |
| Bladder internal sphincter: PNS effect; cholinergic receptor |
relaxes; M3 |
| Ureter: SNS effect; adrenergic receptor |
contracts; alpha1 |
| Ureter: PNS effect; cholinergic receptor |
relaxes; M3 |
| Prostate capsule: SNS Effect; adrenergic receptor |
contracts; alpha1 |
| Uterus (pregnant): SNS effect; adrenergic receptor |
relaxes; beta2 |
| Uterus (pregnant); PNS effect; Cholinergic receptor |
variable; M3 |
| Penile arteries: SNS effect; adrenergic receptor |
contracts (detumescence); alpha1 |
| Penile arteries: PNS effect; cholinergic receptor |
relax (erection); M3 |
| SNS Postganglionic Nerve Terminal: SNS Effect; Adrenergic Receptor |
decrease NE release; alpha2 |
| SNS postganglionic nerve terminal: PNS Effect; cholinergic receptor |
decreses NE release; M3 |
| alpha1 Receptor Effects |
contract radial m. of iris (mydriasis); increases sweating (stress); constricts vasculature of skin (inc TPR/BP); contracts spleen/prostate capsule/penile aa/seminal vesicles/bladder&GI sphincters; dec nasal/salivary/gastric secretions |
| alpha2 Receptor Effects |
inhibit NE release; inhibit insulin release; dec synthesis of aqueous humor; increase platelet aggregation |
| beta1 Receptor Effects |
increase rate/force of myocardial contraction; increase renin secretion (inc blood vol); relaxes ciliary m. |
| beta2 Receptor Effects |
inc synthesis of aqueous humor; dilate bronchi; relax GI wall/bladder wall/pregnant uterus; inc skeletal muslce & liver glycogenolysis; inc glucagon secretion; inc skeletal m contractility |
| Metabolic Effects of beta receptors: Glycogenolysis |
skeletal muscle (b2); liver (b2, a1) |
| Metabolic Effects of b receptors: Lipolysis |
fat cells: b3 (a1, b1, b2) |
| Epinephrine (adrenaline, epipen): non-selectice a/b agonist (a1, b1, b2) |
vasoconstriction (skin), inc rate/contractility of heart, dilates bronchi; |
| Epinephrine (adrenalin, epipen): Cardiac Arrest |
injected directly into heart for b1 effects |
| Epinephrine (adrenalin, epipen): Hypersensitivity/Anaphylaxis |
antagonize vasodilation induced by histamine/leukotrienes (normalize permeability of venules); beta2 bronchodilation inhibits release of inflammatory mediators |
| Epinephrine (adrenalin, epipen): Adverse Drug Reactions |
tachycardia, increased BP |
| Epinephrine (adrenalin, epipen): Topical Hemostasis |
a1 vasoconstriction; also prolongs effect of local anesthetics |
| Norepinephrine (noradrenalin, levophed): a/b non-selective agonist (a1, b1) |
vasoconstriction, positive cardiac chrono/inotropic effects (VERY little effect on b2 vasodilation) |
| Norepinephrine (noradrenalin, levophed): Indication |
shock - counteracts hypotension |
| Norepinephrine (noradrenalin, levophed): Adverse Drug Reactions |
bradycardia (dt baroreceptor vagal reflex); inceased BP |
| Phenylephrine (neo-synephrine) |
a1-Selective Agonist |
| Phenylephrine (neo-synephrine): Nasal decongestant |
constricts nasal vasculature, shrinks swollen membranes |
| Phenylephrine (neo-synephrine): hypotension |
antagonizes hypotension associated w/anesthesia |
| Phenylephrine (neo-synephrine): Mydriasis |
contracts radial m. of iris |
| Epinephrine |
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 |
| Clonidine (catapres): Precautions During Therapy |
orthostatic hypotension (stimulationof presynaptic a2 receptors decreases NE release causing vasodilation) |
| Clonidine (catapres): Precautions about Abrupt Cessation |
hypertension (decreased stimulation of presynaptic a2 receptors increases NE release)...must wean pt off drug |
| Clonidine (catapres): Drug Interactions |
tricyclic antidepressants (TCA) block a1 receptors ==> block anti-HT effects of clonidine |
| a-Methyl Dopa (aldomet): a2a-Selective Agonist |
metabolized to a-methyl NE |
| a-Methyl Dopa (aldomet): Hypertension |
dt clonidine-like CNS MOA; safe use in pregnancy |
| a-Methyl Dopa (aldomet): Adverse Drug Reactions |
limit use; hepatotoxicity; hemolytic anemia |
| Dobutamine (dobutrex): b1-Selective Agonist MOA |
(-) isomer (a1 agonist + weak b1 agonist) and (+) isomer (a1 antagonist + potent b1 agonist) ==> NET EFFECT |
| Dobutamine (dobutrex): Inotropic effect > Chronotropic effect |
increases contractility and CO; lack of b2 effect (less vasodilation/less activation of baroreceptor reflex; LESS TACHYCARDIA) |
| Dobutamine (dobutrex): Caution |
tolerance w/prolonged use |
| Dobutamine (dobutrex): Indications |
cardigenic shock, refractory CHF, acute cardiac compensation (IV infusion; 2min onset), Myocardial Infarction |
| Albuterol (proventil): Asthma |
bronchodilation, anti-inflammatory, inhibit release of inflammatory mediators from mast cells, increase mucus clearance by cilia |
| Albuterol (proventil): Caution (downregulation/desensitization) |
agonist of b receptors; activates adenyl cyclase, inc cAMP, activates phosphokinase A, phosphorylates b receptor protein = Reduced Effect of Agonist! |
| b2 Selective Agonist Inhalers: Albuterol |
Onset (5min); Duration (4-6hr); acute bronchospasm, prevents exercise-induced asthma |
| b2 Selective Agonist Inhalers: Bitolterol (tornalate) |
Onset (2-4min); Duration (4-6hrs) |
| b2 Selective Agonist Inhalers: Salmeterol (severent) |
Onset (10-20min); Duration (>12hrs); maintenance (mild to moderate asthma); nocturnal symptoms; w/inhaled corticosteroid reduces need to inc steroid dose |
| Albuterol (proventil): Adverse Drug Reactions |
tremor, tachycardia (b2 = 25% of cardiac b); arrhythmias with high dose; death??? |
| Ritodrine (yutopar): b2 selective agonist |
Indication for arresting premature labor |
| Ritodrine (yutopar): Adverse Drug Reactions |
cardiac stimulation, hypotension, neonatal hypoglycemia |
| Dopamine (intropin): dopamine agonist MOA |
"renal dose" <2ug/kg/min; stimulates D2 presynaptic and D1 postsynaptic receptors; diates renal/mesenteric/coronary vessels |
| Dopamine (intropin): b1 agonist |
medium dose (2-10ug/kg/min); positive inotropic effect |
| Dopamine (inotropin); a1 agonist |
High dose (10ug/kg/min); vasoconstriction |
| Dopamine (intropin): indications |
shock a/w low CO and compromised renal fxn; CHF; acute renal failure |
| Fenoldopam (corlopam): Dopamine D1 Agonist |
dilates renal, mesenteric, and coronary aa; reaches steady state serum level in 20min; (also weak a2 agonist) |
| Fenoldopam (corlopam): Indication |
short term (up to 48hrs) Rx for severe hypertension |
| Fenoldopam (corlopam): Adverse Drug Reactions |
dose-related hypotension; tachycardia (risk of exacerbated CHF); headache, flushing |
| Amphetamine (Dexedrine, Dextrostat): Increases Transmitter Release - Peripheral Effects |
Increases release and inhibits uptake of NE |
| Amphetamine (Dexedrine, Dextrostat): Increases Transmitter Release - CNS Effects |
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?) |
| Methampthetamine (Desoxyn, "speed"): Increase transmitter release |
compared to amphetamine there is a greater CNS effect and less severe peripheral effect |
| Amphetamine (dexedrine) and Methamphetamine (Desoxyn "speed"): Adverse Drug Reactions |
anorexia, paranoia, aggressive behavior, arrhythmias, subarachnoid hemorrhage, convulsions, vomiting/diarrhea, euphoria, hypertension, ischemic stroke, coma |
| Methamphetamine (Desoxyn, Speed): Long-term abuse |
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 |
| Methylphenidate (Ritalin, Concerta): Increases Transmitter Release |
mild amphetamine, less CNS stimulation, appetite suppression, tachycardia, phsychosis; 3-5hr duration, tolerance develops |
| Atomoxetine (strattera): Inhibits NE uptake |
selective inhibitor of NE uptake, not CNS stimulant; slower onset; second line Rx for non-responders/intolerant to CNS stimulants |
| Atomoxetine (strattera): compared to amphetamine |
not a CNS stimulant, less "hill and valley" effects; less efficacy? |
| Atomoxetine (strattera): Adverse Drug Reactions |
usu results in discontinuation (nausea, sedation, irritability, temper tantrums) |
| Atomoxetine (strattera): Suicidal Ideation? |
FDA public health advisory issued 9/05; call for mfg to issue patient medicaiton guide for parents |
| Pemoline (cylert): Increase Transmitter Release |
efficacy similar to methylphenidate |
| Pemoline (cylert): Adverse Drug Reactions |
**Severe Liver Toxicity; CNS problems similar to methylpenidate; less cardiovascular problems |
| Pseudophedrine (Sudafed): Inc NE release/a1b1 agonist |
increases release of NE, weak agonist of a1 and b1 receptors |
| Pseudophedrine (Sudafed): Indications |
nasal decongestant, urinary incontinence (a1 contracts internal sphincter) |
| Pseudophedrine (Sudafed): Warning |
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 |
| MAO Inhibitors: Drug Interactions |
Meperidine (demerol); Dextromethorphan, Tricyclic antidepressants, SSRIs, L-tryptophan (inc serotonin synth); Sumatriptan (CNS 5-HT agonist) |
| MAO Inhibitors: Serotonin Syndrome |
HT, shivering, diaphoresis, muscle rigidity, fever, agitation, hallucinations |
| MAO Inhibitors: "Cheese Reaction" |
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 |
| Guanethidine (ismelin): Adverse Drug Reactions |
similar to a-methyltyrosine and reserpine |
| Phenoxybenzamine (dibenzyline): non-selective irreversible a-receptor agonist |
a1 = a2; 48hr turnover time |
| Phenoxybenzamine (dibenzyline): Indications |
1. Pheochromocytoma (long-term for inoperable cases; 1-3wks pre-op to control BP; concomitant Rx w/a-methyltyrosine and/or b-blocker; 2. Autonomic hyperreflexia dt spinal cord transection |
| Phentolamine (regitine): Non-selective Reversible a-Receptor Agonist |
a1 = a2; indicated for: 1. Raynaud's disease (arterial injection/infusion; improves finger blood flow/digital pulse vol/forearm flow; reduces vasospasm); 2. Pheochromocytoma; 3. Erectile Dysfxn (intracavernosal injection) |
| Phentolamine (regitine): Adverse Drug Reactions |
IV: severe tachycardia/arrhythmias/myocardial ischemia; vasodilation activates baroreceptor reflex/inc SNS activity; blockade of a2 presyn receptors inc NE release; 2. PO: tachycardia, nasal congestion; 3. Inhibits ejaculation |
| Prazosin (minipress): Selective Reversible a-Receptor Antagonist |
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) |
| Terozasin (hytrin): Selective Reversible a-Receptor Antagonist |
indicated for: Hypertension and Benign Prostatic Hypertrophy |
| Terozasin (hytrin): Adverse Drug Reactions |
First dose effect; slow titration schedule (days 1-3 = 1mg HS; days 4-14 = 2mg HS; wks 2-6 = 5mg HS; wks 7+ = 10mg HS) |
| Tamsulosin (Flomax): Selective Reversible a-Receptor Antagonist |
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) |
| Alfuzosin (uroxotral): Selective Reversible a-Receptor Antagonists |
a Tamsulosin "me too" drug |
| Doxazosin (cardura): Selective Reversible a-Receptor Antagonists |
indicated for: BPH and HT (effective as MONOTHERAPHY or w/diuretics, b-blockers, Ca-channel blockers, angiotensin-converting enzyme (ACE) inhibitors); exhibits "First Dose Effect" |
| Pharmokinetics of Selective Reversible a-Receptor Antagonists: Prozasin |
Serum half-life = 2-3hrs; 2-3 dose/day |
| Pharmokinetics of Selective Reversible a-Receptor Antagonists: Alfuzosin |
Serum half-life = 3-5hrs; 1dose/day |
| Pharmokinetics of Selective Reversible a-Receptor Antagonists: Terazosin |
Serum half-life = 9-12hrs; 1dose/day |
| Pharmokinetics of Selective Reversible a-Receptor Antagonists: Tamsulosin |
Serum half-life = 9-15hrs; 1dose/day |
| Pharmokinetics of Selective Reversible a-Receptor Antagonists: Doxazosin |
Serum half-life = 22hrs; 1dose/day |
| b-Receptor Antagonists (Blockers) |
compounds vary receptor selectivity, local anesthetic action, lipid solubility, elimination half-life; Partial b-agonist action (intrinsic sympathomimetic activity (ISA); Acebutolol, Carteolol, Penbutolol, Pindolol; less drop of rest-HR/CO/periph flow) |
| b-Receptor Antagonists (blockers): Pharmokinetics |
First-pass metabolism (Propranolol, metoprolol) pt/dose variability; Long half-life, Renal excretion (dose adjust); Shorter half-life (1/day usu effective) |
| Sympatholytic b-Receptor Antagonists: 1st Generation Non-Selective |
Propranolol (Inderal) |
| Sympatholytic b-Receptor Antagonists: 2nd Generation Selective b1-Cardioselective beta blockers |
Acebutolol, Altenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol |
| Sympatholytic b-Receptor Antagonists: 3rd Generation Non-selective b-blockade + a-blockade (vasodilation) |
Carvedilol (coreg), Labetolol (normodyne) |
| Acebutolol |
b1-selective; partial agonist, local anesthetic |
| Atenolol |
b1-selective |
| Betaxolol |
b1-selective; slight anesthetic |
| Bisoprolol |
b1-selective |
| Carteolol |
not selective, partial agonist |
| Carvedilol |
non-selective (also causes a1 adrenoceptor blockade)
|
| Celiprolol |
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 |
