Phar 752 Pharmacology and Medicinal Chemistry Peripheral Nervous System Theresa M. Filtz, PhD Philip J. Proteau, PhD Fall 2006
Autonomic Nervous System
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Readings for Peripheral Nervous System Pharmacology & Medicinal Chemistry Review Golan: Chapters 1 to 4 Goodman and Gilman: Chapter 1, Part II Introduction to the ANS and Cholinergic Module (I) Wilson and Gisvold, ed. 11: Chapter 17, Cholinergic Drugs Golan: Chapter 5, pg 66-69, Chapter 6, pp 71-75, Chapter 7 Goodman and Gilman: Chapters 6, 7, 8, and 9 Adenergic Module (II) Wilson and Gisvold, ed. 11: Chapter 16, Adrenergic Agents Golan: Chapter 8 Goodman and Gilman: Chapter 10 Vocabulary List for the Autonomic Nervous System—fair exam fodder adrenergic afferent anaphylactic shock anhidrosis baroreflex (or baroreceptor reflex) bradycardia cholinergic diaphoretic efferent euphoretic exocytosis ganglionic hemodynamic shock hypocalcemia hypokalemia
Autonomic Nervous System
indirect agonist lacrimation miosis muscarinic mydriasis nicotinic paravertebral priapism sialogogue sympatholytic sympathomimetic tachycardia tachyphylaxis tocolytic agent xerostomia
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AUTONOMIC PHARMACOLOGY Neuronal conductance and neuronal transmission •
Conductance--action potential starts in the soma and propogates along the axon by opening of voltage-sensitive Na+ channels (+) ions move into the cell causing excitatory depolarization inhibitory hyperpolarization results from (+) ions moving out or (-) ions moving in
•
Terminal depolarization results in opening of voltage-sensitive Ca++ channels
•
Neurotransmitters are stored in Ca++-sensitive vesicles
•
Transmission—Ca++-sensitive vesicles fuse with the nerve terminal membrane and release neurotransmitter into the synaptic cleft
•
Receptors on the post-synaptic cell are activated by neurotransmitter
Puffer fish, spiders, and cosmetic potions: A variety of toxins have been isolated from animal, plant, and bacterial sources that inhibit neuronal conductance and transmission. Tetrodotoxin (a bacterial toxin concentrated by marine organisms such as pufferfish) is a Na+ channel blocker that interrupts axonal conductance. Βlack widow spider venom (α-latrotoxin) forms a Ca++ channel in the neuronal membrane allowing Ca++ unregulated entry into the nerve terminus and release of neurotransmitter until depletion occurs. Botulin toxin (from Clostridium botulinum of food-poisoning fame) has some therapeutic and cosmetic uses as injectible Botox®. Botulin toxin inhibits Ca++-dependent binding of vesicles to plasma membranes thereby inhibiting neurotransmitter release. Underarm injections can eliminate the release of neurotransmitters that cause sweating. Direct intramuscular injection of botulin toxin has also been used to treat cerebral palsy, torticollis (neck muscle spasm) and achalasia (spasm of the lower esophageal sphincter) with effects lasting for 9 months or longer. Relaxation of facial muscles by localized botulin injections is the latest anti-wrinkle fad. Autonomic Nervous System
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Gross anatomy of the Autonomic Nervous System (ANS) Peripheral nervous system divisions •
Somatic nervous system Innervation of striated (skeletal) muscle Control of voluntary movement No ganglia between spinal cord and target muscle
•
Autonomic nervous system Innervation of smooth muscle, glands, organs, blood vessels, fat, skin, etc. Involuntary control of bodily functions E.g.,respiration, blood pressure, secretions, body temperature, digestion, heart rate
Ganglionic connections between spinal cord and target organs Utilize acetylcholine as a neurotransmitter
Sympathetic division (SNS) Innervation producing an "excited" state Flight, fight, fright response Coordinated activation to prepare body for exertion and/or trauma Long post-ganglionic nerves release norepinephrine (noradrenalin) Adrenal medulla functions like a sympathetic ganglion but releases epinephrine (adrenalin) into the bloodstream
Parasympathetic division (PNS) Innervation producing a relaxed state Rest and digest responses Target organs activated as needed Short post-ganglionic nerves release acetylcholine
Autonomic Nervous System
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Autonomic Nervous System
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Three major neurotransmitters in the ANS Chemical neurotransmitters utilized by ANS •
•
•
•
Acetylcholine (ACh) Preganglionic neurons Somatic neurons Post-ganglionic PNS neurons CNS
O
N+ H3C
O
CH3 CH3
Acetylcholine (ACh)
Norepinephrine (NE) Post-ganglionic SNS neurons CNS Epinephrine (EPI) Adrenal Medulla CNS
CH3
Historical note : Otto Loewi isolated a
HO
HO
vagal compound termed "vagusstoffe" (stuff from the vagus) that decreased heart rate upon direct application. Renamed OH acetylcholine, this was the first conclusively identified neurotransmitter. NH2
OH
HO
H N
HO
CH3
Other neurotransmitters (NE) (EPI) ATP, adenosine, serotonin, peptidesNorepinephrine such as atrial naturetic factor and manyEpinephrine others
PNMT (Phenylethanolamine N-Methyl Transferase)
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Organ by organ breakdown of sympathetic and parasympathetic responses •
Basal tone at rest of most organs is parasympathetic Some exceptions: Blood vessels Exclusively sympathetic innervation of most blood vessels leads to vasoconstriction as the basal tone (maintaining blood pressure even at rest) Sympathetic innervation of blood vessels in striated (skeletal) muscle and liver is vasodilating Blood flow to the heart and brain is mostly controlled by local factors and pressure differentials, not by the autonomic nervous system
Liver glycogenolysis, fat cell lipolysis, renin secretion Exclusively sympathetically controlled
•
Exclusively PNS innervations Most glands (secretory, sweat, lacrimal,pulmonary etc) leading to increased output Special exception-- localized sympathetic cholinergic sweating in the palms, underarms (Why?)
•
Examples of PNS and SNS cooperativity Sexual response
•
Examples of physiological antagonism of dual SNS and PNS control of target organs Heart rate, force and contractility Bronchiol constriction GI and bladder motility and tone GI and bladder sphincters PNS indirectly controls SNS
Pupillary constriction (brief review of ocular anatomy) Accomodation for near and far vision
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Signal Transduction—REVIEW from Phar 735 • • •
G protein coupled receptors (GPCR) Heterotrimeric (three subunit) G proteins Effector enzymes
•
Ligand-gated ion channels
Signal Transduction rules of thumb •
Increased cytosolic calcium will cause contraction for any type of muscle
•
Increased cyclic AMP levels cause smooth muscle relaxation BUT cardiac muscle stimulation
•
Opening of K+ channels is inhibitory Inhibits neurotransmitter release Inhibits cardiac contraction
SMOOTH MUSCLE SIGNAL TRANSDUCTION M1 Muscarinic receptor Angiotensin receptor Histamine H1 receptor Cysteinyl leukotriene receptor Oxytocin receptor P2Y purinergic receptors
"2-adrenergic receptor H2 histamine receptor Endothelin receptors GPCR
GPCR PIP2
G!q
DAG
PKC
Adenylyl Cyclase
G!s
PLC-"
IP3
ATP
+
+
Ca 2+ Ca 2+
+
Ca 2+
ER/SR
Ca2+/calmodulin
+
cyclic AMP
MLCK
pump P
Ca 2+
P
+
PKA
-
P P
Contraction
Autonomic Nervous System
myosin
P
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myosin
Relaxation
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CHOLINOMIMETICS—DRUGS WHICH MIMIC THE EFFECTS OF ACETYLCHOLINE RELEASE CHOLINERGIC SIGNALING •
Choline uptake and ACh synthesis in neuronal cytoplasm Choline acetyltransferase synthesizes ACh from choline and acetate
•
Vesicular uptake required for ACh release
•
Ca++-dependent release of ACh into the synaptic cleft
•
Activation of post-synaptic receptors
•
Catabolism of ACh by acetylcholinesterase (Dr. Proteau will cover this enzyme in detail)
•
Choline re-uptake
•
Inhibition of ACh release by M2 muscarinic receptors on presynaptic neurons
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CHOLINERGIC RECEPTORS Nicotinic Cholinergic receptors Ligand-gated Ion Channels for Acetylcholine (Ach), two subtypes NM (muscular nicotinic) receptors on skeletal muscle innervated by somatic ACh neurons NN (neuronal nicotinic) receptors on post-ganglionic neurons and adrenal medulla,
5 subunit structure, forms a barrel with ion pore in the middle Requires binding of two molecules of ACh, probably between subunits, to open channel Cations (Na+, K+, Ca++) flow through the open ion pore
Location Skeletal muscle Autonomic post-ganglionic neurons Adrenal Medulla
Muscarinic Receptors •
G protein coupled receptors
•
m1 ,m3, m5 (M1) Couple to Gq/11 family of G proteins Activate phospholipase C-β enzymes Increases IP3, DAG, intracellular Ca++ levels, protein kinase C (PKC) activation
Location at parasympathetically innervated organs (predominantly m3 receptors) Glands (pulmonary secretory, GI secretory, sweat, lacrimal, nasopharyngeal), increasing secretions GI smooth muscle, increasing motility and tone Bladder smooth muscle, increasing tone and emptying Bronchiol smooth muscle, increasing bronchoconstriction Iris sphincter, producing miosis Ciliary muscle, accomodating for near-sightedness
Location OUTSIDE of parasympathetic nervous system Vascular endothelium, causing NO release leading to blood vessel relaxation and dilatation m1,m3, and m5 are in the brain
•
m2, m4 (M2) Couple to Gi/o family of G proteins Inhibit adenylyl cyclase Inhibit Ca++ channel opening
Couple to release of Gβγ proteins Activate K+ channels causing cell hyperpolarization Hyperpolarization inhibits neurotransmitter release
Location (predominantly M2 receptors) Heart, decreasing rate and force of contraction Presynaptic sympathetic neurons Preganglionic, cholinergic nerve terminals (discussed later), inhibiting Ach release Brain Autonomic Nervous System
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Effects of muscarinic receptor agonists, a.k.a. parasympathomimetics, or directacting cholinomimetics •
Few muscarinic agonists distinguish among the 5 muscarinic receptor subtypes
•
Effects of muscarinic agonists on the cardiovascular system Direct muscarinic effects on heart mimic ACh release from vagus nerve Decrease heart rate at sino-atrial node Decrease conductivity through AV node, may contribute to AV block Decrease contractile force of ventricles
Muscarinic effects on vascular endothelium No ACh release at vascular endothelium (no PNS innervation) M3 receptors activate PLC-β to cause NO (endothelium-derived relaxing factor) release Vascular smooth muscle relaxation, blood vessel dilation, and hypotension ensue
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Presynaptic M2 receptors on SNS adrenergic neurons Promote vasorelaxation by inhibiting NE release onto vascular smooth muscle Enhance heart rate decrease by inhibiting NE release Promote relaxation of GI and bladder sphincters by inhibiting NE release Promote bronchoconstriction by inhibiting NE release onto pulmonary smooth muscle
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Effects of a Muscarinic Receptor-specific agonist Eye Pupil size Lacrimal glands Salivary Glands Skin Vascular beds Sweat glands GI tract Motility Secretions Blood Supply Pancreatic Secretions Insulin Bladder Liver Glycogenolysis Gluconeogenesis Fat Uterus Pregnant Nonpregnant Male Sex Organs Lungs Pulmonary Smooth Muscle Secretory Glands Heart Rate Contractile Force Coronary Blood Supply Vascular Smooth Muscle Blood Pressure Skeletal Muscle Contactile Tone Blood Supply
Autonomic Nervous System
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Effects of muscarinic receptor agonists: Therapeutic and problematic sites of action Organ
•
Indication
•
Problems & Contraindications
Eye
•
Acute closed angle glaucoma by causing miosis Chronic glaucoma by contracting ciliary muscle
• •
Watery eyes Blurred vision from ciliary muscle contraction
• Bladder
•
Bladder atony and urinary retention following surgery by increasing tone and output
• •
Incontinence Pain and swelling in cases of blockage
GI tract
•
Abdominal distension and GI atony following surgery by increasing tone and output
•
Diarrhea, cramping, belching
Stomach
•
Esophageal reflux by promoting stomach emptying
•
Increased acid secretion aggravates ulcers
Glands
•
Sjögren’s syndrome, anhidrosis and dry mouth
•
Excess sweating and salivation
Heart Lungs
• •
•
Bradycardia
Blood Vessels
•
• • • •
Bronchoconstriction Excess secretions Hypotension Dermal vasodilation and flushing
Eye Miosis through contraction of the iris sphincter may help dislogde an adherent iris in acute closed angle glaucoma Contraction of the ciliary muscle may improve aqueous humor flow in chronic open angle glaucoma
Urinary tract Painful swelling and pressure may ensue if urinary retention is due to blockage of urethra or ureter, therefore, not indicated in benign prostatic hyperplasia and be careful when using post-trauma, (e.g. postpartum)
Heart Bradycardia may be dangerous in cardiac compromised patients
Lungs Bronchoconstriction can be dangerous in asthmatics or COPD patients
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Glands Sjögren's syndrome Autoimmune disorder Anti-M3 muscarinic receptor antibodies are produced Inhibit activation of M3 receptors Leads to eventual destruction of secretory glands
Primary symptoms are dry eyes, severely dry mouth, and anhidrosis May also include bladder irritability, constipation, fluctuating blood pressure, dilated pupils, and blurred vision
•
Muscarinic agonist side effects Most serious
Most common (SLUDS+)
Bradycardia Bronchoconstriction Hypotension Acid secretion, exacerbation of peptic ulcers
Salivation Lacrimation Urination Defecation Sweating Miosis and blurry vision
Classes of muscarinic agonists and particular uses •
ACh analogue muscarinic agonists Duration of action limited by acetylcholinesterase Usefulness limited by poor selectivity for muscarinic versus nicotinic receptors Acetylcholine (Miochol®) Endogenous neurotransmitter for muscarinic receptors Rapidly hydrolyzed by acetylcholinesterase (AChE) Also activates all nicotinic receptors (Nm and Nn) which is problematic Used in the eye to induce miosis, short-term
Methacholine (Provocholine®) Carbachol (Miostat®) Bethanechol (Urocholine®) Long duration of action, NOT a substrate for AChE Reduced activity at nicotinic receptors Poor absorption from GI Used to increase GI motility and Bladder emptying
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•
Plant Alkaloids and synthetic muscarinic agonists NOT substrates for AChE (see handout), thus long duration of action Amanita muscarii Muscarine-poison Prototype derived from poisonous mushrooms High selectivity for muscarinic receptors over nicotinic receptors Problematic muscarinic side effects (be able to list)
Pilocarpine (Ocusert pilo®, Akarpine®, Salagen®) High selectivity for muscarinic receptors over nicotinic receptors Used topically to treat glaucoma Used as a sialogogue to treat dry mouth Associated with excessive diaphoresis (sweating)
Cevimiline (Evoxac®) M1-selective muscarinic agonist Approved in 2000 for Sjögren's syndrome
Autonomic Nervous System
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PHAR 752 Medicinal CHEMISTRY of Cholinergic and Adrenergic Drugs Dr. Philip Proteau Pharmacy Bldg. Rm. 127 Office hours M-F 12-1 pm.
[email protected] or by appointment. You will be responsible for knowing the structures of a few select compounds (i.e. be able to draw with correct stereochemistry -- THESE COMPOUNDS WILL BE CLEARLY INDICATED DURING LECTURE AND IN THE HANDOUT), but focus on structural classes and functional groups. The trade names of the agents will be included, but the generic names will be used throughout and will be expected on the exams. The main indications for the drugs will be mentioned, but not an exhaustive coverage of possible uses. When studying, do not simply try to memorize what drug is used for what condition, but try to understand how structural features of a particular drug might affect its use for a particular indication or in a particular situation (for example, what structural features lead to a short-acting neuromuscular blocking agent vs. a long-acting agent?) Also, do not try to memorize each structure as a completely separate entity. Look for the similarities in structures so that you can remember agents by class. Focus on how the chemistry of the agents affects their activity. Reading assignment: “Cholinergic Drugs and Related Agents” Wilson and Gisvold’s Textbook of Organic, Medicinal, and Pharmaceutical Chemistry, 11th edition, Chapter 17, pp. 548-595. “Adrenergic Agents”, Wilson and Gisvold, Chapter 16, pp. 524-547. The Goodman and Gilman text provides additional coverage of the topics.
Cholinergic agents
O
CH3 N+ O
Cl-
HO
CH3 CH3
Acetylcholine (chloride)
N
N+ (CH3)3 ClH3 C
O
Muscarine (chloride)
CH3
N
S-+-Nicotine
BE ABLE TO DRAW THESE THREE STRUCTURES (including correct stereochemistry).
Autonomic Nervous System
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Muscarinic Agonists Acetylcholine chloride O
CH3 N+
H 3C
O
CH3 CH3
Cl-
Four questions relating to the conformation of ACh (Casy). !1.!Does the “active” conformation of a cholinergic ligand correspond to its preferred stereochemistry or is an energetically less favored form bound to the receptor? !2.!Is there a unique mode of ligand binding to cholinergic receptors or do multiple modes exist? !3.!May the dual effects (nicotinic and muscarinic) of ACh be explained in terms of conformational isomerism? !4. Do agonist and antagonist ligands occupy the same or different binding sites? Stereochemistry of acetylcholine. (CH3)3N+ H
(CH3)3N+ OCOCH3
H
H H
Synclinal (Gauche)
H
H
(CH3)3N+ H
(CH3)3N+ OCOCH 3
H
H
H
H
H
OCOCH3
Antiplanar
H OCOCH3
Anticlinal (Eclipsed #2)
H
H H
Synplanar (Eclipsed #1)
Acetylcholine as a therapeutic agent. !Non-selective !Short half life due to rapid hydrolysis by AChE and other cholinesterases. !Limited use - can be useful when directly injected into the eye to produce miosis in surgery. Autonomic Nervous System
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PHAR 752 Cholinergic Handout Acetylcholine Stereochemistry Several analogs of acetylcholine were synthesized in which the ethylene bridge of ACh was contained within a cyclopropyl ring. The cyclopropyl ring locks the conformation of the backbone of ACh, preventing free rotation. Testing the activity of these analogs at muscarinic receptors indicated that the (+)-trans isomer was equipotent to ACh, suggesting that the active conformation of ACh at the muscarinic receptor (at least the type of receptor used in the study), is the anticlinal conformation or close to this conformation. In contrast, the preferred conformation of ACh in the solid form or in solution is closer to the synclinal (gauche) conformation. The studies also demonstrated a marked stereoselectivity at the muscarinic receptor. I-
H
H3COCO
H
H3COCO
(CH3)3N+
I-
N+(CH3)3
N+(CH3)3 H
H
(CH3)3N+ H
OCOCH3
H H3COCO
H H
(+) trans (1S, 2S)-Acetoxycyclopropyltrimethylammonium iodide (ACTM)
cis-Acetoxycyclopropyltrimethylammonium iodide
Approximates anticlinal conformation
Approximates synplanar conformation
Equipotent to ACh at muscarinic receptor
Racemic cis-compound had essentially no activity at the muscarinic receptor
(+) trans (1S,2S) ACTM 517x as potent as (-) trans (1R,2R) ACTM at muscarinic receptor
Weak nicotinic agonist
(+) and (-) trans ACTM were weak nicotinic agonists Autonomic Nervous System
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Muscarinic Agonists O
CH3
CH3 N+
H 3C
O
CH3
Cl-
CH3
Acetyl !"methylcholine chloride (Methacholine chloride)
O
CH3 N+
H2N
O
CH3 CH3
Cl-
Carbachol Miostat®
O
CH3
CH3 N+
H2N
O
CH3 CH3
Cl-
Bethanechol chloride Urecholine®
Autonomic Nervous System
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Muscarinic Agonists HO CH3 N+
Cl-
CH3
O
H 3C
CH3
2S,3R,5S-muscarine chloride
Muscarinic Agonist SAR !1.!The molecule must possess a nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium salt. !2.!For maximum potency, the size of the alkyl groups substituted on the nitrogen should not exceed the size of a methyl group. !3.!There should be an oxygen atom, preferably an ester-like oxygen or ether-like oxygen, capable of participating in a hydrogen bond. !4.!There should be a two-carbon unit between the oxygen atom and the nitrogen atom. The classical SAR approach gives guidelines only. It is not expected to be an endpoint. SAR always build on themselves. H3CH2C
H
CH3 N
O N
O
Pilocarpine
Pilocarpine - The stereochemistry as drawn is essential for muscarinic agonist activity. Any change in stereochemistry or ring opening of the lactone ring results in loss of activity. Note: pilocarpine does not fit the classical muscarinic agonist SAR. Autonomic Nervous System
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Muscarinic Agonists N
S O CH3
Cevimeline (Evoxac®- To treat dry mouth associated with Sjögren's syndrome)
O
Template for Design of Future Agonists. OCH3
N CH3
Arecoline
Autonomic Nervous System
Arecoline - This natural product is the main alkaloid of Areca catechu. The nut of this plant is called betel nut and is used on the Indian subcontinent as a mild stimulant and digestive aid. Arecoline acts mainly at muscarinic receptors, but has some activity at nicotinic receptors. Analogs of arecoline are being investigated for activity as M1 selective agonists.
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Muscarinic Antagonists Naturally occurring alkaloids and semisynthetic derivatives
H3C N
H CH2OH O
Atropine
O
(BE ABLE TO DRAW THIS STRUCTURE)
H 3C N O
H CH2OH O
Scopolamine
Autonomic Nervous System
O
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Muscarinic Antagonists Naturally occurring alkaloids and semisynthetic derivatives
CH3 H 3C
Br-
N+
CH3 H CH2OH O
O
Ipratropium bromide Atrovent®, Combivent®
H3C
CH3 N+
Br-
O
H OH S
O
Tiotropium bromide Spiriva®
Autonomic Nervous System
O
S
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SAR FOR MUSCARINIC ANTAGONISTS R1 R2
X
(CH2)n
N
R3
1)!Substituents R1 and R2 should be carbocyclic or heterocyclic rings for maximal antagonist potency (at least one ring should be aromatic; rings can be connected). The size of substituents is limited to a phenyl ring or equivalent; a naphthalene ring abolishes activity. 2)!The R3 substituent may be a hydrogen atom, a hydroxyl, or a hydroxymethyl group (R3 may be a component of the R1 or R2 ring system). More potent with hydroxyl or hydroxymethyl. 3)!The X substituent in the most potent anticholinergics is an ester. It can also be an amide or an ether (or in some cases the X group can be omitted from a structure - see the procyclidine structure). 4)!The N substituent can be either a quaternary ammonium salt or a tertiary amine. The alkyl substituents on the nitrogen atom are usually methyl, ethyl, propyl, or isopropyl. 5)!The distance between the X group and the amine nitrogen can vary from 2 to 4 carbons (n = 2 - 4), but the most potent agents have two methylene units in the chain.
Autonomic Nervous System
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Quaternary Ammonium Muscarinic Antagonists O H3C H3C
N+ O
Br-
OH
Glycopyrrolate bromide Robinul®
N+
Cl-
OH O
O
Trospium chloride Sanctura®
Amine Muscarinic Antagonists
O N
CH2OH
N H3C
Tropicamide Mydriacyl®, Tropicacyl®
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Tertiary Amine Muscarinic Antagonists (with functional selectivity for the urinary bladder)
H3C
N
OH O
H3C
O
Oxybutynin Ditropan®
CH3
HO H N
Tolterodine Detrol®
N O H O
N
Solifenacin succinate Vesicare® Autonomic Nervous System
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Antimuscarinic Antiparkinsonian Agents
H3C N
•CH3SO3H H O
Benztropine mesylate Cogentin®
OH N
•HCl Procyclidine hydrochloride Kemadrin®
Autonomic Nervous System
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Muscarinic receptor ANTAGONISTS Few in clinincal use distinguish among the five muscarinic receptor subtypes All are competitive antagonists at the muscarinic receptors •
Therapeutic indicationsand problematic sites and contraindications. Mushroom poisoning
Organ
•
Indication
•
Eye
•
Retinal exam requiring mydriasis Acute glaucoma, alternating with a miotic, to break adhesion between iris and lens
•
Cardiac stimulation, concurrent with epinephrine in cardiac failure Reflex sinus bradycardia or atrial fibrillation that may follow cardiac catheterization Peptic ulcer by blocking stomach acid secretion GI spasms and irritable bowel syndrome by slowing motility Incontinence, reduced bladder capacity, and irritable bladder syndrome by reducing bladder contractility Pre-anaesthetic to decrease salivation Chronic obstructive airway diseases (e.g. emphysema), chemically-irritated airway constriction, and asthma
•
•
Heart
•
• Stomach
•
GI tract
•
Bladder
•
Glands
•
Lungs
•
Blood Vessels
•
CNS
• •
Autonomic Nervous System
• •
Problems & Contraindications Chronic glaucoma due to narrowing of humor passages Photophobia Blurred vision from blockage of ciliary muscle contraction Tachycardia by blocking parasympathetic basal cardiac tone
•
Nausea, delayed stomach emptying
•
Constipation
• •
Urinary retention Benign prostatic hyperplasia
• • •
Xerostomia Anhidrosis Increased susceptibility to infection due to decreased respiratory secretions
• Motion sickness by acting on the vestibular apparatus Tremors associated with Parkinson’s disease and side effects of anti-psychotics
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•
Hallucinations and drowsiness
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Muscarinic receptor antagonists •
Belladonna (beautiful lady) alkaloids and semisynthetic derivatives Atropine (from Atropa belladonna) Historic uses as a cosmetic and poison (Catherine de Medici’s ring) Hierarchical effects of atropine based on dose: 0.5 mg→Dry mouth, dry skin 1.0 mg→Increased heart rate, thirst 2 mg→Pupillary dilatation, blurred vision, tachycardia 5 mg→Reduced peristalsis, urinary retention, hot dry skin, fatigue, flushing 10 mg→Rapid and weak pulse, ataxia, hallucinations, delirium, coma Used for cardiac stimulant effects Useful in treating mushroom (muscarine) poisoning Combined with an opioid (diphenoxylate) in Lomotil® for diarrhea Useful in treating nerve gas poisoning (discussed later in detail) Long duration of action (will dilate pupil for 7-10 days) Homatropine has a much shorter duration of action, making it useful for eye exam
Scopolamine (Transdermscõp® from Datura stramonium “Jimson weed”) Natural derivative of atropine Easily crosses blood/brain barrier Used for treating motion sickness Amnesia, sedation, stupor and hallucinations Criminally abused to render victims compliant
Ipratropium (Atrovent®) Poor systemic penetrance--few side effects when inhaled Useful as an inhaled agent in treating chronic obstructive airway disease and asthma Few effects on pulmonary secretions
•
Synthetic Tertiary Amines and Quaternary Ammoniums, muscarinic antagonists Tiotropium (Spiriva®) Same therapeutic/pharmacologic profile as ipratropium Longer duration of action
Pro-pantheline (Pro-Banthine®) GI and bladder antispasmodic agent, useful in the treatment of irritable bowel syndrome
Tropicamide (Mydriacyl®) Shorter duration of action than atropine (about 6 hours) Useful in eye exams for pupillary dilation and treatment of iritis
Tolterodine (Detrol®), Oxybutynin (Ditropan®), Trospium (Sanctura®), Solifenacin succinate (VESIcare®) Treatment for urinary incontinence, urgency, and bladder hyper-irritability
•
Tertiary amines with CNS penetrance/Anti-Parkinson’s agents, Benztropine (Cogentin®), Procyclidin (Kemadrin®)
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Indirect-acting cholinomimetics, or acetylcholinesterase inhibitors (a.k.a. Cholinesterase inhibitors, AChE inhibitors, anti-cholinesterases) •
Review of cholinergic neuron and ACh hydrolysis Review of sites of release of ACh in the ANS Preganglionic neurons Postganglionic PNS neurons Somatic neurons
Inhibiting AChE, leading to increased ACh levels and duration of action theoretically: will affect Muscarinic receptors on PNS target organs will affect Nm receptors on skeletal muscle will affect Nn receptors in autonomic ganglia will affect Nn receptors on adrenal medulla
Inhibitors of AChE, leading to increased ACh levels and duration of action practically: will mostly affect muscarinic receptors on target organs will also activate Nm receptors on skeletal muscle won't penetrate into ganglionic sites or adrenal medulla at therapeutic doses (protected by a barrier similar to blood/brain barrier)
Acetylcholinesterases Serine esterase family of enzymes Acetylcholinesterase is located at neuroeffector junctions membranes Pseudocholinesterase (a.k.a. butyryl cholinesterase) is produced by the liver and in the circulation
Enzymatic degradation of ACh (covered by Dr. Proteau) Very rapid, 8 hrs to reactivation) "Aging" of phosphorylated AChE (in 1 hour) leads to a permanently phosphorylated enzyme that can NOT be reactivated
Very lipid soluble and readily cross the blood/brain barrier, pulmonary and intestinal membranes Isoflurophate (DFP; Floropryl®) and Echothiophate (Phospholine®) Very long duration of action Used topically to treat glaucoma Echothiophate is safer due to decreased lipid solubility and decreased systemic absorbance
Nerve Gases (Sarin, Tabun, Soman, VX, etc) Airborne organophosphates Rapidly cross membranes and barriers Death from asphyxiation may result in minutes
Insecticides (Malathion, Parathion) Can be detoxified rapidly by mammals Over-exposure is similar to nerve gas poisoning
Treatment for organophosphate poisoning Give atropine within seconds to minutes to reverse muscarinic effects (Atropen®) Pralidoxime An oxime reactivator of AChE Must be given within minutes to hours of exposure Will attack the acylated phosphate and regenerate the esteric site Will reactivate AChE if "aging" of the enzyme has not occurred No antidote available if sufficient time has passed for "aging" of phosphorylated AChE to occur Support respiration
Autonomic Nervous System
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Acetylcholinesterase Mechanism CH3 CH3 CH3
O
Acetylcholine H3C AChE Ser
+N
O
O
O H
Note: "AChE" represents the bulk enzyme. The Ser, His, and Glu residues are all part of a single AChE enzyme molecule.
N
-O
NH
Glu AChE
His AChE
CH3 CH3 CH3
OH 3C AChE Ser
+N
O
O
O + HN
NH
-O
Glu AChE
His AChE
CH3 +N CH3 HO CH3 Choline
Acetylated serine intermediate O AChE Ser
O H
CH3 O
O
H N
NH
-O
Glu AChE
His AChE
OAChE Ser
O
O
CH3
O
H + HN
NH
-O
Glu AChE
His AChE O H3C OAcetate Regenerated Active Enzyme
Autonomic Nervous System
AChE Ser
O
O H N
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NH
-O
His AChE
Glu AChE
Phar 752 Fall 2006
Acetylcholinesterase Inhibitors Reversible Inhibitors Physostigmine
H3C H3CHN
O N O
N
H
CH3
CH3
Autonomic Nervous System
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(H3C)2N
Acetylcholinesterase Inhibitors
O
Reversible Inhibitors O N+(CH3)3 Br-
Neostigmine bromide Prostigmin® Reversible, covalent modifier
OH
Cl-
N+
H 3C
CH3
CH3
Edrophonium chloride Tensilon®, Reversol® Reversible, non-covalent
Cl Et Et O
H N
O
N H
N+
Cl-
ClN+ Et Et
Ambenonium chloride Cl Mytelase® Reversible, non-covalent Autonomic Nervous System
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Proposed Binding of Ambenonium at AChE Active site AChE active site cavity
NH Cl Et Et
Trp 279
Tyr 121
OH
NH
HO
Tyr 334
N+
HN
O
N H
O
HN
N+
Trp 432
Et Et
Trp 84
Cl
Glu 327 Ser 200 His 440
Cartoon depiction of how ambenonium might interact with the acetylcholinesterase binding cavity. Additional aromatic residues that line the binding cavity/channel can interact with the second quaternary ammonium group of ambenonium, providing for high affinity binding. This model may explain the high potency of "bifunctional" inhibitors of AChE.
Autonomic Nervous System
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Acetylcholinesterase Inhibitors Reversible Inhibitors for Treatment of Alzheimer's O H3CO
N
H
H3CO
Donepezil (Aricept®)
O
CH3
O
N CH3 N(CH3)2 H
CH3
Rivastigmine (Exelon®)
H
OH
H O H3CO
N CH3
Galantamine (Razadyne®) Autonomic Nervous System
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AChE Inhibitors - Covalent Modifiers; Semi-reversible Inhibitors; Carbamates Three carbamate AChE inhibitors were discussed in lecture. A generic mechanism for a methylcarbamate inhibitor was used as an example. This handout provides abbreviated mechanisms for each of the three carbamates. The details for the transfer of the carbamate group from an inhibitor to the active site serine will be essentially the same as for the mechanism of acetylcholine hydrolysis. The exact form of the carbamoylated enzyme intermediate varies, as does the estimated half-life for hydrolysis, but the key point is that hydrolysis to regenerate the active enzyme is on the minute time scale, rather than hundreds of microseconds. H3C H3CHN
O
O N+ H O
N
H
CH3 AChE
Ser OH
AChE
CH3
Ser O
NHCH3
Carbamoylated enzyme intermediate R-OH H2O t1/2 = 3-5 min (estimate)
R-OH = phenolic by-product
Physostigmine
AChE
Ser OH
Regenerated active enzyme O (H3C)2N
O AChE O
Ser O
N(CH3)2
Carbamoylated enzyme intermediate R-OH N+(CH3)3 Br-
AChE
Ser OH
H2O t1/2 = 15-30 min
R-OH = phenolic by-product
Neostigmine AChE
Ser OH
Regenerated active enzyme O AChE
Ser OH
CH3
O
O AChE
N
Ser O
R-OH
H
Carbamoylated enzyme intermediate
N+(CH3)2 H
H2O t1/2 = 30-45 min (estimate)
CH3 AChE
R-OH = phenolic by-product Autonomic Nervous System
N CH3
CH3
Rivastigmine
CH3
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Ser OH
Regenerated active enzyme Phar 752 Fall 2006
Acetylcholinesterase Inhibitors A Nutraceutical?
CH3
NH
H3C H2N
O
(-)-Huperzine A
Autonomic Nervous System
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Irreversible Acetylcholinesterase Inhibitors Echothiophate iodide Phospholine iodide®
Autonomic Nervous System
O (EtO)2
P
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N+(CH3)3 IS
Phar 752 Fall 2006
Irreversible Acetylcholinesterase Inhibitors
O O
P
O
F
Diisopropylfluorophosphate (DFP) Isoflurophate Floropryl®
O O
P
CH3
F
Sarin
S H3CO
P
CO2Et S
OCH3
CO2Et
Malathion Ovide®
Autonomic Nervous System
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Cholinesterase Reactivator
Pralidoxime chloride (2-PAM) Protopam® chloride
Cl-
N
N+ CH3
OH H
Autonomic Nervous System
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Ganglionic Signaling and Blockade •
Ganglionic Signaling Activation of NN receptors by ACh is rapid, excitatory, and REQUIRED for development of an action potential in post-synaptic cell Activation of other receptors or input from other neurons in the ganglia may potentiate or inhibit the primary effect of NN activation, but have no effect alone Special summation in the ganglia is the summing of all potentiating and inhibitory inputs modifying the NN-activated EPSP and determining whether a threshold is reached whereby an action potential is generated down the post-ganglionic neuron
•
Ganglionic Blockade Agents that activate or the inhibit NN signaling in the ganglia (nicotinic "agonists" and "antagonists") both ultimately produce blockade Primary actions are variable-- depend on predominant tone of an organ, age, sympathetic tone, others factors.
Site Blood vessels Bladder and GI sphincters Heart Eye GI tract Urinary bladder Salivary glands
Predominant Tone Sympathetic Sympathetic Parasympathetic Parasympathetic Parasympathetic Parasympathetic Parasympathetic
1° Effect of ganglionic blockade Hypotension ?? Tachycardia Mydriasis, blurred vision Decreased motility Urinary retention Dry mouth
Neuromuscular Signaling and Blockade •
Neuromuscular Signaling NM nicotinic receptors at the muscle endplate activated by ACh released from somatic nerves
•
Both non-depolarizing and depolarizing neuromuscular blockers exist
•
Some neuromuscular blockers are NM selective because they can not cross into the ganglionic space
Characteristics of Ganglionic and Neuromuscular cascade •
Nondepolarizing blockade Non-depolarizing blockers are ion channel antagonists Competitively block the ACh binding sites
Actions can be reversed by an excess of ACh due to competitive nature of blockade
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•
Depolarizing blockade Depolarizing blockers are ion channel agonists Opening the ion channel causes an initial depolarization of the post-ganglionic neuron (or the adrenal medulla) Persistant stimulation induces Phase I followed by Phase II blockade Phase I blockade-ion channel remains open in the presence of a depolarizing blocker and repolarization can not occur Phase II blockade-ion channels closes, repolarization of the cell occurs, but the NN receptor is desensitized and unable to respond to further stimulation for a time
Depolarizing blockade can NOT be reversed by excess ACh Must wait for resensitization of the ion channels to occur over time
Depolarizing blockers •
Depolarizing ganglionic blockers Nicotine Some selectivity for NN over NM receptors Ultimately, high dose effects on NM receptors will cause muscle twitching and blockade
Initial excitation followed by persistant blockade Most noticeable effect of nicotine is the initial release of EPI following excitation of the adrenal medulla NN receptors EPI will increase heart rate, blood pressure
Special effects of nicotine, activation followed by depolarization of: NN receptors on pain afferents NN receptors on chemosensory neurons that cause increased respiration NN receptors on stretch sensory neurons that lead to reflex vomiting
Addictive properties based on CNS effects No antidote, induce vomiting
Potential therapeutic applications of nicotine/nicotin-like agents Smoking cessation patches Analgesic Neuroprotective effects?? GI protective effects to reduce inflammation in ulcerative colitis
Varenicline Partial agonist at (α4)2(β2)3 and full agonist at (α7)5 nicotinic receptors Predominant CNS nicotinic receptor subtypes Nicotine withdrawal symptoms due to elevated receptor levels Irritability, insomnia, restlessness Aches and pains Constipation Increased appetite, sugar cravings Varenicline--as a partial agonist--will reduce withdrawal symptoms without activating dependency pathways Varenicline will double the abstinence rate compared to placebo over 52 weeks Autonomic Nervous System
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•
Depolarizing neuromuscular blocker Succinylcholine NM (neuromuscular) nicotinic receptor selective Opens the ion channel and causes an initial depolarization of the muscle cell leading to contraction and twitching for ~ 1 min Persistant stimulation renders the muscle cells incapable of repolarization and blockade ensues Phase I and Phase II blockade follow the same pattern as described above for ganglionic blockade
Following the initial contraction, a short term (~5 min) paralysis ensues with succinylcholine Succinylcholine is hydrolyzed by circulating plasma cholinesterases (pseudocholinesterases) and thus has short duration of action Short duration makes it useful where short term paralysis is required Electroshock therapy Setting fractures and dislocations Endotracheal intubations
Problems There is no chemical antidote for a depolarizing blocker Hyperkalemia (release of K+ into bloodstream) due to some affinity for K+ channels. Most problematic for patients in electrolyte imbalance or taking digitalis May have muscle pain and soreness from initial twitching Duration of action may be dangerously extended in patients with liver disease or genetic defects resulting in low levels of circulating cholinesterase May cause MALIGNANT HYPERTHERMIA when used in conjunction with inhalational anaesthetics in some patients Malignant Hyperthermia is a drug reaction (autosomal dominant) characterized by dangerous increases in body temperature during surgery. Succinylcholine plus inhalational anaesthetics may ++ induce a hypermetabolic response of muscle tissue due to excess Ca release. Treatment consists of cooling, heat dissipation, O2 administration, contol of acidosis, and Dantrolene. Dantrolene blocks ++ Ca release from the sarcoplasmic reticulum and helps to control hypermetabolism leading to hyperthermia
Non-depolarizing blockers •
Non-depolarizing ganglionic blockers-very limited clinical use Mecamylamine (Inversine®) Some selectivity for NN over NM receptors, adjust dose to affect only NN receptors Competitively block the channel and ACh binding sites Actions can be reversed by an excess of ACh due to competitive nature of blockade Used to control blood pressure and bleeding during surgery Tested off-label for CNS neuroprotective effects
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•
Nondepolarizing neuromuscular blockers -curare-like compounds Selectivity at NM receptors based on inability to cross ganglionic barrier
δ-tubocurarine (curare) is the classic paralytic agent Used traditionally in South America to coat arrow tips to paralyze prey No initial excitation, only blockade resulting in paralysis (80-120 min duration) Sequential order of paralysis follows: Eye Jaw Throat and neck Appendages Abdominal muscles Intercostal muscles and diaphragm Dose can be titrated to avoid asphyxiation but produce a waking paralysis Poisoning is treatable with AChE inhibitors
Therapeutic Use of curare and curare-like drugs Muscle relaxant and surgical adjuvant
Problems associated with curare and curare-like drugs Action terminated by excretion in urine May have extended duration of action in patients with renal insufficiency Histamine release also associated with curare, be careful with asthmatics Potentially dangerous synergism with some antibiotics (e.g. streptomycin, tetracyclin) Antibiotics chelate Ca++ and contribute to muscle paralysis Antibiotics prolong duration of action of curare-like drugs beyond expectations
Cisatracurium (Nimbex®) 30-40 min duration terminated by metabolism, not excretion, better choice for patients with reduced renal function
Pancuronium (Arduan®) Vecuronium and Rocuronium Ammonio steroids no histamine release, preferred for asthmatics greater selectivity for NM over NN receptors Pancuronium is long-lived (120-180 min), renal elimination Rocuronium and Vecuronium are of intermediate duration, liver metabolized
Autonomic Nervous System
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Nicotinic agonist N CH3
N
S-+-Nicotine
Nicotinic partial agonist N NH N
Varenicline
O N NH
(-)-Cytisine
Non-depolarizing Ganglionic (NN) Blockers
HN
CH3 HCl CH3 CH3
CH3
Mecamylamine hydrochloride (Inversine®) Autonomic Nervous System
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Depolarizing Neuromuscular Blocking Agents O
Cl-
O
N+(CH3)3 N+(CH3)3 O
Cl-
O
Succinylcholine chloride
Nondepolarizing Neuromuscular Blocking Agents CH3
OCH3
N
HO H O
H3CO
H H3C
O
HO
Autonomic Nervous System
N+ CH3
Tubocurarine
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Nondepolarizing Neuromuscular Blocking Agents (Benzylisoquinoline) H3CO
H3CO H3CO
H3CO
Autonomic Nervous System
OCH3 N+
CH3
O
H3C
O O
O
Cisatracurium besylate Nimbex® 1R cis-1'R cis
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N+
OCH3 OCH3
OCH3
Phar 752 Fall 2006
Nondepolarizing Neuromuscular Blocking Agents (Ammonio steroids) O
CH3
N+
CH3
CH3
O
CH3 N+
H H3C
Br-
H
H
Br-
O H O
CH3
Pancuronium bromide
O
CH3 CH3
N
O
CH3 N+
H H3C
H
H
Br-
O H O
CH3
Vecuronium bromide Norcuron®
O
CH3
O
O N
CH3 H
CH3
BrN+
H H
HO H
Rocuronium bromide Zemuron® Autonomic Nervous System
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Autonomic Nervous System
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ADRENERGIC SIGNALING Review of the SNS •
Ach is released by preganglionic fibers (short)
•
NE is released by postganglionic fibers synapsing on target organs (long)
•
EPI is treleased into general circulation by the adrenal medulla, a de facto sympathetic post-ganglionic tissue
•
Dopamine is not a direct neurotransmitter in the SNS, but an important precursor to NE and EPI
Biosynthesis of Catecholamines •
Catecholamines Catechol ring (dihydroxy aromatic ring) and amine group
•
Tyrosine Amino acid precursor to all catecholamines 98% used for protein synthesis, 2% used for catecholamines Taken up by nerve
•
Tyrosine Hydroxylase (TH) Converts tyrosine to DOPA Cytosolic Enzyme Rate limiting enzyme in catecholamine biosynthesis and highly regulated Negative feedback inhibition by increased catecholamine levels Positive feedback stimulation by impulse regulation Stimulation of the neuron leads to increased Ca ++ levels in the nerve terminus Increased Ca++ levels activate CaM kinase to phosphorylate TH Phosphorylation increases TH affinity for pteridine co-factors, increases activity Phosphorylation decreases TH affinity for catecholamines, decreases negative feedback inhibition
Inhibited by α-methyl-ρ-tyrosine (Metyrosine) Non-selective inhibition of all catecholamine biosynthetic pathways Useful only for treatment of pheochromocytoma-adrenal tumor which produces excess EPI
•
L-aromatic acid decarboxylase (L-AAD) Converts DOPA to Dopamine Cytosolic enzyme Non-specific enzyme, decarboxylates other aromatic amino acids as well Inhibited by Carbidopa Carbidopa is used in Parkinson's disease which is characterized by a lack of dopamine in the CNS Carbidopa won't cross blood/brain barrier Useful in controlling peripheral side effects of L-DOPA treatment in Parkinson's disease
Autonomic Nervous System
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Catecholamine Biosynthesis CO2H H
L-Tyrosine
NH2
HO
Tyrosine hydroxylase (TH) tetrahydrobiopterin HO
CO2H H
L-Dopa
NH2
HO
L-Aromatic amino acid decarboxylase (L-AAAD) pyridoxal phosphate HO
NH2
Dopamine HO
Dopamine !-hydroxylase ascorbate
OH HO
NH2
R (-) Norepinephrine
HO
Phenylethanolamine N-methyl transferase (PNMT) S-adenosylmethionine OH HO
NHCH3
R (-) Epinephrine
HO
Autonomic Nervous System
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Norepinephrine Biosynthesis Inhibitors CO2H H 3C
NH2
HO
Metyrosine Demser®
HO
CO2H H 3C
NHNH2
HO
Carbidopa Lodosyn® (with Levodopa = Sinemet®)
Autonomic Nervous System
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•
Dopamine-β-hydroxylase (DβH) Converts Dopamine to Norepinephrine Vesicular Enzyme Dopamine must first be transported into vesicle to be made into NE
Non-specific enzyme, hydroxylates other aromatic amino acids as well •
Phenylethanolamine-N-methyl transferase (PNMT) Converts NE to Epinephrine Only present in the adrenal medulla and the CNS, NOT present in SNS nerve terminals Cytosolic Enzyme NE is first shuttled out of granules (vesicles of the adrenal medulla chromaffin cells) before conversion to EPI EPI is then taken up again by granules
Stress-induced release of glucocorticoids stimulates synthesis of TH and PNMT in adrenal medulla chromaffin cells-- positive regulation Epinephrine negatively regulates PNMT activity by feedback inhibition
The Adrenergic Nerve Terminal •
Synthesis
•
Vesicular Uptake Vesicles actively take up dopamine, NE, and EPI Catecholamines are labile and protected in vesicle storage Dopamine uptake is required for NE synthesis Reserpine (Serpasil®) blocks vesicular uptake of catecholamines
•
Release Ca++ dependent vesicle (or granule) fusion with plasma membrane required
•
Re-uptake NE and EPI action terminated by recycling Re-uptake I Specific re-uptake of NE into pre-synaptic nerve terminals Uptake I proteins are large transporter molecules with 12 membraine-spanning domains Highly selective for specific biogenic amines and catecholamines, stereoselective, and of moderate capacity Distribution restricted to SNS nerve terminals and the CNS Bidirectional Uptake I can be blocked by Cocaine and tricyclic antidepressants (e.g. Imipramine)
Re-uptake II Non-specific re-uptake of catecholamines into non-neuronal cells Low affinity, low specificity, high capacity system Mops up EPI distributed into circulation (no Uptake I system for EPI, only Uptake II) Autonomic Nervous System
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•
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Indirect agonists (e.g. tyramine) Drugs which cause unregulated release of the endogenous transmitter Compete with NE for reuptake into nerve terminal and uptake into vesicles Displace NE from vesicles and from the nerve terminal causing build up in the synapse
Tachyphylaxis Initial increase in NE release followed by decreasing NE release as indirect agonist depletes supply of NE
•
Mixed function agonists (e.g. amphetamine) Have both indirect effects, displacing and releasing NE, and direct agonist effects on receptors
•
Degradation Low efficiency compared to AChE Catecholamine actions largely stopped by Re-uptake Catechol-O-methyl transferase (COMT) Acts on both EPI and NE
Monoamine oxidase Two forms, MAO-A and MAO-B. Degrades phenylethylamines found in foods Acts on both EPI and NE taken up by Uptake I or Uptake II Inhibitors used for CNS effects
The Wine and Cheese Reaction Be careful when eating wine and cheese and taking an MAO Inhibitor Tyramine is found in high levels in red wines, hard cheeses, and other foods but is normally degraded rapidly by MAO. MAO inhibitors block tyramine degradation. Tyramine is an indirect agonist (see above) and will initially stimulate a large release of NE which is not metabolized in the presence of an MAO inhibitor. Large circulating amounts of NE may precipitate a sympathetic crisis including hypertension and tachycardia leading to MI or stroke.
Product of degradation Vanillylmandelic acid (VMA) which is excreted in urine VMA levels are an indicator of SNS activity Adrenal medulla tumors (pheochromocytoma) cause enormous release of EPI detectable by high VMA levels in urine
Autonomic Nervous System
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Degradation of Norepinephrine (NE)
OH
OH HO
NH2
HO
NE
1) MAO
HO
2) Aldehyde dehydrogenase
HO
CO2H
3,4-Dihydroxymandelic acid
COMT = Catechol-O-Methyltransferase MAO = Monoamine Oxidase
COMT
OH
OH H3CO
NH2
1) MAO 2) Aldehyde dehydrogenase
HO
Normetanephrine
Autonomic Nervous System
COMT
H3CO
CO2H
HO
3-Methoxy-4-hydroxymandelic Acid (a.k.a. vanillylmandelic acid or VMA)
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Adrenergic Receptor Subtypes •
Structure All adrenergic receptors are G protein coupled receptors
•
G protein coupling, effector protein activation, and second messenger production (review from signal transduction module in Phar 735) Gαq activates phospholipase C-β enzymes Increased Ca++ levels in smooth muscle lead to contraction Gαs activates adenylyl cyclase (and L-type Ca++ channels in the heart) Increased cyclic AMP and cytosolic Ca++ increases heart rate and contractility Increased cyclic AMP in smooth muscle promotes relaxation Gαi inhibits adenylyl cyclase Decreased cyclic AMP in smooth muscle promotes contraction Decreased cyclic AMP in heart decreases rate and contractility Gβγ activates inward rectifying K+ channels (GIRK) through release from Gi/o Leads to cellular hyperpolarization and inhibition of presynaptic neurotransmitter release Gβγ also activates G protein-coupled receptor kinases (GRK) such as β-adrenergic receptor kinase (β-ARK) Leads to phosphorylation of G protein-coupled receptors and receptor desensitization (see below)
Adrenergic receptors and subtypes α1
α2
β
Subtypes G protein Effector enzymes
A,B,C
A,B,C
1,2,3
Gq +phospholipase C
Gi -adenylyl cyclase
2nd messengers
IP3, DAG, and Ca++
↓cyclic AMP
Gs +adenylyl cyclase + Ca++ channels (heart) ↑cyclic AMP ↑[Ca++]i (heart)
Autonomic Nervous System
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Receptor regulation •
Regulation of receptor responsiveness by agonists and antagonists Desensitization Upon chronic application of agonists, cells will attempt to avoid overstimulation by blocking the ability of the receptor to keep stimulating the signal transduction pathway Problematic in long term use of β agonists to control asthma Partial agonists tend to cause very little receptor desensitization Extent of desensitization seems to correlate with intrinsic activity of the agonist Molecular pathway is best understood for β2 adrenergic receptors. Short time frame-within seconds to minutes Activation of β2 receptors liberates Gβγ from Gαs Gβγ activates a G protein-coupled receptor kinase (GRK) GRK phosphorylates the β2 adrenergic receptor at multiple sites in the C tail Phosphorylation of the C tail causes β-arrestin to bind to the β2 adrenergic receptor and block further interaction with G proteins
Stimulatory Hormone
P
P
GRKinase
P
P P
P
P
P
stin
G!s
G"#
GPCR
e Ar r
X GPCR = G protein coupled receptor GRKinase = G protein receptor regulated protein kinase
Down-regulation Longer term negative feedback loop-hours to days After β-arrestin binding, receptors are internalized away from the membrane No effect until all spare receptors are internalized
Supersensitization Occurs following long term blockade of receptors with antagonists Up-regulation (increased levels) of receptors leads to supersensitivity to activation Problematic if taking β-blockers (antagonists) longterm. Abrupt withdrawal of β-blockers increases likelihood of a myocardial infarction for up to 2 weeks following cessation of therapy Autonomic Nervous System
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Baroreflex pathway Changes in blood pressure normally activate baroreceptors on the aorta, sending a signal through the afferent vagus nerve to the brainstem. Connections in the brain stem monitor blood pressure and send messages through the efferent vagus nerve to change heart rate in compensation by increasing or decreasing ACh release from vagus nerve.
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Location and Function of adrenergic signaling •
Function to prepare for vigorous activity and potential trauma Shunt blood away from digestive and house keeping organs (skin, GI, kidney, bladder) α1 mediated vasoconstriction
Shunt blood to skeletal muscle for vigorous activity β2 mediated vasodilation Greater effect of EPI than NE
Shunt blood to lungs, heart, brain for alertness and vigorous activity NE and EPI have very slight direct vasodilatory effects in these organs α1 mediated vasoconstriction of major blood vessels creates a pressure differential that diverts blood to heart, brain, and lungs Local vasodilatory factors in heart, lung, and brain also contribute to increased blood flow
Increase energy availability, increase blood glucose levels α2 mediated inhibition of insulin release from pancreatic islets β2 mediated glucagon secretion from pancreas α1 and β2 mediated increases in glycogenolysis and gluconeogenesis in liver β2 mediated glycodenolysis in skeletal muscle β1 and β3 mediated lipolysis and mobilization of fat reserves
Increase O2 supply in anticipation of increased demands β2 mediated bronchodilation β2 mediated inhibition of mast cell degranulation
Increased cardiac output in anticipation of increased demand β1 mediated increases in heart rate, force, and contractility
Preparation for trauma and blood loss α2 mediated potentiation of platelet aggregation β1 mediated increases in renin secretion leading to vasoconstriction
Decrease in activity of housekeeping, reproductive, and digestive organs (GI, bladder, uterus) β2 mediated relaxation of myometrial (uterine) smooth muscle β2 mediated relaxation of GI smooth muscle α2 mediated inhibition of ACh release onto GI smooth muscle α1 mediated constriction of uritogenital muscles and sphincters
Open pupils for more light input and better vision α1 mediated constriction of iris radial muscles leading to mydriasis
Autonomic Nervous System
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Adrenergic Receptor Subtypes, Location, and Function §
Subtype Pharm. profile α1 EPI≥NE>>ISO (Gαq)
α2
EPI≥NE>>ISO
Tissue Major blood vessels and vasculature in dermal, GI, renal, bladder, and secretory tissue (excepting skeletal and hepatic)* Eye GI Sphincters Bladder Sphincters Liver Eye
(Gαi) Pancreatic Islets Presynaptic nerve terminals
β1
ISO>EPI=NE
CNS# Nasal vasculature Heart
(Gαs) Kidney
β2
ISO>EPI>>NE
(Gαs)
β3
ISO=NE>EPI
Eye Hepatic and skeletal muscle vascular smooth muscle Pulmonary smooth muscle GI smooth muscle Bladder detrusor muscle Pregnant uterus (myometrium) Skeletal muscle Mast cells Pancreas Liver Eye Fat
1° effect Constriction, ↑peripheral resistance, ↑diastolic blood pressure Contraction of radial muscles →→ mydriasis Constrict Sphincters, ↓outflow Constrict Sphincters, ↓ outflow Glycogenolysis→→↑blood glucose ↓ production of aqueous humor, ↑clearance ↓Insulin release→→↑blood glucose ↓Neurotransmitter (NE or ACh) release ↓Blood Pressure, inhibit baroreflex Constriction ↑Heart rate, ↑contractility, ↑force →→ ↑cardiac output ↑Renin secretion →→vasoconstriction ↑Production of aqueous humor Relaxation, ↑blood flow to liver and skeletal muscle Relaxation→→ ↑airflow Relaxation, ↓motility Relaxation, ↓outflow Relaxation ↑Glycogenolysis, ↑K+ uptake ↓Degranuation ↑Glucagon secretion Glycogenolysis→→↑blood glucose ↑Production of aqueous humor Lipolysis (complex process)
(Gαs) § Predominant subtype, others many exist and exert actions under varying conditions *Pulmonary, cardiac, and cerebral vasculatures are initially constricted by SNS stimulation through α1 receptors; however, local vasodilatory peptides and other factors conspire to produce vasodilatation with concerted SNS stimulation leading to increased blood flow to the lungs, heart, and brain. # Multiple adrenergic subtypes present in the CNS mediate appetite and alertness Autonomic Nervous System
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Cardiovascular Effects of NE, EPI and ISO infusion •
Systolic blood pressure (SBP) is correlated with cardiac output (CO)
•
Diastolic blood pressure (DBP) is correlated with peripheral resistance (PR)
•
Mean arterial blood pressure (MABP) can be taken as an average of the systolic and diastolic blood pressures
•
Affinity of adrenergic receptors for NE: α=β1>>β2 Actions at α1 receptors increase PR and DBP Actions at β1 receptors increase CO and SBP MABP increases as average of DBP and SBP Reflex bradycardia ensues as a result of large increase in MABP
•
Affinity of adrenergic receptors for EPI: α=β1=β2 Actions at α1 receptors increase PR and DBP Actions at β2 receptors decrease PR and DBP Slight decrease in DBP overall Actions at β1 receptors increase CO and SBP MABP increases slightly as average of DBP and SBP No large change in MABP, no reflex action, heart rate remains elevated from direct actions through β1 on the heart.
•
Affinity of adrenergic receptors for isoproterenol: β1=β2>>α Actions at β2 receptors decrease PR and DBP Actions at β1 receptors increase CO and SBP MABP decreases as average of DBP and SBP (effects on vasculature predominate) Reflex tachycardia ensues as a result of decrease in MABP and contributes to greater increase in heart rate than seen with direct action through β1 receptors on the heart.
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Sympathomimetic Drugs •
β adrenergic receptor agonists, α1 adrenergic agonists
•
See structure list in G&G p. 240, covered by Dr. Proteau
Effects of sympathomimetics •
Contraindications of general sympathomimetic drugs Cardiac disease including coronary artery occlusion Increased demand on cardiac muscle can produce an MI
Hypertension Non-specific sympathomimetics will increase vasoconstriction Specific a2 adrenergic receptor agonists ARE indicated
β-blocker therapy (β antagonists) Tricyclic Antidepressants and MAO Inhibitor antidepressants Potentiate and prolong effects of sympathomimetics
Diabetes Sympathomimetics will further decrease insulin levels and increase blood sugar levels
Hyperthyroidism System is already over-stimulated
Pregnancy Vasoconstrictive effects of sympathomimetics can compromise fetal blood flow Hypertension can lead to placenta abruptia (placental separation) Specific β2 agonists ARE indicated in certain cases (premature labor)
Benign prostatic hyperplasia α-agonist constriction of bladder sphincter worsens symptoms
•
Side Effects CNS effects--Anxiety, restlessness, headache, fear Cardiac arrythmias (tachycardic arrythmias), heart palpitations Electrolyte imbalances Hypokalemia from increased K+ uptake by skeletal muscle when combined with K+depleting diuretics
Potential for cerebral hemorrhage from excess cerebral perfusion Urinary retention
Non-selective sympathomimetic compounds: Therapeutic effects •
Epinephrine α, β1, and β2 activity Short-lived, not orally active Drug of choice in anaphylactic shock Opens constricted airways Inhibits histamine release, decreasing local edema and vasodilation Supports blood pressure, maintains cardiac perfusion
Drug of choice in acute cardiac arrest including drug-induced arrest Autonomic Nervous System
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Can immediately jump start the heart
Useful as an adjuvant to local anaesthesia Local vasoconstrictive effects prolong local concentration of anaesthetic
•
Norepinephrine, α, and β1 only Short-lived, not orally active Useful in hypotensive crisis such as SNS degenerative disease Only vasoconstrictive effects No β2 activity, no vasodilatory or bronchodilatory effects
Increase cardiac output as well •
Dopamine (Inotropin®) Drug of choice for hemodynamic shock and useful for septic shock Always administer with plenty of fluid Titrate doses for selective effects Low dose agonist at D1 dopamine receptors Increases renal blood flow to maintain renal perfusion Increases coronary blood flow Higher dose agonist at β1 receptors Stimulates cardiac output Increases renin secretion to decrease urinary output Highest dose agonist at α1 receptors Increases vasoconstriction to support blood pressure May have detrimental effects on renal perfusion
Indirect and mixed function (multi-site) sympathomimetics •
Ephedrine Pseudoephedrine (Sudafed®) and Phenylpropanolamine Used or abused as stimulants, exercise enhancers and appetite suppressants Decongestants Vasoconstriction decreases swelling, nasal secretions, opens airways
Ephedra is banned after association with heart attacks, strokes, and seizures in healthy young adults Phenylpropanolamine has been banned from OTC cold remedies due to risk of stroke Pseudoephedrine is less potent that ephedrine, but is too easily converted to methamphetamine •
Amphetamine, methamphetamine, methylphenidate (Ritalin®), phentermine CNS stimulants Promote alertness, wakefulness, increased ability to concentrate Suppress appetite by increasing NE release in satiety centers in hypothalamus Addictive properties
Autonomic Nervous System
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Endogenous Adrenergic Agonists
OH HO
R (-) Norepinephrine NH2
Be able to draw this structure with correct stereochemistry
HO
OH HO
HO
Autonomic Nervous System
R (-) Epinephrine
NHCH3
Be able to draw this structure with correct stereochemistry
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Degradation of Norepinephrine (NE) (Same general scheme applies to epinephrine) OH
OH HO
NH2
HO
NE
1) MAO
HO
2) Aldehyde dehydrogenase
HO
CO2H
3,4-Dihydroxymandelic acid
COMT = Catechol-O-Methyltransferase MAO = Monoamine Oxidase
COMT
OH
OH H3CO
H3CO
1) MAO
NH2
2) Aldehyde dehydrogenase
HO
3-Methoxy-4-hydroxymandelic Acid (a.k.a. vanillylmandelic acid or VMA)
OH
OH NH2
MAO
HO
NH H
HO
HO
Imine
Non-enyzmatic hydrolysis
The imine is the true product of MAO oxidation. Once the imine is released by the enzyme, it is spontaneously hydrolyzed to the aldehyde
OH
OH HO
CO2H
HO
Normetanephrine
HO
COMT
O H
HO Autonomic Nervous System
Aldehyde
HO
dehydrogenase
HO
CO2H
3,4-Dihydroxymandelic acid
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Ser204 Ser267
O H H
O O
H
H O
H
H H
O H
NH2 O
H2N
CH3
Asn293
CO2
Asp113
(R)-(-) - Epinephrine Illustration of the Easson-Stedman hypothesis representing the interaction of three critical pharmacophoric groups of epinephrine with the complementary binding areas on the !2-adrenergic receptor as suggested by site-directed mutagenesis studies.
Adapted from Wilson & Gisvold, Ch. 16, Fig. 16-4
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SAR of Phenylethanolamine Adrenergic Agonists General: 1)
A primary or secondary aliphatic amine (compare with cholinergic agents) separated by two carbons from a substituted benzene ring is minimally required for high agonist activity in this class. Charged at physiologic pH.
2)
Most agents in this class have a hydroxyl group on Cβ of the side chain which must be in the R absolute configuration for maximal direct activity (although many agents are sold as racemic mixtures). {S isomers, in general, have lowered activity, similar to compounds without the hydroxyl.} Degree of stereoselectivity depends on receptor subtypes.
3)
The nature of the other substituents determines receptor selectivity and duration of action.
OH H N
2' 3' 1 or !
R3 4'
R1 R2
2 or "
5'
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Adrenergic Agonists Modification at R1 OH H N
HO
HO
CH3 CH3
Isoproterenol
H3C
OH HO
HO
H N
Colterol
OH H N
O
CH3 CH3 CH3
O
CH3 CH3 CH3
O O
Bitolterol Tornalate®
H3C
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Adrenergic Agonists Modification ! to the nitrogen (R2)
OH HO
NH2 CH3
HO
!-Methylnorepinephrine 1R,2S OH HO
NH2 CH3
HO
!-Methylnorepinephrine 1R,2R
OH HO
H N
HO
CH3 CH3
CH3
Isoetharine Bronkosol®, Bronkometer®
Autonomic Nervous System
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Adrenergic Agonists Modification ! to the nitrogen HO
NH2
HO
Dopamine OH H N
HO
HO
CH3
Dobutamine Dobutrex®
R3 Modifications OH H N
HO
CH3 CH3 CH3
OH
Terbutaline Brethine®,Bricanyl®, Brethaire®
Autonomic Nervous System
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Adrenergic Agonists
OH H N
HO
R3 Modifications
CH3 CH3 CH3
HO
Albuterol, salbutamol Proventil®, Ventolin® Xopenex®
OH H N
HO HO
Salmeterol xinafoate Serevent®
Autonomic Nervous System
O OH CO2H
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Adrenergic Agonists OH H N
O H
More R3 Modifications
H N CH3
HO
Formoterol Foradil®
OCH3
OCH3 OH H N NH2 O OCH3
Midodrine ProAmatine®
OH H N
HO
CH3
OH
Ritodrine Yutopar®
Autonomic Nervous System
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Adrenergic Agonists OH HO
Another R3 modification
NHCH3
Phenylephrine NeoSynephrine®
Compounds with Mixed Actions at Adrenergic Receptors OH NHCH3 CH3
1R,2S Ephedrine OH NHCH3 CH3
1S,2R
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Compounds with Mixed Actions at Adrenergic Receptors OH
OH NHCH3
NHCH3
CH3
CH3
1S,2S
1R,2R Pseudoephedrine
OH NH2 CH3
Phenylpropanolamine
NHCH3
NH2
CH3
CH3
Methamphetamine
Amphetamine
OH NH2
HO
Octopamine OH NHCH3
HO
Synephrine
Autonomic Nervous System
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!-Adrenergic Agonists (Imidazolines)
CH3 H N
HO N
H3C H3C
CH3 CH3
Oxymetazoline Afrin®, Ocuclear®
H N N
Tetrahydrozoline Visine®
!2-Selective Agonists HN
HN Cl
N Cl
Clonidine Catapres®
Autonomic Nervous System
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!2-Selective Agonists
HN HN Cl
N Cl
NH2
Apraclonidine Iopidine®
Br N
H N
N HN
N
Brimonidine (Alphagan®)
Autonomic Nervous System
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!2-Selective Agonists
HN HN
N
Cl
N S N
Tizanidine (Zanaflex®)
NH2 HN
NH O
Cl
Cl
Guanfacine Tenex®
OH HO H 3C HO
HO
CO2H NH2
HO
Methyldopa Aldomet®
Autonomic Nervous System
NH2 CH3
!-Methylnorepinephrine 1R,2S
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General summary of Structural Features for α and β Adrenergic Agonists (Note: exceptions are possible) For β selectivity: 1) The nitrogen substituent must be bulky (isopropyl or larger; bulkiness can be present at the end of a long chain - salmeterol). 2) If only one hydroxyl aromatic ring substituent is present it must be at the 4’ position (para to sidechain; e.g. ritodrine). If two substituents are present, either the 3’,4’ (meta and para to sidechain) or 3’, 5’ (both meta positions relative to sidechain) patterns are acceptable (e.g. 3’,4’colterol; 3’,5’-terbutaline). The ring substituents must be small (hydroxyl, hydroxymethyl, or Nformyl) and capable of hydrogen bonding. β 2 over β 1 selectivity: Bulkier nitrogen groups lead to β2 selectivity. t-butyl group > isopropyl The bulky aryl alkyl chains of salmeterol, formoterol, and ritodrine also help to provide β2 selectivity. In addition to the structural features listed above, β-selective agonists all have a hydroxyl group at the β carbon of the phenylethylamine substructure, except dobutamine (Dobutamine, without the C1 hydroxyl, is β1-selective, but only because of unique actions of its enantiomers. It actually has action at both α and β receptors). This β-hydroxyl, however, is not exclusive to the β-selective agonists. Many α-agonists also have a hydroxyl group at the β-position. For α selectivity (rules less defined; general guidelines below) 1)
Small nitrogen substituent = H or CH3 or imidazoline If the compound contains an imidazoline ring, then there must be a lipophilic substituent ortho to the sidechain of the aromatic ring (preferably two ortho substituents) for α-agonist selectivity.
2)
The aromatic ring should be substituted for α-selectivity. For phenylethylamine compounds, the single 3’ OH (phenylephrine) or the 2’,5’ dimethoxy (midodrine) substitution pattern leads to αselectivity.
3)
The substituent at the α carbon (α to nitrogen), if present, should be no larger than a methyl group (α-methylnorepinephrine). An ethyl group α to the nitrogen leads to β selectivity (isoetharine – also has N-isopropyl group for β-selectivity).
α 2 over α 1 selectivity Along with lipophilic ortho substituents, a guanidino group in the sidechain is present in five of the six α2-selective agents presented (clonidine, apraclonidine, brimonidine, tizanidine, guanfacine). Exception = α-methylnorepinephrine. (Note: The guanidine group by itself will not provide α2-selectivity; the remainder of the structure is also important.)
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β2-selective sympathomimetics •
Therapeutic Indications Asthma Short term therapies for immediate relief Long term prophylactic therapies
Acute respiratory distress and bronchospasm Allergic reactions and excess histamine release inhibition of mast cell degranulation allergic reactions are a component of a large percentage of asthmatic attacks
Uterine hyperactivity in premature labor •
Contraindications Coronary artery disease Most β2-selective agonists are NOT completely β2 selective and some stimulation of the heart will occur with systemic penetrance
Patients concurrently on β-blocker therapy (β antagonists), MAO Inhibitors, or tricyclic antidepressants Hyperthyroidism Diabetes β2 agonists will contribute to increased blood sugar levels by increasing glucagon secretion
Glaucoma β2 agonists will increase production of aqueous humor and exacerbate increased intraocular pressure
•
Side Effects CNS anxiety, restlessness Tachycardia and arrythmias Electrolyte (K+) imbalances Nervous muscle twitchiness from hypermetabolic state of skeletal muscles Decreased bronchoplasticity from chronic β2 agonist treatment may exacerbate asthmatic symptoms in the long run
Primary therapeutic uses for β-agonists •
Tocolytic Agents (drugs used to inhibit uterine contractions in premature labor) Ritodrine (Yutopar®), Terbutaline β2 agonists inhibit uterine smooth muscle contractions Used I.V. to prevent labor for up to 48 hours Receptor desensitization and down-regulation limits usefulness longer than 48 hours However, 24 hours pre-natal can be sufficient time to administer steroids that will improve neonatal lung function at birth
•
Short acting β2 agonists for acute treatment of asthma, chronic obstructive airway diseases, and acute bronchoconstriction Rapid onset of action, very effective drugs
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All will cause receptor desensitization and down-regulation if used chronically, may lead to noncompliant airways in the longterm. Can create a dangerous situation in an acute asthmatic attack Albuterol (Proventil®), Ventolin®)-very commonly used May be nebulized for infants and young children Oral systemic and inhalational forms
Terbutaline (Brethine®, Brethaire®) Truly β2 selective Can be given subcu. in status asthmaticus (patient is unconscious)
Bitolterol (Tornalate®) Prodrug, esterified phenyl ring hydrolyzed to catechol ring in lung Esterases may be more predominant in lung than in heart Potentially greater specificity of action in lung, fewer cardiac side effects
•
Long acting β2 agonists for longterm adjunct asthmatic therapy Not for acute attacks, longer time to onset of action Less receptor desensitization Good for night time therapy (q 12 hrs) Formoterol (Foradil®) Relatively quick onset of action can be useful Receptor desensitization can be controlled by concurrent administration of steroids
Salmeterol (Serevent®) Slower onset of action than Formoterol-counsel patients Partial agonist--very little receptor desensitization
No true β1 selective agonists with therapeutic utility Multi-action sympathomimetic •
Dobutamine Mix of stereoisomers with α1 and β activities α1 agonist and antagonist activities cancel out vascular effects, no net effect on peripheral resistance Remaining cardiovascular activity appears “β1 selective” on the heart Increases cardiac output, no effect heart rate Possibly through opposing α1 and β1 agonist effects on heart rate.
Actions are not well understood
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Pharmacogenetic considerations •
Patient variability in response to β-agonists is dependent upon allelic differences in β2 adrenergic receptor sequence** 13 known β-receptor alleles expressed in the human population Arg16/Arg16 β-receptor genotypes have greater initial responses to β-agonists but desensitize more quickly than Gly16/Gly16 or Arg16/Gly16 genotypes (0.4-0.6 frequency) Glu27/Glu27 genotypes show greater vasodilatory responses to β-agonists than Gln27/Gln27 genotypes. (0.4-0.6 frequency) **Complete haplotype analysis is a better predictor of drug response than single allele presence.
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α1-selective sympathomimetics •
Therapeutic Indications Topical vasoconstriction, mucus membrane decongestion Hypotension α1 receptors mediate vasoconstriction
Paroxysmal atrial tachycardia (PAT) α1 receptors mediate vasoconstriction and increase blood pressure Increased blood pressure leads to a reflex bradycardia
Adjuvants with topical anaesthetics Cause vasoconstriction to increase local concentration of topical anaesthetic
Appetite suppressant Mydriatic for eye exams •
Contraindications and Side Effects Hypertension Urinary retention Reflex bradycardia and arrythmias from increased blood pressure CNS effects—nervousness, tremors, irritability, heart palpitations, sweating
•
Mitodrine (Midodrine®, Pro-amantine®) Oral and IV hypertensive agent Useful for treating hypotension from spinal anaesthesia Useful for treating PAT
•
Phenylephrine-replacing pseudoephedrine as an oral decongestant Direct α1 agonist nasal and ocular decongestant α1 receptors mediate vasoconstriction of venous beds in the nose
Problems with rebound congestion after discontinuation Receptor desensitization and down-regulation occurs with chronic use
α1 receptor sympathomimetics with some α2 subtype activity •
Tetrahydrozaline (Visine®), Oxymetazoline (Afrin®) Imidazoline- type structure Ocular decongestants, decreases redness and swelling by vasoconstriction Rebound congestion may be a problem Nasal tissue necrosis with chronic use α2 receptors mediate vasoconstriction of arteriole AND venous beds in the nose
Cocaine is a mixed function agonist that is frequently abused by nasal inhalation. Topical nasal application leads to venous AND arteriole nasal vasoconstriction. Cocaine has a therapeutic use in treating uncontrolled nosebleeds in emergent settings. However, chronic use can lead to severe nasal tissue necrosis and chronic bleeding Autonomic Nervous System
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α2-selective agonists, Sympatholytic agents •
Therapeutic indications Hypertension α2 receptors are largely pre-synaptic and inhibit NE release resulting in decreased SNS signaling Blood vessels are the only organs with a predominantly sympathetic tone. Inhibition of NE release decreases blood pressure CNS α2 receptors also decrease blood pressure Αctivation of CNS imidazoline receptors by α2 agonists may possibly contribute to antihypertensive activity
Glaucoma α2 receptors in the eye inhibit production of aqueous humor by vasoconstriction and increase clearance
Treatment of withdrawal α2 receptors in the CNS reduce the anxiety and tachycardia associated with opiate, alcohol, and tobacco withdrawal
Anti-spastic agents α2 receptors in spinal cord???
•
Contraindications and side effects Diabetes α2 receptors mediate decreased insulin release from pancreas
Suppressed heart rate Decreased release of NE onto the heart Little reflex tachycardia because of α2 blockade in the brainstem baroreceptor synapses Bigger problem in elderly patients with stiff arteries and an already compromised baroreflex
Postural hypotension Blocks the ability of the body to compensate for gravitational effects from sitting or standing
Sedation Sympatholytic CNS effects
•
Systemic agents for hypertension and withdrawal symptoms Clonidine (Catapres®) Guanfacine (Tenex®) Less imidazoline activity than clonidine, more α2 selective
α-methyldopa (Aldomet®) Prodrug, converted by catecholamine biosynthetic enzymes to α-methylNE α-methylNE is a potent α2 agonist
•
Topical agents for glaucaoma Apraclonidine (Iodpine®), Brimonidine (Alphagan®) Reduced CNS penetration and side effects
•
Tizanidine (Zanaflex®) Approved anti-spasmodic agent
Autonomic Nervous System
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Development of Non-Selective !-Adrenergic Antagonists OH H N
Cl
CH3 CH3
Cl
Dichloroisoproterenol
OH H N
CH3 CH3
Pronethalol
CH3 O
N H
CH3
OH
Propanolol Inderal®
Autonomic Nervous System
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Non-Selective !-Adrenergic Antagonists
CH3 O
N H
CH3
OH
Pindolol Visken®
N H
O OH N
O
N
N
H N
CH3 CH3
S
CH3
S(-) Timolol Blocadren®, Timoptic®
Autonomic Nervous System
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Non-Selective !-Adrenergic Antagonists
OH H N
CH3 CH3
H3CO2SHN
Sotalol (Betapace®)
Non-Selective !-Adrenergic Antagonists with "1 Antagonist Activity O
OH H N
H 2N CH3
HO
Labetalol Normodyne®, Trandate®
O O
N H OH H3CO
N H
Autonomic Nervous System
Carvedilol Dilatrend®
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Selective !1-Adrenergic Antagonists
CH3 O
N H
CH3
OH
Metoprolol Lopressor® OCH3
CH3 O
N H
CH3
OH
Esmolol Brevibloc®
O OCH3
CH3 O
O
N H
CH3
OH H3C
Acebutolol Sectral® HN
CH3 O
Autonomic Nervous System
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Non-Selective !-Adrenergic Antagonists H3C H N
N N
HO
Phentolamine Regitine®
Cl N CH3 O
Phenoxybenzamine Dibenzyline®
Autonomic Nervous System
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Selective !1-Adrenergic Antagonists O O
N H3CO
N
N
Prazosin Minipress®
N H3CO NH2
O O
N H3CO
N
N N
Terazosin Hytrin®
H3CO NH2
O CH3 H3CO
N
HN
O
N N
H3CO NH2
Autonomic Nervous System
Alfuzosin Uroxatral®
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Selective !1-Adrenergic Antagonists H N
H2NO2S
H3CO
CH3
O O
Tamsulosin (Flomax®)
Autonomic Nervous System
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Summary for α and β adrenergic antagonists
PHAR 752
General α Antagonists (two agents) Phentolamine - an imidazoline based antagonist with two aromatic rings in addition to the imidazoline ring. The extra bulk of the second aromatic ring likely contributes to antagonist action. Phenoxybenzamine - The only receptor antagonist that has been presented that has a βchloroethylamine substructure - key for irreversible alkylation of the α-receptor. α 1-selective antagonists - (prazosin, terazosin, alfuzosin, tamsulosin) therapeutic uses for α-antagonists
These agents see the greatest
The first three are based on a quinazoline core structure which has a 4-position amino group that is important for α1-selectivity. Additional structural features are a variable diamine sidechain (the piperazine ring is not necessary for antagonist action; an acyclic side chain also works) and a variable acyl group that forms an amide linkage to the remainder of the side chain. Tamsulosin is structurally distinct. It is a 3',4'-disubstituted-phenethylamine which has an aryl alkyl N-substituent.
General β Most are based on an aryloxypropanolamine substructure. Also note that amine substitution is an isopropyl or t-butyl group, the same as seen for β-selectivity in agonists. Key structural features are ortho, and most of the time, meta substituents on the aromatic ring. The aromatic ring does not have to be a phenyl ring. More extensive substitution of the aromatic ring is possible, with pentasubstitution being maximal (note that this does include the ortho and meta substituents seen in other general β-antagonists) Exception - sotalol = A general β-blocker based on a phenylethanolamine substructure (quite similar to β-agonists). The key structural feature that makes sotalol an antagonist is a bulky group (methanesulfonamide) at the para position rather than a hydroxyl that would be present in an agonist. General β with additional α 1-antagonist activity Two agents - Labetalol (an equal mixture of 4 isomers) and carvedilol (a pair of enantiomers). In both cases one isomer contributes the main β -blocking activity while the α1-antagonist action can be due to more than one isomer. The key factor to remember is that the isomers contribute differently to the overall pharmacology of the mixture. Also note that labetalol is based on the phenylethanolamine substructure while carvedilol is an aryloxypropanolamine. β 1-Selective antagonists These are based on the aryloxypropanolamine compounds. The key structural features for β1selectivity are a para substituent and the absence of a meta substituent (an ortho substituent is OK).
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Non-selective β adrenergic antagonists •
All are competitive antagonists
•
Effects are most pronounced under conditions of stress, exercise (blocking an elevated basal SNS tone)
•
Therapeutic Indications Hypertension Decrease in cardiac output (β1 blockade) results in decreased systolic blood pressure Decrease in renin secretion (β1 blockade in kidney) results in vasodilation Paradoxical effects. Short term β2 blockade in normotensives will cause limited vasoconstriction as expected β2 blockade in hypertensives leads to decreased systolic AND diastolic blood pressure
Post MI therapy, ischemic heart disease, angina, congestive heart failure Decrease O2 demand in the heart, decrease workload on cardiac muscle by blocking β1 receptors, decrease afterload by vasodilation
Compensatory cardiac hypertrophy in heart failure Reverse overgrowth of heart muscle due to excess SNS activity
Ventricular tachycardic arrythmias Block cardiac β1 receptors to decrease heart rate, decrease AV nodal conduction, and increase refractory period
Performance anxiety CNS effects of β blockers
Tremors Drug induced tremors, such as accompany lithium carbonate Familial palsy (not Parkinson’s disease)
Prophylactic treatment of migraine Unknown mechanism
Chronic Glaucoma Decrease aqueous humor production by blocking β1 and β2 receptors in the eye
Symptoms of hyperthyroidism Blocks the symptoms mimicking SNS over-activity No effect on the disease itself
Management of pheochromocytoma Pheochromocytoma is a tumor of the adrenal medulla that constitutively releases large amounts of EPI Need to block effects of EPI on the body before surgical removal Use a non-specific β antagonists in conjunction with an α antagonist
•
Asthma—future potential for β-blockers Blockade of β2 receptors in lungs increases airway resistance and may potentiate mast cell degranulation—this seems bad for asthmatics BUT, research suggests that longterm treatment with β-blockers may improve airway elasticity by blocking excess SNS signaling
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•
Contraindications Asthma? Insulin-dependent diabetes Counterintuitive contraindication, β2 blockade should decrease glucagon release and aid in lowering blood sugar Effects masks the symptoms of hypoglycemia (increased heart rate, tremors) of vital importance to diabetics Hyperglycemia, the main problem in diabetes, is toxic in the long term Hypoglycemia, a side effect of insulin treatment, can kill quickly
•
Common side effects Exercise Intolerance Reduced airflow Restriction of blood flow to skeletal muscles Reduced cardiac output
Hyperkalemia Especially during exercise Block skeletal muscle uptake of K+ (β2 blockade)
Mast cell degranulation Bradycardic arrythmias Blockade of β1 receptors in the heart Particularly in patients with inadequate myocardial reserve
Malaise--Sedation, fatigue, depression CNS effects Depression may occur in a susceptible population
Withdrawal syndrome Rebound tachycardia upon abrupt withdrawal due to receptor supersensitization MI may ensue in susceptible patients Problematic for up to 2 weeks following cessation of therapy Discontinue by tapering the dose
•
Propranolol (Inderal®) Precursor of all β-antagonists Decreases nervousness and tremors—performance anxiety, familial and drug-induced tremors Decreases heart rate and cardiac output Decreases systolic blood pressure (cardiac effects), inhibits renin production, and peripheral resistance with chronic use (unknown mechanism) to treat hypertension Used topically to treat glaucoma by inhibiting aqueous humor production
•
Sotalol (Betapace®) Little or no blood/brain barrier permeability No sedative effects
Used predominantly for cardioprotective effects Longer lasting than propranolol Autonomic Nervous System
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•
Timolol (Timoptic) Used topically to treat glaucoma Be careful in asthmatics, systemically absorbed
•
Pindolol (Visken®) Partial agonist (partial antagonist) Moderately decrease heart rate and cardiac output Safer in patients with congestive heart failure (avoid bradycardic arrythmias in cardiac compromised patients Very little receptor supersensitivity, better withdrawal profile Effects of β-blockade are most pronounced under conditions of stress or exercise
h e a rt ra te (b pm )
120 105
Exercise or stress
90
75 Rest
60 0
-10
-9
-8
-7
-6
-5
log [pindolol] M
β1-selective antagonists •
Therapeutic Indications Hypertension Decrease in cardiac output (β1 blockade) results in decreased systolic blood pressure Decrease in renin secretion (β1 blockade in kidney) results in vasodilation Absence of β2 effects allows for β2-mediated vasodilation to occur Other unknown factors contribute to decrease in blood pressure with use of β receptor antagonists
Post MI therapy, Ischemic heart disease, Angina Decrease O2 demand in the heart, decrease workload on cardiac muscle by blocking β1 receptors
Compensatory cardiac hypertrophy Overgrowth of heart muscle due to excess SNS activity Autonomic Nervous System
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Ventricular tachycardic arrythmias Block β1 receptors to decrease heart rate
•
Contraindications and Side Effects See non-selective β-blockers above **none of the β1 antagonists is completely β1-selective Preferred for asthmatics (fewer β2 side effects)
•
Metoprolol (Lopressor®), Atenolol (Tenormin®) β1 full antagonists Useful for treating hypertension in asthmatic patients Blocks stress-induced increase in blood pressure better than propranolol Allows for SNS stimulated, β2-receptor mediated vasodilation in skeletal muscle
•
Acebutolol (Sectral®) Weak β1 partial agonist (partial antagonist)
•
Esmolol (Brevibloc®) Very short duration β1 blocker Used to treat ventricular tachycardic arrythmias and in other situations where brief cardiac blockade is warranted
β2-selective antagonists •
None of therapeutic value currently marketed
α,β-non-selective partial agonists, antagonists, indirect agonists •
Labetolol (Normodyne®) Mix of four stereoisomers, each with unique properties RR: β1 antagonist and β2 partial agonist SR, SS: α1 antagonists RS: no activity
Uptake I inhibitor (indirect agonist) Overall effect Block α1 receptors, decrease peripheral resistance Block β1 receptors, decrease cardiac output, renin secretion Partial β2 agonist, increased vasodilation in skeletal muscle
Very effective antihypertensive agent •
Carvedilol (Dilatrend®) Mix of two enantiomers S: β antagonist R and S: α1 antagonists
Good antihypertensive agent Additional antioxidant and antiproliferative effects on vascular smooth muscle protect against atherosclerotic complications of hypertension
Autonomic Nervous System
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α-antagonists •
All are competitive except for phenoxybenzamine
•
Will cause an EPI reversal effect (think this through)
•
Therapeutic indications Hypertension Block α1-mediated vasoconstriction Decrease peripheral resistance
Congestive heart failure Decreased peripheral resistance leads to less workload and increases cardiac output
Benign prostatic hyperplasia Urinary retention and outflow difficulties Block α1-mediated constriction of the bladder sphincter and prostate capsule Longterm, may block hypertrophy of the prostate capsule
Pheochromocytoma Treat with α-antagonists plus a non-selective β-antagonist Manage side effects of excessive EPI production and release Hypertension, tachycardia, restlessness
Frostbite and Reynaud’s syndrome Increased blood flow to the extremities
Treatment for tyramine poisoning •
Side effects Tachycardia Reflex tachycardia due to decreased mean arterial blood pressure Blockade of α2 inhibition of baroreflex leads to greater baroreflex response Blockade of α2 inhibition of NE release onto heart leads to greater NE release Sustained increases in heart rate upon stimulation
Postural hypotension Block ability to respond to gravitational effects on blood flow Dose at bedtime and remain supine for 2 hours to avoid Remind patients to be careful after taking a hot shower or hot tub
Nasal congestion Inhibition of ejaculation
Autonomic Nervous System
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Non-selective α antagonists Used to manage pheochromocytoma in combination with propranolol Useful in hypertension and congestive heart failure if increases in heart rate are wanted •
Phentolamine (Regitine®) Competitive α antagonist Serotonin receptor antagonist activity GI side effects
Also blocks 5-HT receptors and activates GI muscarinic receptors leading to increased motility and gastric secretions •
Phenoxybenzamine (Dibenzyline®) Irreversible α antagonist, alkylating agent Long duration antagonist, >24 hours effectiveness Reversal requires synthesis of new receptors
Also blocks 5-HT and histamine receptors
α1-selective antagonists •
Therapeutic Indications See non-selective α antagonists above
•
Side Effects See non-selective α antagonists above Less tachycardia than with non-selective agents No blockade of α2 inhibition of baroreflex or α2 inhibition of NE release
•
Prazosin (Minipress®), Terazosin, (Hytrin®), Alfuzosin (Uroxatral®) Anti-hypertensives, decrease peripheral resistance Treatments for benign prostatic hyperplasia Less inhibition of ejaculation claimed for alfuzosin
•
Tamsulosin (Flomax®) Treatment for benign prostatic hyperplasia Selective for α1A over α1B receptors 70% of receptors in prostate are α1A
Not a very effective anti-hypertensive, but dizziness and fainting are possible side effects
α2-selective antagonist •
Yohimbine (Yocon®)-rarely used "Indirect" sympathomimetic Block α2 inhibition of NE release Inhibition of CNS α2 receptors leads to increased blood pressure
Autonomic Nervous System
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GLAUCOMA Normal aqueous humor flow •
From the interior of the eye, aqueous humor flows through the ligaments connecting the ciliary muscle to the lens, around the lens and through the pupil (the open center of the iris) and into the anterior chamber
•
Aqueous humor is absorbed from the anterior chamber by the Canal of Schlemm
Two types of glaucoma: acute, closed angle and chronic, open angle •
Acute closed angle glaucoma is characterized by an abnormal lodging of the iris against the lens, impeding flow of aqueous humor, leading to increased intraocular pressure (IOP)
•
Chronic open angle glaucoma is characterized by excess aqueous humor, from either overproduction or impaired absorption by the Canal of Schlemm
Treatment for glaucoma •
Acute closed angle glaucoma is best treated by pupillary constrictors Cholinomimetics Problems with accomodation for far vision and night vision
Constrict the iris sphincter and dislodge the iris, opening a pathway for aqueous humor flow Contraction of the ciliary muscle increases space for aqueous humor flow through the ciliary ligaments •
Chronic open angle glaucoma may be treated with agents that inhibit production of aqueous humor including β-adrenergic receptor antagonists Problems with concurrent airway disease
α2 adrenergic receptor agonists Problems with photosensitivity through α1-mediated mydriasis Problems with drug reactions through alkylation
Carbonic anhydrase inhibitors, e.g. dorzolamide Carbonic anhydrase converts carbon dioxide and hydroxide into bicarbonate HCO3- ⇔ CO2 +OHRequired enzyme for aqueous humor production Systemic administration can cause metabolic acidosis, leading to kidney stone formation Allergic sensitivity reactions
Autonomic Nervous System
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•
Chronic open angle glaucoma may also be treated with agents that increase aqueous humor drainage Prostaglandin analogues or pro-drugs, e.g. latanoprost, unoprostone (Rescula®) May cause an irreversible increase in pigmentation of the iris, eyelid, and lashes
Cholinomimetics Cannabinoids, including Δ9-tetrahydrocannabinol Mechanism of action to reduce IOP not well understood Tolerance develops Must be taken systemically, no topical penetrance
Autonomic Nervous System
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Glaucoma Drugs - Carbonic Anhydrase Inhibitors
HN
H 2N
S
O
S
S O
O
O
Dorzolamide (Trusopt®)
HN
N
H2N
S
O
S
S O
O
O
O
Brinzolamide (Azopt®)
Autonomic Nervous System
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Glaucoma Drugs - Prostaglandin Analogs
HO CO2H
HO
OH
Prostaglandin F2! (PGF2!)
HO CO2iPr
HO
O
Unoprostone isopropyl (Rescula®)
HO CO2iPr
HO
OH
Latanoprost (Xalatan®)
Autonomic Nervous System
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Glaucoma Drugs - Prostaglandin Analogs HO CO2iPr O HO
OH
Travoprost (Travatan®)
CF3
HO CONHC2H5
HO
OH
Bimatoprost (Lumigan®)
Autonomic Nervous System
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