AUTONOMICS: SYMPATHETIC AND PARASYMPATHETIC NERVOUS SYSTEM

Parts of the Nervous system

1. Central Nervous System (CNS) - brain, spinal cord
2. Peripheral Nervous System (PNS) - neurons outside the brain & spinal cord
A. Somatic - voluntary regulation of skeletal muscles
B. Autonomic - involuntary regulation of smooth muscle, cardiac muscle & glands
Pathway: brain stem / spinal cord! preganglionic neuron (NT)! post-ganglionic neuron (NT)! target organ

Sympathetic / Adrenergic Parasympathetic / Cholinergic

(Fight, Flight, Fright) (Rest & Digest)

Anatomic

Roots Thoracolumbar (T1-T12, L1-L5) Craniosacral (CN 3, 7,9 & 10, S3-S4)

Location of Ganglia Near the spinal cord Near the target organ

Length of Fibers
Preganglionic Short Long
Postganglionic Long Short

Neurotransmitters
Preganglionic Acetylcholine Acetylcholine
Postganglionic NE, Epinephrine, Dopamine Acetylcholine

Receptor
Ganglia Nicotinic Nicotinic
Target Organ Alpha, Beta, Dopamine Muscarinic, Nicotinic

Organ Response

Pupils Dilation Constriction

Bronchi Bronchodilation Bronchoconstriction

Heart (+) chronotropic (-) chronotropic

(+) inotropic (-) inotropic

GIT
Sphincter Closed Opened
Intestinal wall muscle ↓ motility ↑ motility

Bladder
Sphincter Closed Open
Wall muscles Relaxation Constriction

Male genitalia Ejaculation Erection

Uterus Relaxation Contraction

Blood vessels Vasoconstriction Vasodilation

Sweat glands ↑ sweating (apocrine glands: soles & ↑ sweating (exocrine glands or
palms) thermoregulatory sweat glands)

SYMPATHETIC NERVOUS SYSTEM

RECEPTOR LOCATION EFFECT

Alpha 1 Blood vessels Vasoconstriction

Pili erector muscle Contraction

Pupils Mydriasis

Sphincters (GIT / GUT) Closed

Alpha 2 Presynaptic terminal / Autoreceptor Modulation of NE release (Negative feedback mechanism)

(Central) Decreased catecholamine release
Decreased sympathetic vasomotor tone (vasodilation)
Inhibit lipolysis & insulin release

Postsynaptic terminal Relaxation of smooth muscles

(Peripheral) Vasoconstriction

Beta 1 Heart (+) Chronotropy, (+) Inotropy

Kidney Renin release

Beta 2 Bronchus Bronchodilation

 Uterus Relaxation

Blood vessels Vasodilation

Skeletal muscle Contraction

Pancreas Stimulate insulin release

Beta 3 Adipose tissue Promote lipolysis

Dopamine 1 Blood vessels of renal, mesenteric, coronary, & Vasodilation

cerebral vascular beds

Dopamine 2 CNS Stimulation

PARASYMPATHETIC NERVOUS SYSTEM

RECEPTOR LOCATION EFFECT RECEPTOR LOCATION EFFECT

M1 CNS Stimulation N (neural) CNS Stimulation, seizures

Gastric parietal cells Increased HCl production Ganglia Stimulation of SNS & PNS

Myenteric plexus Stimulation N Neuromuscular end Muscle contraction,

(muscular) plate fasciculation

M2 Blood vessels Vasodilation DUMBELS - cholinergic effects

Bronchus Bronchoconstriction Diarrhea
Urination
Genitourinary Urination Miosis
Bradycardia, Bronchoconstriction
Intestines Contraction Emesis
M3 Heart Bradycardia Lacrimation
Salivation, Sweating
Exocrine glands Sweating

Gastrointestinal muscles Contraction

Gastrointestinal Increased
secretions

M4 CNS Enhanced locomotion

M5 CNS Unknown
Salivary glands
Iris/ciliary muscle

AUTONOMIC DRUGS: ADRENERGIC AGONISTS & ANTAGONISTS

SYNTHESIS & RELEASE OF NOREPINEPHRINE (NE) - given with local anesthetics (prolongs effect)
S/E: HTN, palpitations, arrhythmia
1. Synthesis
- tyrosine ! dihydroxyphenylalanine or DOPA ! b. Norepinephrine (Levophed)
dopamine (rate-limiting step is hydroxylation of tyrosine) - shock / hypotension
- metyrosine inhibits the rate-limiting step S/E: HTN, palpitations, arrhythmia

2. Uptake into Vesicles c. Dopamine (Docard)

- dopamine enters vesicle:Dopamine ! NE - shock / hypotension, heart failure, renal failure (to increase
- reserpine inhibits transport into vesicle blood flow to kidneys)
S/E: HTN, palpitations, arrhythmia
3. Release
- Ca causes release of NE low dose: dopamine receptors
- guanethidine & bretylium block NE release moderate dose: β receptors
- amphetamine, methamphetamine, ephedrine, & tyramine high dose: α receptors
cause NE release
d. Dobutamine (Dobutrex)
4. Binding to receptor - heart failure
S/E: HTN, palpitations, arrhythmia
5. Removal
- methylated by catechol O-methytransferase (COMT) 2. α Agonists
- oxidized by monoamine oxidase (MAO)
- reuptake by neuron: cocaine & TCAs inhibit reuptake α1 Agonists:
- urine metabolites: vanillylmandelic acid (VMA), 1. Phenylephrine (Neo-Synephrine, Dimetapp)
metanephrine, normetanephrine 2. Phenylpropanolamine (Neozep, Decolgen, Tuseran,
Disudrin, Sinutab)
ADRENERGIC AGONISTS / SYMPATHOMIMETICS 3. Pseudoephedrine (Sudafed)
Direct-Acting- directly bind to the receptor - nasal decongestant
S/E: HTN
1. α, β Agonists
4. Methoxamine
a. Epinephrine (aka adrenaline) - hypotension
- anaphylaxis (bronchodilator) S/E: HTN
- cardiac arrest
 α2 Agonists: ADRENERGIC ANTAGONIST / BLOCKERS
1. Clonidine (Catapres) Direct-Acting- directly blocks receptors
- treatment of HTN
SE: withdrawal induced rebound HTN Αlpha Blockers
1. α1 Blockers
2. Methyldopa (Aldomet) - Prazosin, Doxazosin, Terazosin
- prodrug - HTN, benign prostatic hyperplasia (BPH): bladder relaxation,
- active: α-methyldopamine & α-methylNE prevents urinary retention
- HTN in pregnancy S/E: orthostatic hypotension especially after the first dose
SE: (+) Coomb’s test
2. α2 Blocker
3. β Agonists - Yohimbine
- impotence (penile injection)
β2 Agonists:
- Salbutamol (Ventolin), Terbutaline (Bricanyl), 3. α1 & α2 Blockers
Metaproterenol -Phenoxybenzamine
- asthma - HTN due to pheochromocytoma (tumor of adrenal medulla
- terbutaline: premature labor / tocolytic (↓ uterine (overproduction & release of epinephrine & NE))
contraction) S/E: postural hypotension
S/E: stimulates β 1 at high doses: palpitations, tremors
-Phentolamine
β1 & β 2 Agonist: - pheochromocytoma-associated HTN
- Isoproterenol S/E: postural hypotension
- cardiac arrest
S/E: HTN, palpitations, arrhythmia Βeta Blockers
1. β1, β 2 Blockers
Indirect-Acting- promotes NE release - Propranolol, Timolol, Nadolol, Pindolol, Labetalol, Carvedilol
- HTN
1. Tyramine - hyperthyroidism, MI, angina, arrhythmia, migraine
- red wine, beer, cheese, chocolates prophylaxis, panic attacks
- can cause HTN in depressed patients taking MAOI - glaucoma: Timolol, Nadolol (↓ aqueous humor production)
S/E: Bronchoconstriction (C/I for asthmatic patients)
2. Amphetamine, Metamphetamine
- attention deficit hyperactivity disorder (ADHD), appetite 2. β1 Blockers
suppression - Bisoprolol, Betaxolol, Esmolol, Atenolol, Acebutolol,
S/E: HTN, palpitations, dependence, insomnia, psychosis Metoprolol, Celiprolol
- CBEAM
Mixed (Direct-Acting & Indirect-Acting) - HTN
- blocks β 2 receptors at high doses
1. Ephedrine
- alkaloid from ma huang (Ephedra sinica) Indirect-Acting- blocks release of NE
- urinary incontinence, bronchospasm, hypotension, nasal 1. Guanethidine
congestion, narcolepsy 2. Reserpine: alkaloid from Rauwolfia serpentina
S/E: HTN, palpitations, arrhythmia, insomnia - both used for HTN (rarely used)

AUTONOMIC DRUGS: CHOLINERGIC AGONISTS & ANTAGONISTS

SYNTHESIS & RELEASE OF ACETYLCHOLINE (ACH) Direct-Acting Cholinergic Agonists

1. Synthesis A. Choline Esters

- acetylCoA: mitochondria
- choline: hemicholiniums inhibit its transport 1. Acetylcholine
- choline acetyltransferase - prototype, no clinical use because of widespread effects &
rapidly hydrolyzed by AChE
2. Storage in Vesicles - S/E: DUMBELS
- vesamicol inhibits this step
2. Bethanechol (Urecholine)
3. Release - ↑ intestinal motility after surgery (Bowel)
- dependent on extracellular calcium (exocytosis) - urinary retention (Bladder)
- spider venom causes release - S/E: DUMBELS
- botulinum toxin blocks release
Botulinum toxin (Botox) 3. Carbachol
- glaucoma (topical); if patient is tolerant to pilocarpine
4. Binding to Receptor
- acetylcholine receptor (cholinoceptor) 4. Methacholine
- diagnosis of asthma
5. Degradation of Acetylcholine
- acetylcholinesterase (AChE) B. Alkaloids
- acetate + choline
1. Pilocarpine: alkaloid from Pilocarpus sp.
6. Recycling of Choline - glaucoma (DOC); Sjögren's syndrome (decreased salivation,
decreased lacrimation)
CHOLINERGIC AGONISTS - reduces intraocular pressure by causing contraction of the
- acetylcholine ! muscarinic receptors ciliary body to facilitate outflow of aqueous humor
S/E: enter CNS (hallucinations, seizures), DUMBELS
1. Direct-acting- bind, activate receptor
2. Indirect-acting- inhibit AChE ! ↑ ACh 2. Arecoline: from betel nut (Areca catechu)

3. Muscarine: from mushroom Amanita muscaria

Indirect-Acting Cholinergic Agonists / Cholinesterase
Inhibitors
A. Organophosphates (OP)
- binds to AChE forming a stable phosphate-ester bond !
inactivation of AChE ! ↑ ACh (irreversible without treatment)
a. Isofluorophate, Echothiophate - glaucoma
b. Malathion, Parathion - pesticides; active metabolites:
malaoxon, paraoxon
c. Tabun, Sarin, Soman - chemical warfare / nerve gas
- S/E: DUMBELS
Antidotes:
1. Pralidoxime - reactivates AChase by removing OP; should be
given before AChE loses one of its alkyl groups (aging)
2. Atropine- anticholinergic / muscarinic blocker
B. Carbamates
1. Physostigmine: aka Eserine
- alkaloid from Calabar bean / ordeal bean Physostigma
venenosum
- glaucoma (2nd DOC after pilocarpine)
- antidote for anticholinergic poisoning (atropine, TCAs,
phenothiazine)
Alice in Wonderland:
▪ mad as a hatter - hallucinations, confusions
▪ blind as a bat - blurring of vision (cycloplegia & mydriasis)
▪ dry as a bone - dry mouth, ↓ sweating, ↓ intestinal &
bronchial gland secretion
▪ red as a beet - tachycardia, vasodilation / flushing
▪ hot as hare - fever / hyperthermia
b. Scopolamine (Buscopan, Transderm-Scop)
- aka hyoscine
- alkaloid from henbane (Hyoscyamus niger)
- prevent motion sickness (transdermal patch)
- + morphine (obstetric anesthetic)
-S/E: reverse of DUMBELS
c. Ipratropium (Atrovent)
- more peripheral effect (lungs), less CNS effects
- asthma
d. Pirenzepine
- peptic ulcer
e. Cyclopentolate (Cyclogyl), Tropicamide (Mydriacyl)
- opthalmoscopic examination

2. Neostigmine (Prostigmin) f. Benztropine (Cogentin), Trihexyphenidyl (Artane)

- treatment of myasthenia gravis (MG) - Parkinson’s disease
▪ Myasthenia gravis (MG)
- disease affecting skeletal muscle neuromuscular Other drugs that block muscarinic receptors:
junctions 1. Antihistamines
- autoimmune; degrades nicotinic receptor & block Ach 2. Antipsychotics
binding to receptors on muscle end plates 3. Tricyclic antidepressants
- ptosis, diplopia, difficulty in speaking & swallowing, S/E: reverse of DUMBELS
extremity weakness
- antidote for tubocurarine poisoning - NM / nicotinic blocker 2. Neuromuscular (NM) Blockers / Skeletal Muscle Relaxants
- block nicotinic receptors in muscles ! paralysis
3. Pyridostigmine (Mestinon): treatment of MG
a. Nondepolarizing
4. Carbamate insecticides: Carbaryl, Methylcarbamate - tubocurarine from Curare (Strychnos sp.) used as arrow
(Baygon) poison in South America
- Pancuronium, Atracurium, Vecuronium
C. Quaternary Amine - facilitates intubation for mechanical ventilation, muscle
relaxant during surgery
Edrophonium (Tensilon) - S/E: bronchoconstriction, hypotension due to histamine
- diagnosis of MG (Tensilon Test: ↑ muscle strength, ↓ ptosis) release, respiratory paralysis
- antidote in tubocurarine poisoning - Antidote: Neostigmine

Others: b. Depolarizing
1. Ambenonium - (Mytelase) MG - Succinylcholine
2. Tacrine; Donepezil; Rivastigmine; Galantamine - depolarizes (transient fasciculations) ! repolarizes (flaccid
- Alzheimer’s disease: loss of cognitive function paralysis)
- to delay the progression of disease [not to stop progression] - facilitates intubation for mechanical ventilation, muscle
relaxant during surgery
CHOLINERGIC ANTAGONISTS / BLOCKERS - S/E: bronchoconstriction (due to histamine release),
hypotension, respiratory depression, arrhythmia, malignant
1. Muscarinic Blockers hyperthermia (fever, muscle rigidity)
- Antidote: Dantrolene - block Ca release ! ↓ muscle
a. Atropine: aka hyoscyamine contraction
- prototype, alkaloid from deadly nightshade (Atropa
belladonna) & jimsonweed (Datura stramonium) 3. Ganglionic Blockers

Uses: a. Hexamethonium, Mecamylamine, Trimethaphan

1. ophthalmoscopic examination - block ganglia without prior stimulation
- mydriasis & cycloplegia (C/I for patients with glaucoma) - hypertension (rarely used due to lack of selectivity)
2. organophosphate poisoning
3. bradycardia b. Nicotine
- initially stimulate then block ganglia
Effects: Reverse of DUMBELS - tobacco, cigarettes (Nicotiana tabacum)
Constipation - tolerance
Urinary retention - patch, gum (Nicorette), nasal spray: smoking cessation,
Mydriasis, paralysis of accommodation (cycloplegia) ! prevents nicotine withdrawal
blurring of vision
Tachycardia, bronchodilation Lobeline
Dry mouth, ↓ sweating - from Indian tobacco (Lobelia inflata)
Hallucinations
 AUTACOIDS

Autacoids Receptors, Location and effects

- autopharmacological agents or local hormones 1. 5HT1A
- local release & action limited to a specific site Location: CNS (presynaptic)
- histamine, serotonin, prostaglandin, leukotriene, bradykinin Effect: inhibits release of 5HT
2. 5HT1B/1D
HISTAMINE L: Blood Vessels
- derived principally from dietary histidine, which is E: Vasoconstriction
decarboxylated by L-histidine decarboxylase 3. 5HT2A/2B
- found in mast cells & basophils L: Smooth muscles (Bronchi, Uterine, Blood vessels)
- H1 receptor: allergic & anaphylactic responses E: Contraction
- H2 receptor: increased secretion of acid & pepsin 4. 5HT3
L: Chemoreceptor trigger zone
Triple Response of Lewis (exhibited when Histamine is E: Emesis
released) elicited by: 5. 5HT4
A. Intradermal infection of Histamine L: GIT
B. Stroking the skin with a sharp object E: Peristalsis
1. Erythema/Redness (point/line): local vasodilation (H1)
2. Spreading of Erythema/Redness:Sensory Nerve Major physiological effects:
stimulation (H1) ▪ vasoconstriction, platelet aggregation (5HT2)
3. Swelling: endothelial cell contraction (H1) ▪ increased release of Ach in the enteric region (5HT4)
▪ nausea/emesis (5HT3)
A. ANTIHISTAMINES / H1 BLOCKERS ▪ behavioral actions that influence anxiety, appetite,
- seasonal rhinitis, conjunctivitis, cold, urticaria depression, aggression, & impulsivity (5HT1, 5HT2, 5HT3)
▪ decrease presynaptic neurotransmitter release (5HT1D)
Specific Agents:
▪ Diphenhydramine (Benadryl), Dimenhydrinate, Meclizine A. SEROTONIN AGONISTS
(Bonamine)- nausea & vomiting associated with motion 1. Sumatriptan, Rizatriptan, Naratriptan, Zolmetriptan,
sickness & vertigo Almotriptan, Frovatriptan
▪ Promethazine - antiemetic - migraine
▪ Hydroxyzine (Iterax) - mild anxiolytic - C/I: HTN, IHD

First-Generation Antihistamines 2. Ergot alkaloids

Alkylamines, Ethanolamines, Piperazines, Phenothiazines, - from fungus that infects grain Claviceps purpurea
Piperidines, Ethylenediamines - Ergotamine: postpartum hemorrhage, migraine HAs
- Lysergic Acid Diethylamide (LSD) - hallucinogen
Second-Generation Antihistamines - toxicity: ergotism (St. Anthony’s fire)
Piperidine:(True/Non Sedating)
- Terfenadine 3. Cisapride & Tegaserod
- Fexofenadine (Telfast) - Cisapride: GERD
- Loratadine (Claritin) - Tegaserod: constipation-predominant IBS
- Astemizole - S/E: arrhythmia

Piperazine: (Less Sedating) B. SEROTONIN ANTAGONISTS

- Cetirizine (Zyrtec)
S/E: sedation, anticholinergic effects, arrhythmia (Terfenadine,
Astemizole)
B. H2 BLOCKERS
- Cimetidine (Tagamet), Ranitidine (Zantac), Famotidine (H2
BLOC), Nizatidine (Axid)
- peptic ulcer, GERD, Zollinger-Ellison syndrome
S/E: Cimetidine - enzyme inhibition, androgenic effects
(impotence & gynecomastia in men & galactorrhea in women)
1. Ergot Alkaloids
- from fungus that infects grain Claviceps purpurea
- Ergonovine, Methylsergide, Bromocriptine
- Ergonovine: postpartum hemorrhage, migraine HAs
- Methylsergide - migraine prophylaxis
- Bromocriptine - hyperprolactinemia, Parkinson’s disease
- toxicity: ergotism (St. Anthony’s fire)
2. Ondansetron, Granisetron, Dolasetron, Alosetron
- prevent & treat nausea & emesis secondary to antineoplastic
therapy
- Alosetron: diarrhea-predominant IBS

SEROTONIN EICOSANOIDS
- 5-hydroxytryptamine (5HT) -Autacoids derived from Arachidonic Acid (20 C)
- derived from amino acid tryptophan - Phospholipids (PLA2)-Primary Pathway
- Phosphatidylinositol (PLC)-Alternative Pathway

Cell Membrane
Phospholipids
Phospholipase "Steroids
Arachidonic Acid

Zileuton ! Lipooxygenase Cyclooxygenase " NSAIDs

Leukotrienes Prostaglandins,Thromboxanes
-bronchoconstriction - COX1 PGs - ↓ HCl, mucus production ! ulcer
- phlegm production - COX2 PGs - pain, inflammation

Leukotriene Receptor Blocker: Zafirlukast

Most NSAIDS inhibit both COX1 and COX2. Celecoxib inhibit COX2
only—> Inc. Thromboxanes - platelet aggregation—> stroke, MI —>
inhibited by Aspirin
- distribution: GIT (enterochromaffin cells & nerve cells), CNS,
blood
- metabolized by MAO
 2. Narcotics: MOA- A. mimics the action of endogenous opioids
Location Effects by binding to opioid receptors; B. Simulate the release of
opioid peptides (endorphins)
Blood Vasoconstriction:TXA2, PGF
Vessels Vasodilation:PGI2, PGE series Non Narcotics: P-aminophenol derivatives
-A. Acetaminophen/Paracetamol/APAP: Analgesic, Antipyretics,
Bronchi Bronchoconstriction:: LT Weak Anti-inflammatory; Antidote: N-Acetylcysteine
Bronchodilation: PGI2, PGE series -B. Phenacetin: (Prodrug) converts —> Acetaminophen when
metabolized
GIT Cytoprotection:PGE series
Non Narcotics: Non Steroidal Anti-Inflammatory Drugs
Uterus Contraction & Dysmenorrhea:PGF,
(NSAID)
PGE series
MOA: COX Inhibitors:↓↓in PG and Eicosanoid
Platelets Aggregation:TXA2 synthesis:↓↓inflammation
Inhibition:PGI2, PGE
2 Isoforms of Cycleoxygenase
Eyes Decrease IOP:PGF 1. COX1: “Constitutive enzymes”
Important for producing PGs that play roles in normal cell
CYCLOOXYGENASE activity/maintenace/function
• Prostaglandin
– Cytoprotection Example: Cytoprotection
– Pain Vasodilation
– inflammation
• Prostacyclin (PGI2) 2. COX2: “Inducible Enzymes”
– Vasodilation Important for producing PGs that sustain in the inflammatory
– Inhibition of platelet aggregation process
• Thromboxane For pain and inflammation
– Vasoconstriction For inhibition of platelet aggregation (PGI2 & PGE1)
– Platelet aggregation (potent)
– (Reverses PGI2 effects) Non Selective COX Inhibitors: Both inhibits COX 1 and COX 2
-Aspirin: Antipyretic, Anti-inflamatory, Antiplatelet
5-LIPOXOYGENASE -Other Salicylates: Diflussinal, Methylsalicylate: Topical
• Leukotrienes Analgesic
– Stimulate chemotaxis -Pyrazolone Derivatives (Not an NSAID): Phenylbutazone,
• LTC4 & LTD4 Dipyrone, Sulfinpyrazone
– Slow reacting substances of Anaphylaxis -Indole Derivatives: Indomethacin
– Bronchoconstriction -Pyrrole Alkanoic Acid Derivative: Tolmetin
-Phenyl Acetic Acid Derivetive (“-ac”)
PROSTAGLANDINS • True Phenylacetates: Sulindac, Alclofenac,
• Misoprostol (Cytotec) Diclofenac
– PGE analog • Acetic Acid Derivatives: Ketorolac, Etodolac,
– Cytoprotection Nabumetone
– Use: NSAID induced ulcer -Fenamates (“-fenamic acid”): Mefenamic Acid, Meclofenamic
– Side Effect: Abortifacient Acid, Flufenamic Acid
• Epoprostenol -Oxicam Derivatives: Piroxicam
– PGI2 analog -Propionic Acid Derivatives (“-pro-”): Ibuprofen, Naproxen,
– Vasodilation Flurbiprofen, Ketoprofen
– Mgt. Primary Pulmonary HTN
• Dinoprostone Selective COX Inhibitors: inhibits only 1 type of COX
– PGE2 analog Selective COX 2: Meloxicam
– Cervical ripening Specific COX 2 (-coxib): Celecoxib, Etoricoxib, Valdecoxib,
– Use: Abortifacient Rotecoxib
• Alprostadil Advantage: Not Associated with GI effects
– PGE analog S/E: Acute Thrombotic Events (MI, Stroke)
– Vasodilation
– Use: Mgt. Erectile Dysfunction Narcotics: Opiates (Natural) and Opioids (Semi/Synthetic)

LEUKOTRIENES Receptors
- slow-reacting substance of anaphylaxis
- specific actions: 1. Mu (M)
▪ heart ((-) inotropy, smooth muscle chemotaxis) -Majority of opiod effects
▪ GIT (neutrophil chemotaxis) -Analgesia
▪ Pulmonary (bronchoconstriction, increased permeability, -Euphoria
increased mucus secretion) -Miosis (Pin-point pupils)
-Constipation
LIPOOXYGENASE INHIBITORS -Respiratory Depression
- Zileuton: asthma -Addiction

LEUKOTRIENE ANTAGONISTS 2. Kappa (K)

- Zafirlukast, Montelukast -Additional analgesia in women
- asthma
- Churg-Strauss syndrome (eosinophilic vasculitis) 3. Delta
- taken with food (Zafirlukast) -Mediate spinal analgesic effect
-Modulate rapid tolerance to M opiods
ANALGESICS
2 Types of Analgesics Summary of Effects
Central
1. Non narcotics: MOA- weak inhibitors of Prostaglandins in the Sedation Respiratory Depression
periphery Analgesia Miosis
-A. P-aminophenol derivatives Addiction Convulsion
-B. NSAID’s
Peripheral - CNS effects: headaches, dizziness, tinnitus, deafness,
-Heart: Bradycardia (except Meperidine) drowsiness, confusion, nervousness
-Vascular BV- Venodilation - allergic reactions: asthma, urticaria, photosensitivity
-Biliary Tract- Contraction (except Meperidine)
-GIT: constipation 1. Salicylates
-Uterine SM: Tocolysis - Salicylic acid & Benzoic acid (Whitfield’s Ointment)
-Mast Cells & Basophils: Degranulation of Histamine - Aspirin (Bayer, Aspilets, Cortal)
- Methylsalicylate (Bengay, Omega, Efficascent Oil, Salonpas)
Clininical Uses
Analgesic Agents Mgt. of Acute Pulmonary Edema S/E:
Anesthetic adjuncts Antidiarrheal (Loperamide) - hyperuricemia (<2g/day)
Antitussive (Codeine) - Salicylism (vomiting, tinnitus, decreased hearing & vertigo)
- toxic doses: metabolic acidosis, respiratory depression, coma
Side Effects (alkalinize urine with NaHCO3)
Frequent yawns Hyperventilation
Mydriasis Rhinorrhea C/I:
Inc. Hostility Convulsion - children & adolescents for viral infection (with or without
Tolerance- w/in 2-3 weeks chronic use fever) (Reye’s Syndrome)
Addiction- Withdrawal Syndrome/Abstinence Syndrome
2. Pyrazolone Derivatives
Contraindications - Phenylbutazone - Oxyphenbutazone
Pregnant (risk withdrawal in a newborn) - Azapropazone - Antipyrine
Patients with Head trauma (Increases ICP) - Aminopyrine - Dipyrone
Full Agonist + Partial Agonist= Dec. Analgesia
3. Indole Derivatives
- Indomethacin (Indocin) - treat patent ductus arteriosus
Classification Drugs

Strong Full Agonist Morphine, Methadone, 4. Phenylacetic Acid Derivatives

Fentanyl, Meperidine, - Ketorolac (Toradol) - replaces morphine in some
Hydromorphone, situations involving mild to moderate postsurgical pain
Oxymorphone, - Sulindac
Levorpanol, Heroin - Diclofenac (Voltaren)

Weak Full Agonist Codeine and its 5. Naphthylacetic Acid Prodrug

derivatives - Nabumetone
- long half-life (>24 hours)
Partial Opiod Agonist Nalbuphine-M Rx
Pentazocine- Kappa Rx 6. Pyrrolealkanoic Acid Derivative
Butorphanol, - Tolmetin
Buprenophrine
7. Propionic Acid Derivatives
Full Antagonist Naloxone, Naltrexone, - Naproxen (Flanax) - Ibuprofen (Advil)
Nalorphone, Nalmetone - Ketoprofen (Orudis) - Fenoprofen
Levallorphan - Carprofen - Tiaprofen
- Oxaprozin: long half-life (50-60 hours)
MUSCULOSKELETAL DRUGS: DRUGS FOR
RHEUMATOLOGIC DISORDERS 8. Phenylalkanoic Acid Derivative
Inflammation -Flurbiprofen
- reaction to tissue injury
- redness, edema, pain, heat 9. Oxicams
- Piroxicam (Feldene) - Meloxicam (Mobic)
Eicosanoid - Tenoxicam
- prostaglandins, leukotrienes, thromboxane - long half-life (Piroxicam (57 hours), Meloxicam (20 hours),
- derived from arachidonic acid which is liberated from cell Tenoxicam (72 hours))
membrane phospholipids by phospholipase
- cyclooxygenase, lipooxygenase 10. Fenamates
- Mefenamic Acid (Ponstan, Dolfenal)
Rheumatoid Arthritis (RA) - Meclofenamate
- autoimmune disorder
- inflammation in the membrane lining of the joints and often Selective COX2 inhibitors
affects internal organs - Celecoxib (Celebrex) - Rofecoxib (Vioxx)
- Valdecoxib (Bextra) - Etoricoxib
Osteoarthritis (OA) - less erosion of the GI mucosa
- degenerative joint disease - less inhibition of platelet aggregation
- chronic cartilage degeneration
- most common form of arthritis Acetaminophen/ Paracetamol (Biogesic, Tylenol)
- N-acetyl-p-aminophenol
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAID) - active metabolite of phenacetin (banned to due to renal
- nonselective inhibitors of COX1 & COX2 failure)
- analgesic, antipyretic but weak anti-inflammatory
Uses: - S/E: depletes glutathione which binds to toxic metabolites of
1. Anti-inflammatory - rheumatoid arthritis, osteoarthritis, paracetamol (NAPQI) INC. hepatotoxicity
gouty arthritis, ankylosing spondylitis - Antidote: N-acetylcysteine (Fluimucil) - acts as a precursor
2. Analgesia - mild to moderate pain (myalgia, dental pain, for glutathione
dysmenorrhea, headache)
3. Antipyretic - fever
4. Antiplatelet

S/E:
- GI toxicity: ulceration, bleeding
- renal toxicity: impaired renal function, fluid retention
- hematological: ↓platelet aggregation
DISEASE-MODIFYING ANTIRHEUMATIC DRUGS (DMARD)
- reduce & prevent joint damage, preserve joint function
- reduce inflammatory markers
- immunosuppressants

More Commonly Used:

1. Hydroxychloroquine
2. Sulfasalazine
3. Methotrexate

Less Frequently Used:

1. Gold salts like Auranofin
2. Azathioprine
3. Cyclosporine
4. D-Penicillamine

Newer DMARDs:
1. Leflunomide
2. Infliximab
3. Etanercept
4. Anakinra

Gouty Arthritis

Terms:
Hyperuricemia
- elevatedPATHWAY
level of serum uric acid

DNA, RNA PURINES

HYPOXANTHINE XANTHINE
OXIDASE

XANTHINE
XANTHINE
OXIDASE
URATE
OXIDASE URIC
ACID
ALLANTOIN

Gout
- characterized by recurrent acute attacks of urate crystal -
induced arthritis

Tophi
- deposits of monosodium urate usually in & around the
joints, cartilage, & kidneys

Acute Gouty Arthritis

1. NSAIDs
2. Colchicine
- impairs leukocyte migration to inflammed areas and disrupts
urate deposition & the subsequent inflammatory response
3. Corticosteroids
- NSAIDs, colchicine (ineffective, C/I)
- Methylprednisolone (intra-articular injections)
- Prednisone (PO)
- Corticotropin (IM)
- Triamcinolone (IM)

Chronic Gouty Arthritis

- prevention of gouty attack
-
1. Allopurinol (Purinase)
- xanthine analog
- inhibits xanthine oxidase

2. Uricosurics
- Probenecid
- Sulfinpyrazone
- ↑ uric acid excretion