Opioids
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1.
Opioids – produce stuporous, sleep like state (narcotic)
o Fxn depends on receptor location
 Limbic system = change perception (pain and other)
 Chemoreceptor trigger zone (CTZ) = vomiting
 Nucleus of the solitary tract (NST) = cough suppression
Receptor types
o All GPCR – rhodopsin subfamily
o Similar structure, all drugs x-react to some extent
o Mu – Morphine prototype agent
 high dependence risk
 euphoria, sedation
 miosis, ↓GI motility, smooth muscle spasm, antidiuresis
 hyperpolarizes (inhibits) GABA neuron and ↑ dopamine release by no longer inhibiting post-synaptic cell
(feel good!)
o Delta – Mouse vas deferens
 Medium dependence
 More respiratory depression than μ
 Otherwise similar
o Kappa – Ketocyclazocine prototype agent
 Less respiratory depression
 Less dependence
 Dysphoria
 Diuresis
 Spinal analgesia only – doesn’t work in brain
 Hyperpolarizes excitatory neuron to ↓ release of dopamine (feel bad!)
Opioid Pharmacokinetics
o Absorb well in GI tract but first pass metabolism in liver so IV admin better
o 1/3 protein bound in plasma
o Action of most opioids is in brain so plasma [] doesn’t = speed and duration of action
o Metabolism: hepatic conjugation of morphine + glucuronic acid →
 morphine-6-glucuronide is an active metabolite!
o Excretion in kidney
Structure of morphine class – MUST HAVE
1. Free 3’ OH
2. N+
Opioid Agonists
a. Morphine
2.
i. Analgesia – alters perception and reaction to pain. Secondary pain (dull, visceral, diffuse, C fiber).
Nociceptive pain. Good with adjuvants (NSAIDS, etc.)
ii. Respiratory depression - ↓ brainstem response to CO2 levels
iii. Cough suppression - ↓ activity of Nucleus of solitary tract cough center (medulla) – not stereoselective,
so either isomer will give you this effect!!!
iv. Nausea + Vomiting - ↑ activity CTZ (chemoreceptor trigger zone)
v. Miosis – stim. Oculomotor nerve nucleus –
1. Narcotic triad = pinpoint pupil, coma, shallow breathing
vi. Convulsion – inhibits interneuron GABA release
vii. Alters temperature set point (hypothalamus) - ↓ @ low dose, ↑ @ high dose
viii. Neuroendocrine - ↓ plasma LH and testosterone = menstrual irregularities, M impotence
ix. Euphoria - ↑ Dopamine release VTA
x. Tolerance + Physical dependence
xi. Cardiovascular – Orthostatic hypotension (loss of baroreceptor reflex)
xii. GI Tract – Slower gastric emptying = constipation,
xiii. Contraction of ureter – problems peeing
xiv. Prolongs labor
xv. Flushing of skin – dilation of cutaneous BV
xvi. Immunosuppressive
Tx: Pain (preventive, secondary pain), Cough (also sedative), Diarrhea, Dyspnea (calming + analgesic),
3.
Contraindications – asthma (resp. depression), head injury (sedation), hepatic or renal disease (prob. With excretion,
metabolism), drug abuse potential, low blood volume, biliary colic, menstrual cycle problems
a. Codeine
b. Oxycodone
c. Meperidine – M agonist that causes excitation (hallucination, convulsion) rather than sedation (active
4.
5.
6.
metabolite). Bad with MAOI.
i. Obstetric analgesia – fetus can metabolize, low systemic effect due to high CNS penetration, doesn’t
prolong labor
d. Fentanyl – Most potent synthetic M agonist (80x morphine). Less hemodynamic effects, easier to maintain BP
so used in dissociate analgesia.
i. Highly lipophilic – can be administered transdermally, rapid distribution
e. Sufentanyl – See Fentanyl
f. Methadone – Synthetic M agonist.
i. Long Half Life – 20 hr. No “Rush” due to prolonged action, slower onset” – suppress heroin withdrawal
in maintenance or abstinence programs
g. Propoxyphene – highly cardiotoxic. D-isomer active. Long half life (12 hr) but metabolite has even longer (30
hr) = accumulation, toxicity. Treat moderate pain, but bad choice.
Partial Opioid Agonists
a. Butorphanol – mixed agonist at M, K receptors. Addicts don’t like (K activity), but can still be addictive due to
partial M activity. No effects on withdrawal.
b. Pentazocine – M antagonist, K agonist. Respiratory depression not proportional to analgesic effect – OD won’t
kill. Dysphoric. Ideal for pts. With abuse potential although it can be bad in CV patients.
c. Nalbuphine – Pts. With abuse potential. Like Pentazocine but less dysphoria, less increase in cardiac load.
Competes with morphine = precipitate withdrawal.
d. Buprenorphine – Partial M agonist with HIGH receptor affinity. Binds and cannot come off receptor so
activity can’t be reversed by M antagonist. Good for long-term prevention of abstinence symptoms. No effect
from heroin after taking.
e. Dezocine – M antagonist, K agonist. Analgesic (?) Increases cardiac load, pulmonary vascular resistance. Can
be used by addicts.
Opioid Antagonists – No activity by selves, just stop opioid effects if present. Tx opioid overdose. If any suspicion that pt.
may have overdosed on opioid, give antagonist – no side effects. Could be ultra-potent version (fentanyl) so may need to
administer a LOT, go at it until they wake up!
a. Naloxone – M antagonist. Reverses sedative, resp, CV effects 1-2 min after injection. 1-4 hr duration.
b. Naltrexone – 2x as potent M antagonist. 24 hr duration, tx opioid overdose, opioid addiction.
Other
a. Tramodol – M agonist (addictive). Also inhibits NE, 5HT reuptake, increasing analgesic effects.
b. Dextromethorphan – inactive stereoisomer that works only for cough suppression. Abuse – can give
dissociative high due to action at NMDA receptor. Can potentiate morphine’s analgesic effect (req. less)
General Anaesthesia
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Goals of GA
1. Smooth + Rapid induction and emergence
2. Produce unconsciousness
3. Analgesia
4. Sk. M. relaxation
5. Suppression of some reflexes (sensory and autonomic)
6. Amnesia
 Note: 2-4 = Complete anaesthetic (ether is only real one)
 Usually have to use a combination of agents to get complete anaesthesia (when multiple agents are used the term is
balanced anaesthesia)
Dentistry = conscious sedation = anxiolysis and analgesia
Stages of Anaesthesia
o I – anaesthesia → conscious sedation, dentistry
o II – nausea, vomiting, amnesia → BAD, can skip with balanced anaesthesia
o III – “surgical” → unconsciousness
 Plane 1 = dental work
o IV – respiration stops, death
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Mechanism Theories
1. Meryer-Overton → agent reaches given membrane [], disrupts shit
 More lipid soluble = more potent
2. Receptor Hypothesis → agent alters fxn. Of specific neuronal proteins (ligand gated ion channels)
 Shown to change fxn. Of GABA, NMDA, Nicotinic ACH receptors
3. Neurophysiologic Hypothesis → agents target neuronal centers and synaptic transmission BOTH
 Affects consciousness, analgesia, muscle relaxation
 Both pre + post-synaptic involvement
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Inhalation Anaesthetics
o Req. special room design, precautions
o Gas = N2O (inorganic!)
o Volatile liquid = desflurane, isoflurane
 Halogenated organic compounds→ metabolism can damage kidney, liver. Malignant hyperthermia
Depth of Anaesthesia = [agent] in brain
o [agent] in brain depends on partial pressure in inspired air
o Concentration in inhaled air = concentration in the brain
Rate of induction depends on solubility in blood
o Dissolved in blood = doesn’t get to brain, so gases with ↑ blood:gas partition coefficient have to fill the blood sinkhole
before they get gas concentrations (= brain concentrations) at high enough level
 Once sinkhole is filled you attain brain concentrations same as in the inspired air – depth law stays the same
o ↑ concentration inspired = ↑ rate of induction
 Adjust quantities throughout induction/maintenance
 If non-irritant (sevoflurane) may have ↑ [] at start to induce, then ↓ to maintain
MAC = [] at which 50% of pts. Unresponsive
o Dose 1.4x MAC for surgery
o Units = % of total pressure in inspired air
o Can combine agents and add MACs to reduce side effects and still get complete anaesthesia
o Not influenced by weight or sex, just age
Emergence = regaining consciousness
o Depends on rate of elimination of anaesthetic from brain
o Exhaled mostly, delivery of agent to lungs is a function of the cardiopulmonary fxn. Of the pt.
o Metabolism can occur in liver → toxic halides!
Effects of Inhalational GA on organs
o CV - ↓ contractility, sensitization to Epi., ↓ TPR
o Resp. - ↓ respiratory centers → put pt. on ventilation assistance
o Kidney – can get nephrotoxicity, ↓ GFR
o Sk. M. relaxation
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N20 – Nitrous Oxide
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Desflurane
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Only gaseous inhalation anaesthetic
Only inorganic anaesthetic
Used as adjunct to other anaesthetics (105% MAC)
Rapid onset
Good analgesia
No muscle relaxation, CV effects, minimal resp. effects
(-) dysphoria, abortion, probs w/ hematopoiesis, abuse potential
Newest inhalation anaesthetic
bad for induction - irritant
maintenance phase
6-7% MAC
Rapid onset
Poor analgesia
Good muscle relaxation
Resp. depression, ↑ HR, ↓ BP
(-) Respiratory irritant, malignant hyperthermia
Isoflurane
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Most widely used inhalation anaesthetic
Anaesthetic of choice
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IV Anaesthetics
o Effective in seconds, used in induction
o Lipid soluble = fast recovery, distributed to fatty tissues
o Used increasingly for entire procedure – Induction AND Maintenance
o (+) Better induction, ↓ CV depression, ease of administration (no worry over operative air pollution)
Barbituates (Thiopental)
o GABA receptor agonist
o 1st IV anaesthetic, most commonly used
o Now only used in induction
o Hyperalgesia at subanaesthetic dose!!!
o ↓BP → reflex ↑HR
o Respiratory depression
o Contraindicated – elderly, asthmatics, shock, CHF
Benzodiazepines (Midazolam, Diazepam)
o Adjunct
o Induction in CV patients
o Deep conscious sedation
o Anxiolysis, sedation, amnesia, Sk. M. relaxation
o Rapid onset, long action (1 hr)
o No analgesia
o Minimal CV, respiratory problems
o (-) irritant, long half life, drowsiness
Opioids (Fentanyl)
o μ agonist
o Adjunct – analgesia, sedation, anxiolysis, Sk. M relaxation
o Synthetic – 100x morphine potency
o Good analgesia
o Profound resp. depression
o (-) mood alteration, tolerance, dependence, addiction
o (-) unpleasant recall, nausea/constipation
Ketamine
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NMDA receptor agonist
Dissociative anesthesia – unique state
 Anesthesia, amnesia, catalepsy (eyes open w/ intact reflexes)
Burn dressing changes, complex radiology, etc.
PCP like complex
Rapid onset, short duration
↑HR, CO, BP
Minimal resp. effects
(-) Negative emergence phenomena (pt. freaks out!) → give with benzos
Propofol
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Potent (1.2% MAC)
Rapid onset
Moderate analgesia, muscle relaxation
Minor CV effect, Moderate respiratory depression
(-) Respiratory irritant, malignant hyperthermia
GABA potentiation, endocannabinoid system
Unique ring structure
Conscious sedation, GA induction and maintenance
Intensive care sedation
Faster, more pleasant recovery than barbs
rapid onset, short duration
No analgesia
Respiratory depression, CV okay in healthy pt.
(-) seizures (bad in epilepsy), CV, resp ↓, pain on injection
Dental Conscious sedation
o N2O – technique of choice (20-25%)
 Easy, rapid, well tolerated
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Oral (benzos, chloral hydrate)
 Long duration, can’t reverse, very easy
IM sedation (benzos, antihist.)
 Faster, injection (!), long duration, tissue damage
IV Sedation (benzos, opioids, propofol)
 Rapid, high efficacy
 Difficult procedure, long duration, low pt. acceptance
Local Anesthetics
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Pain neurons are small diameter, no myelin
Neuron Sensitivity to LA depends on:
1. Diameter - ↓diameter = ↑sensitivity
o agent needs to diffuse enough to block 3 nodes, internode distance is smaller with ↓diameter
2. Pattern of impulse traffic
o Fibers conducting rapid bursts of impulses – more sensitive
o Pain = frequent firing (also SNS)
3. Position of fiber in nerve trunk
o Myelin reduces effects if present (barrier)
o Outer fibers are blocked before inner
o Different modalities have different fiber location distribution
4. Inflammation
o LA = weak base. Must be uncharged to diffuse across membrane
o Acidic pH = more LAH+, less gets in
LA blocks C fibers > B fibers > A fibers
o pain > temp > touch > pressure > motor
LA blocks Open + Inactivated Na+ Channels
o @ high firing rates (pain), these accumulate and transmission is disrupted. Little effect at slower firing (touch)
o Target S4 segment of Na+ channel pore
LA Structure
1. Lipophilic aromatic ring → membrane penetration
2. Linker (ester/amide) → allergenicity, metabolism
3. Hydrophilic amino part → H2O solubility, channel blockade
 Weak base, comes in cartridge as LAH+
o Neutral LA crosses membrane, then charged LAH+ form blocks channel
Rate of onset depends on:
1. Mode of delivery (inj. Or surface)
2. concentration
3. size of nerve
4. size of LA mol. (diffusion speed)
5. ionization state of LA mol.
o Lower pKa = faster onset (more uncharged form available)
o Lower pH environment = slower onset, less action (more charged, less uncharged form available to diffuse into
nerve)
Systemic absorption terminates effects.
o Dosage
o Site (absorbed fastest in highly vascular sites)
o Use of Epi. or other vasoconstrictor
 LA = vasodilator
 Bupivacaine > Procaine > Lidocaine > Prilocaine > Mepivacaine
 Vasoconstrictors ↑ duration of action, ↓ systemic toxicity
Administration with Epinephrine (1:100,000 usually)
o 2-3x duration
o ↑ success, intensity of block
o ↓ toxicity (don’t have to use as much LA)
o Contraindications: Pregnancy, CV disease
LA crosses blood-brain barrier, placenta
Amides and slowly metabolized esters distribute to highly perfused tissues, reducing systemic levels
Esters (Procaine, Tetracaine, Cocaine)
o Rapid metabolism (min.) in plasma by pseudocholinesterase
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o Allergic response more likely than with Amide
o Possibility of malignant hyperthermia
o Tetracaine – topical anaesthetic used on eyes, skin, mucosal areas (others can’t be used on eyes)
Amides (Lidocaine, Mepivacaine, Bupivacaine, Prilocaine)
o Preferred agents!
o Longer half life (hours)
o Metabolized in liver – blood flow is rate limiting factor
 Toxicity is possible in pts. With liver disease
o Less allergic response than with esters
Route of Administration
1. Topical → skin, eyes, mucous membranes
o LA poorly soluble in intact skin so little systemic absorption
o Tetracaine (ester) can be used for all three sites
o Lidocaine (amide) not on eyes
2. Injection
o Local infiltration – superficial placement of small amount, block small area (local nerve endings)
 Can cause systemic toxicity if you try to treat large cuts (needs a large qty of LA)
 Procaine, Lidocaine
o Nerve block – injection of LA along a nerve before it reaches the surgical site
 Blocks a wider area without requiring as much drug as would be needed in local infiltration
 Procaine, Lidocaine
3. Epidural – Injection outside the dura mater of SC
o Bupivacaine
4. Spinal – Between arachnoid, pia mater → window into CNS, injected into CSF
o Tetracaine
Adverse Effects – usually because of intravascular injection
o CNS
 Low systemic level = stimulant (tingling, tinnitus, convulsions, lightheadedness)
 High systemic level = depressant (hypotension, respiratory depression, coma)
o Heart
 Used as anti-arrythmic drugs, blocking Na+ channels in overactive regions (Lidocaine!)
 Higher systemic level = decreased cardial excitability
 Cardiotoxic: bupivacaine, etidocaine
o Local – focal necrosis in skeletal muscle, ischemia with Epi. usage
o Allergic Rxn – Esters
o Malignant Hyperthermia – Esters (rare, only in susceptible pts)
Dentistry and LA
o Very safe – healthy pts., lower dosages than medical
o Toxicity due to intravascular injection, Aspirate!!!
o OD possible in children
NSAIDS
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1. Anti-Inflammatory
2. Analgesic
3. Anti-Pyretic
Mechanism – Blocks prostaglandin formation
o PG – Arachidonic Acid derivative
o AA is a component of membrane phospholipids. It is released by Phospholipases (PLA2) in response to stimuli
(physical, chemical, etc)
o (Cyclooxygenase) COX Pathway = AA → PG
o Lipoxygenase pathway = AA → Leukotrienes (LT)
o Thromboxane synthase = PG intermediate → Thromboxanes (TX .. deepest apologies, this is not the ‘treatment’ Tx)
Prostaglandins are produced by all tissues
o Functions of PG
1. Pain (PGE, PGI) → sensitize nerve endings
2. Inflammation (PGD, PGE, PGI) → vasodilate
3. Fever (PGE)
4. Inhibit platelets aggregation (PGD, PGI)
o Side note: TXA2 stimulates platelet aggregation
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5. Contract uterus (PGD)
6. Maintain open Ductus Arteriosus (PGE) - bad, want this to close when born
Leukotrienes
o Produced in lung, leukocytes, blood vessels, epicardium
o Functions of LT
1. Inflammatory response – short half life, act locally
2. Inflammatory cell chemotaxis (LTB)
3. Constriction of bronchial smooth muscle (LTC, LTD)
4. ↑ capillary permeability (LTC, LTD)
o Hyperalgesia and Asthma
Zafirlukast, Montelukast
o LT inhibitors
o Tx: Asthma (chronic, not acute attacks)
NSAIDS inhibit COX (↓ prostaglandin production)
o Alleviate symptoms but don’t resolve the cause
o COX1 = normal functions, constitutively expressed
o COX2 = inflammation, pain, fever. Expression induced @ injury site by inflammatory mediator
o Beneficial effects of NSAIDS believed due to COX2 inhibition
 Side effects due to COX1 inhibition
 COX2 selective NSAIDS were thought to be better (Nabumetone, Etodolac, Celecoxib)
o COX2 / COX1 IC50 ratio
 <1= COX2 Slective (means that you need a higher dose to inhibit COX1 than you do COX2)
 Most NSAIDS are COX1 preferential but therapeutic doses are high enough to work against COX2 as well
Use to treat:
o Mild/Moderate pain
 Mechanism differs from opioids – can be combined (summative effects)
 Don’t cause narcotic side effects
 Superior for some types of pain control
 Work well for dental pain
o Fever
 Inhibition of COX enzyme in the body temperature regulating preoptic hypothalamic region
o Inflammatory Disease
 Requires higher doses
o Inhibition of Platelet aggregation (Aspirin!!!)
 Anti-thrombolytic
 Low dose aspirin is very COX1 selective. It inhibits COX1 on platelets and prevents the production of TXA2
(responsible for unwanted platelet aggregation, vasoconstriction).
 PGI2 inhibits platelet aggregation and vasodilates, but this is produced by COX2 so low dose aspirin does not
prevent its good effects.
o Vascular Headaches
o Prevent colon cancer, Alzheimers
Ceiling effects – analgesic effect tops out at 2-3 tablets, side effects keep increasing
o Advise patients not to take more than directed – won’t reduce pain any more
Adverse side effects
o GI Ulceration
 PG protects stomach lining (via production of mucus, bicarbonate secretion)
 Aspirin worst
 Misoprostol = PG analog that can be taken to offset stomach issues (also H2 antagonists or proton pump
inhibitors)
 Arthrotec = Combination NSAID (Diclofenac) + Misoprostol
o Prevention of Platelet aggregation
 Increased bleeding time, problem in surgery
o Inhibition of uterine motility (lengthens gestation)
o Inhibition of Renal PGs (responsible. for maintaining normal kidney function)
 ↑Renal BP (NSAIDS interfere with Antihypertensive Therapy!!!)
 ↑Retention of Na+, H2O
 High risk pts. – CHF, elderly, diuretic users
o Allergy / Hypersensitivity (mostly aspirin)
Drug interactions
o ↑ bleeding with anticoagulant therapy
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Enhances hypoglycemic effect of diabetes drugs
↓ effect of Anti-HTN drugs
↑ GI toxicity with corticosteroids
Salicylates – Aspirin
o Inhibits platelet aggregation – irreversibly inhibits COX1 on platelets (effect lasts ~10 days)
o GI Ulceration (inhibits cytoprotective PG)
o Hepatic problems – Reyes syndrome if taken during a viral infection
o Hypersensitivity – Arachidonic acid spills over into lipoxygenase pathway → LT production (pts with a history of
asthma)
o Interactions
 Warfarin (bleeding), Alcohol (GI prob.), sulfonylureas (hypoglycemia)
o Contraindications
 Peptic ulcer, hemophilia, hypersensitivity
o Dosage: Antiplatelet < analgesic < anti-inflammatory
Acetaminophen (Tylenol)
o Not an NSAID – Not anti-inflammatory
o Toxic metabolite formed in liver – liver damage can occur if detox enzymes are depleted (alcoholics!)
o Inhibits CNS COX better than peripheral
 Anti-pyretic, analgesic
o Little platelet effect, few GI problems, renal problems
o Less GI side effects
o Interactions
 Drugs that induce cytochrome P450 (barbs, carbamazepine) – would ↑ toxic metabolite production
o Good at post-op dental pain control, available in combinations with centrally acting analgesic (opioids - Percocet)
Other NSAIDS cause reversible platelet inhibition, are metabolized in the liver
Propionic acid derivatives
o Ibuprophen
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4x aspirin potency, better tolerated
Safe, effective, cheap
Some GI effects
o Naproxen
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 Associated with ↑ CV risk in elderly
Acetic Acid Derivatives
o Indomethacin
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Older, lots of side effects
suppress uterine contractions
Close patent ductus arteriosus
o Diclofenac
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Conbined with Misoprostol (PG analog) = Arthrotec → reduces GI side effects
o Etodolac
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COX2 selective, less GI problems
Single dose post-op analgesia
o Ketorolac
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Can use IV administration
Weak anti-inflammatory
↑ Analgesic potency similar to narcotics
Nabumetone
o Long half life (1x daily)
o COX2 Selective
o Better tolerated
COXIBS – COX2 Selective
o Few GI Side effects
o Celecoxib
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 ↑ risk MI, stroke in long term usage (>8 mos)
 Tx: Osteoarthritis
Other COXIBS were taken off market due to ↑ CV Risk
COXIBS not as great as thought? Yes, Few GI Side effects but
 Similar efficacy
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Renal, CV complications
No anti-thrombic properties
Skeletal Muscle Relaxation
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Mechanisms:
1. Spasmolytics – centrally acting
1. ↓ firing of 1˚ muscle motor neuron
2. Inhibition of synaptic transmission
a. Prevent ACH release
b. Depolarizing blockade (continuous stimulation)
c. Antagonize – block muscle receptors
7. Interfere with muscle contraction in response to stimulus
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1. Benzodiazepines (Midazolam, diazepam)
o Allow inhibitory GABA to work better
o Hyperpolarization of excitatory neuron to muscle]
o Sedation and muscle relaxation at same dosage
1. Cyclodiazepine
o Tricyclic antidepressant structure
o ↓ NE reuptake (leaves it in synapse) to ↑ NE’s inhibitory effect on motor neuron
o Antimuscarinic and sedative
1. Baclofen
o GABA analog (inhibitory)
o Hyperpolarizes excitatory neuron (↓ release of excitatory NT)
o Analgesic (↓ release of substance P)
o Little sedation (less than benzos)
2a. Botulinum toxin
o Irreversibly modifies amino acid necessary for vesicle fusion → prevents ACH release
o Localized “denervation”
o Long lasting relaxation
o Tx: blepharospasm, spastic disorders, cosmetology procedures
2b. Succinylcholine
o ACh analog (but not broken down by AChE)
o Agonist @ Nm receptors
o Phase 1 – prolonged depolarization, muscle fasciculations (twitching) → flaccid paralysis
 Not reversible with ↑ ACh levels
o Phase 2 – finally repolarizes but cell is still unresponsive
 Reversible with ↑ACh (give AChEI – neostigmine)
o Rapid onset (<min), short duration
o Use to paralyze larynx, pharynx for emergency intubation
o Hydrolyzed by plasma pseudocholinesterase
o (-) genetic polymorphism (bad version of plasma ChE), farmers (OrganoPhosphates act as AChEI)
o (-) malignant hyperthermia, histamine release, ↑ eye + gastric pressure, bradycardia, ↑↑↑[K+] = cardiac arrest
2c. Tubocurarine, Mivacurium, Atracurium
o Competitive Nm antagonist
o Flaccid paralysis
o No CNS effect
o Newer drugs = rapid onset, shorter duration
o Little autonomic effects, histamine release
3. Dantrolene
o Binds ryanodine receptor
o ↓ Ca2+ release from skeletal muscle sarcoplasmic reticulum
o Inhibits excitation-contraction coupling
o Skeletal muscle selective
o Tx: Malignant hyperthermia (cause = way too much free Ca2+)
 Side effect of General Anaesthetics, succinylcholine
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Anti-Histamines
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Histamine
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Degraded to inactive metabolites by MAO, Diamine oxidase
Found in all tissues, ↑concentration in barrier tissues
Endogenous functions
 Synthesized and stored in mast cells and basophils (inflammatory)
 Neurotransmitter in hypothalamus
 Stimulates acid secretion in stomach mucosal cells
 Fxn in tissue growth and repair
o Release
 Type 1 Immediate Hypersensitivity (IgE mediated) → allergies due to mast cell degranulation
 Other instigators = bee venom, basic drugs, cell membrane damage
 Release inhibited by β adrenergic agonists, cromolyn sodium
o Receptors – H1, H2, H3 (All GPCR)
 H1 –
 Bronchial constriction
 rapid and short term vasodilation (arterioles and capillaries) – hypotension, increased permeability,
edema and reddening
 Hives – flush, wheal, and flare
 Pain and itching - peripheral nerve stimulation
 Motion sickness – CNS effect
 H2
 Slow but sustained hypotension due to vasodilation
 Gastric acid secretion
 ↑ HR, contractility
H1 Antagonists
o Relaxation of bronchial and intestinal smooth muscle
o Less vasodilation
o Less itching
o Tx: allergies, motion sickness, anxiety, sleep aid, cough and cold, adjuct to anaphylaxis treatment
o INEFFECTIVE in treating bronchial asthma – need to prevent histamine release, not try to contain its effects once it is
out there running amok.
o 1st generation drugs – Diphenhydramine (Benadryl), Dimenhydrinate (dramamine), etc etc etc
 Act centrally (sedation!) and peripherally
 Anti-cholinergic effects (Xerostomia, used to Tx. Motion sickness)
o 2nd Generation
 Cetirizine – safe in kids,
 Loratadine – 24 hr action
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Fexofenadine
 Peripheral action only (do not cross blood brain barrier)
 Non-sedating
H2 Antagonists – Cimetidine (early drug), Ranitidine, Nizatidine, Famotidine
o Inhibit all phases of gastric acid secretion (specific fxn, no CNS effect)
o Tx: Ulcers, Gastroesophageal reflux disease
o Contraindicated: Renal impairment, greatly reduce dosage
o (-) changing gastric pH can alter pharmacokinetics of other drugs
o Cimetidine – block hepatic metabolism of estradiol → feminization
Proton Pump inhibitors – Omeprazole and Lansoprazol
o Better than H2 inhibitors for Tx GERD (reflux)
Cromolyn Sodium
o
o
Inhibition of histamine degranulation from mast cells
Tx: Severe bronchial asthma (inhaled allergens)
 Must pretreat