Opioids 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 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 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 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 N20 – Nitrous Oxide o o o o o o o Desflurane o o o o o o o o o 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 o o Most widely used inhalation anaesthetic Anaesthetic of choice o o o o o 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 o o o o o o o o 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 o o o o o o o o o 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 o o o 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 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 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 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 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 o o o 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 4x aspirin potency, better tolerated Safe, effective, cheap Some GI effects o Naproxen Associated with ↑ CV risk in elderly Acetic Acid Derivatives o Indomethacin Older, lots of side effects suppress uterine contractions Close patent ductus arteriosus o Diclofenac Conbined with Misoprostol (PG analog) = Arthrotec → reduces GI side effects o Etodolac COX2 selective, less GI problems Single dose post-op analgesia o Ketorolac 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 o o ↑ 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 Renal, CV complications No anti-thrombic properties Skeletal Muscle Relaxation 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 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 Anti-Histamines Histamine o o o 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 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