Strong opioid agonist

Mechanism: binds all opioid receptors (GPCRs) that 1. closes Ca channels presynaptic, decreasing NT release and 2. opens K channels postsynaptic, hyperpolarizing and inhibiting postsynaptic neuron

Use: Analgesia, acute pulmonary edema, cough, diarrhea, anesthesia

Pharmacokinetics: High first pass metabolism CYP450 in liver, and kidneys; excreted as morphine-3-glucornide; Morphin 6-glucuronide = more pontent analgesic metabolite; Morphine 3-glucuronide = may cause hyperalgesia

Side effects: itching, vomiting, can cross placenta in pregnancy and cause resp dep. and dependance w/ chronic use

DO NOT BECOME TOLERANT TO MIOSIS OR GI EFFECTS  (CONSTIPATION) OF OPIOIDS!

Strong opioid agonists (odd man out)

Use: analgesia; recommended only for very brief course in healthy pts w/o opiate problems; second line agent for acute pain; not suitable for long term use

Effect: NO PUPILLARY CONSTRICTION (miosis) (actually dilates pupils from muscarinic block (mydriasis), Does not prolong labor; can cause euphoria

Mechanism: Mu agonist, also inhibits NE and 5HT reuptake (addiction)

Dx interactions: MAOIs! (phenylzine, selegiline, linezolid (antibiotic) = serotonin syndrom; TCAs and SSRIs because of mechanism

Side effects: seizures, tachy, pupil DILATION, no cough suppression; serotonin syndrome with MAOIs

Difference from other opioids: 

Strong opioid agonist

High abuse potential (highley potent, 100X morphine); duration of action shorter than morphine/meperidine

Use: short surgical procedures (induction/GA maintenance); supplement regional/spinal analgesia; transdermal for chronic pain

*preferred to morphine for hemodynamic responses and maintain cardiac stability*

Transdermal patches or lollipops available

Side effects: truncal rigidity (IV), CYP3A4 metabolized

Metabolized by CYP3A4 extensively (dx interactions)

Moderate to strong opiate agonist

Use: moderate to severe pain, often abused

Schedule II alone or III with acetaminophen (Vicodin)

Side effects: CYP2D6 metabolizm (SSRI and quinidine inhibit CYP2D6)

Moderate to strong opiate agonist

Use: moderate to severe pain, tourette's and restless leg syndrome; CA pain, post-op, post-extraction, post-partum pain; often abused (schedule II)

Metabolized by CYP2D6 for active metabolite so no SSRI and MAOI

Other drugs: oxymorphone - DOESN'T NEED CYP2D6 CONVERSION, so can be used in SSRI and MAOI taking pts

Moderate opiate agonist

Use: Mild-moderate pain (not a scheduled drug in most states, IV in 10 states)

Mechanism: Weak Mu agonist; Inhibits NE/5-HT reuptake, contributes to analgesic effect

Drug interactions: combo with antidepressants = seizures; combo with MAOIs, TCAs, SSRIs = serotonin syndrome; Naloxone WILL NOT completely inhibit analgesia

Side effects: dizziness, sedation, constipation, nausea

Mixed opioid agonist-antagonist

Mechanism: Kappa agonist, partial Mu agonist

Use: Moderate pain (not for addicts or severe pain)

Less resp dep, and GI effects (Mu)

Dx interactions: competes with opioids

*Can precipitate withdrawal in opioid addicts (partial Mu)*

Side effects: dysphoria (Kappa), CNS stim, hallucinations

Analgesic but NOT anesthesia

MAC 104; Blood/gas 0.46; Low potency

Use: conscious procedures (dentistry); combined w/ other anesthetics; Drug of abuse in dentists

Properties: Low ptency for anesthesia; low solubility in blood, therefore rapid onset of action; adjuvant with other inhaled anesthetics to increase rate of induction; little respiratory depression; attenuates hypotension (When combined with other anesthetics) 

Toxicities: Euphoria, Diffusion hypoxia (more than 70%), chronic low level may cause peripheral neuropathy; decreased production of leukocytes and RBCs, causing megaloblastic anemia

DON'T use for eye sx!; use within 3 months of procedure may cause irreversible loss of vision

Inhaled: General anesthetic

MAC: 0.75; Blood/Gas: 2.54 (High, slow induction, rapid awakening)

Toxicities: Sensitizes heart to catecholamines; may cause arrhythmieas; HEPATITIS from repeated exposure; Malignant hyperthermia with succinylcholine!; BV dilation, BP drop, CO depression, relaxes uterus, Decrease renal BF, increase intracranial pressure

Malignant hyperthermia treated with Dantrolene

Metabolism: chlorine and bromine removed from halothane, generating toxic metaboites, may lead to immune response and hepatitis

Other drugs: 

Enflurane (Ethrane^®) - MAC 1.63; B/G 1.90: more rapid induction than halothane; muscle relaxation and analgesia; depresses respiration with increased concentration

Side effects: nausea, vomiting, shivering, uterine relaxation; Production of fluoride during metabolism may cause reversible kidney damage (rare)

Metabolism: releases fluoride ions that can theoretically cause kidney damage (rare)

Inhaled General Anesthetic

MAC 1.17; B/G 1.46

Use: neurosurgery; most commonly used inhaled anesthetic (low tox)

 Advantages: Low toxicity; Decreases BP; no hepatic or renal tox; easy to adjust depth of anesthesia (low B/G); no myocardium depression, no sensitization to catecholamines

Side effects: Resp. depression, uterine relaxation (high concentration); dilates cerebral vasculature (increased IC pressure!)

Inhaled GA

MAC 1.80; Blood/gas 0.69

Use: Children (low irritation), 

Induction and emergence are rapid; least airway irritation; increased IC pressure (minimized with hyperventilating pt); Safest dx for pts with CV disease

Metabolism: releases fluoride ions that can cause kidney damage (rare)

Advantages: Safest drug for pts with cardiovascular disease; renal and hepatotoxicity are rare

Degradation of sevoflurane by CO2 absorbents in anesthesia machines have produces haloalkene (compound A), whid has lead to kidney tox in rats, doesn't happen if machine is working properly.

IV anesthetic: 

Use: DOC for most anesthetic procedures (rapid induction/fast recovery); induction and maintenance of anesthesia

Mechanism: Facilitates GABAergic transmission

Effects: Causes resp depression esp.w/ opioids; Decreased cerebral BF, metabolism, IC pressure

Safe for use in pregnancy; Anaphylactic reactions (from the albumin containing emulsion it's in); Burning/stinging at the injection site (given lidocain for this)

Side effects: severe resp depression especially with opioids, should not be used outside Sx and critical care; anaphylactic reactions (albumin emulsion); propofol infusion syndrome (PRIS) = metabolic acidosis, hyperlipidemia, rhabdomyolysis, enlarged liver

Advantages: Least likely to produce nausea and vomiting; induces anesthesia as quickly as thiopental but emergence is 10X faster; Decreased cerebral bf/metabolism/IC pressure make it useful in neurosurgery; safe in pregnancy

Other drugs: ·      Etomidate (Amidate) - used when pt is at risk for hypotension; action in 1 min, duration = 5 min; very likely to cause nausea/vomiting

IV anesthetics

Mechanism: Blocks NMDA (glutamate) receptors

Type of anesthesia: Dissociative anesthesia (profound analgesia, no response to commands, amnesia w spontaneous respiration, limbs may move, eyes may be open); this is profound analgesia but not anesthsia

Useful for: Children; Vet med; pts at risk for bronchospasm or hypotension, date rape drug

Not used in adults because: Emergence delirium: bizarre dreams, hallucinations, even psychosis (reduced by benzos)

Effects: Catatonic state; potent analgesia; emergence delerium (add benzos), bizzare dreams, hyallucinations, even psychosis; dissociative anesthesia; profound analgesia; very little resp depression, increased BP

Date Rape drub; Drug of abuse

Ester Local Anesthetic

Use: Infiltrative anesthesia and diagnostic nerve blocks 

Mechanism: Short acting, Blocks Na channel and inhibits neuronal firing and the propagation of APs; binds activated and inactivated channel (more than resting channel)

Metabolism: Rapidaly metabolized by butyrylcholinesterase in plasma; Mutations can affect metabolism of ester LAs, prolonging duration of action

Side effects: PABA is an ester metabolite, may cause hypersensitivity

Dx interactions: PABA (metabolite) inhibits sulfonamides; Potency of other LAs is measure as relative to procaine (potency = 1)

Other Drugs: Tetracaine (Pontocaine)- long acting GA (6-8 hrs) slow onset (10 min); ophthalmological and spinal anesthesia

Benzocaine (Americaine)- ALWAYS in non-ionized form (very lipophilic, less affinity for Na channel as a result; used for surface application only (sun burn, burn, pruritis) ; more toxic than others due to increased binding to resting channel

Cocaine- increased SNS tone

Amide Local Anesthetic

Use: Intermediat (60-120 min) anesthetic

Mechanism: Blocks Na channel and inhibits neuronal firing and the propagation of APs; binds activated and inactivated channel (more than resting channel)

Pharmacokinetics: Action dependent on time at site of applications NOT HALF LIFE;

Metabolism: Distribute rapidly and extensively metabolized in the liver by CYP450s (amides)

Other Drugs: Prilocaine (Citanest)- short acting (20-45), metabolite may produce methemoglobinemia;

Bupivicaine (Marcaine)- Long duration of action (6-8 hrs), more sensory than motor block so preferred for spinal anesthesia, infiltration blocks and epidural anesthesia; more toxic

Mepivacaine (Carbocaine)- Intermediate acting GA (60-120 min)

Ropivacaine (Naropin)- Long acting GA (6-8 hrs)

Etidocaine (Duranest); Articaine (Septocaine);

Dibucaine (Nupercainal)- Dibucain number test is a measure of qualitative activity of butyrylcholinesterase, shows pts with mutations in butytylcholinesterase and IDs pts w/ butyrylcholinesterase deficiency

Methamphetamine - Increases release of DA and NE in basal ganglia; may cause amphetamine, psychosis; Rapid physical and psychological dependence; meth mouth, formication (crawling bugs feelin); Cardiotoxic/neurotoxic

Tx for Amphetamine and Methamphetamine = abstinence (withdrawal+crash), inpatient outpatient and supprt services; NA/Cocain Anonymouse

Cocaine- Mechanism:  Inhibits DA reuptake;

Pharm actions: Euphoria and reinforcement due to increased DA in nucleus accumbens and cortex; burs of energy and euphoria

Used for LA and vasoconstriction

Adverse consequences: Cerebral hemorrhage; temp may increase to 108-110; seizures; Physical and psychological dependence: Cardiac effects; "cocaine bugs"

Tx: Detox; inpatient tx; avoid environmental cues; NA/Cocain anonymous

Amphetamine- Mechanism: Increases release of DA, reverses DA transport through the DAT; also inhibits VMAT; usually for Narcolepsy, ADHD (Ritalin, Adderall): also fo obesity 

Effects: Stimulation, allertness, reduced fatigue, increased energy, decreased appetite

Adverse consequences: anxiety, insomnia, irritability; high doses/long term = psychosis, stereotypic behavior (constant repetition of meaningless activity)

Tx for Amphetamine and Methamphetamine = abstinence (withdrawal+crash), inpatient outpatient and supprt services; NA/Cocain Anonymouse

Marijuana- delta-9-tetrahydrocannabinol (THC); Targets presynaptic cannabinoid (CB1) receptors, Inhibits NT release (Glutamate and ACh); endogenous ligand = anandamide; No physical dependence; psychological dependence possible; 

Effects: Increased appetite and antiemetic (CA tx!) Pleasant feeling of well being, introspection, tranquility, rapid mood changes, altered perception of space and time; increased intesity of sensory perceptions

Drawbacks to chronic use: acute depression, acute panic reactions and mild paranoia may occur; amotivational syndrom, reversible reduction in testosterone levels/sperm production and motility; bronchial irritation and inflammation (CA risk of smoking)

Medical effects: anti-emetic (Chemo CA), analgesia (MS), appetite enhancement in AIDS pts

MDMA (Ecstasy)- Mechanism: Increases 5-HT activity by blocking reuptake and stimulating 5-HT receptors (NO DA INVOLVEMENT!);

 Effects: Feelings of peacefulness, acceptance, empathy, feelings of close and trust.

Toxicities: Hyperthermia, dehydration, kidney failures can lead to fatalities; long term serotonin neuron death results; may increase HR and BP; adverse effects = confusion, depression, sleep problems, anxiety, paranoia, muscle tension, teeth clenching, nausea, blurred vision, faintness, chills or sweating

NSAID

Mechanism: Nonselective, irreversible inhibitor of COX-1 and COX-2; peripheral and CNS effects contribut to pain relief; prevents sensitization of pain receptor; inhibit prostaglandin synthesis; inhibits cytokine production too

Use: mild to moderate pain, fever, decrease platelet action, decrease MI and colon CA

Effects: Analgesic (only inflammatory), antipyretic (only febrile and hyperthermia), anti-inflammatory, antiplatelet effects (ACA only); Centrally, acts on hypothalamic area and reduces fever and malaise; binds plasma proteins (50-90%)

Renal excretion - alkalinization of urine promotes excretion (its an acid)

Contraindications - hypoprothrominemia, vit K deficiency, hemophilia, severe hepatic damage (low coag factors), aspirin allergy, pre sx or labor

Pharmacokinetics: slowly crosses BBB, rapidly hydrolyzed in plasma, liver and RBCs; excreted by kidneys

Adverse effects: resp alk, then metabolic and respiratory acidosis (high doses will inhibit resp center); salicylism, hypersensitivity (skin rashes), reye's syndrome (cerebral edema in children with viral infections

Dose dependent toxicities: low-high = resp alkalosis followed by resp depression then resp acidosis; increased bleeding time; low-high = decreased uric acid excretion increased (increased plasma urate) -> increased uric acid excretion (decreased plasma urate, too much ASA though for GI); aspirin astham (increased leukotrienes); GI bleed; renal damage, ARF, nephritis; 

Dx interactions: Decreases effects of beta blockers, ACE inhibitors; increases anticoagulant, insulin release (DM drugs), bleeding from antineoplastic agents, GI ulcer from corticosteroids; antacids changed absorption; Diuretic decrease ASA effects; Increased effect from NSAIDS, penicillins, platelet inhibitors, salicylates, sulfonamides, thrombolytic agents

Other Salicylates: Sodium Salicylate (Uracel-5)

Methyl Salicylate (Oil of Wintergreen)

 Diflunisal (Dolobid)

NSAID: COX-2 inhibitor

Mechanism: Selective COX-2 inhibitor; cause less gastropathy and risk of GI bleed; *Platelets only contain COX-1*

Use: analgesia if PUD hx but not active

Adverse reactions: Increased risk of CV disease (PGI2 inhibition leads to imbalance and increased TXA2! = platelet aggregation/vasoconstriction)

Contraindications: GI disease, asthma, breast feeding, pregnancy, renal failure, sulfonamide hypersensitivity

Nonspecific COX inhibitors; Heteroaril acetic acids

Potent COX inhibitor; increased risk of CV disease

Ketorolac = post-surg. pain

Different Actions:

Mechanisms:

Pharmacokinetics:

Use: Analgesic if pt has ACTIVE PUD; alternative to aspirin for analgesic and antipyretic effects: DOES NOT INHIBIT COX ENZYMES! NOT ANTI-INFLAMMATORY!!!; prefferred for aspirin allergic pts, coag disorders (hemophilia), PUD hx, gouty arthritis, children; NOT as effective for RA

Adverse effects/tox: lacks severeal undesirable side effects (ulcerogenic, blood clotting defects, acid-base imbalance, auditory tox); OD = fatal hepatic necrosis (10-16 gm tox adult, 25 fatal) -> hepatic encephalopathy, coma/death (tox from reduced glutathione); allergic respons, few cases of adverse effects on blood (neutro- pan- leuko- cytopenia)

Tx of acetaminophen intoxications: Gastric emptying, forcer diuresis, hemodialysis, N-acetylcysteine (Mucomyst), give within 10-12 hrs of intoxication; (won't die with remote in hand)

Side effects: less side effects than ASA, but metabolite causes free radical in liver and leads to hepatic necrosis in OD; allergic response, neutropenia/pancytopenia/leukopenia, dose dependent hepatic necrosis (With reduced glutathione), elevated serum transaminase; if alcoholic, CYP450 induced, increasing toxic metabolite load

Wilson's disease tx too

Disease MOdifying Anti-Rhematic Drug (DMARD); Gold Salts

Mechanism: a chelating agent for RA; inhibits formation of collagen; depresses IgM rheumatoid factor in blood; decreases T-cell activity (not B-cell_

Pharmacokinetics: protein binding 80% (albumin); uncomplexed penicillamine is metabolized in liver then excreted in urine/feces

Side effects: high incidence; pruritis/rash, thrombocytopenia, leukocytopenia, agranulocytosis, aplastic anemia; proteinuria, hypoablumineaia, nephrotic syndrome; lupus like disease, pemphigus, goodpasture's syndrome, myasthenia gravis, polymyositis, stenosing alveolitis

RA

Mechanism: antihistamine, anticholinesterase, antiprotease; inhibits prostaglandin synth; inhbitis biosynth of mucopolysaccharide, inhibits, chemotactic stimuli of phagocytosis, stabilized lysosomes; reacts with nucleic acids and tissue proteins

Pharmacokinetics: widely distributed into body tissues; high affinity for melanin (so in epidermis/retina); partially metabolized in liver; t1/2 = 50 days!

Side Effects: pruritis, hemolysis, ototoxicity, retinopathy, peripheral neuropathy

DMRAD

Crohns and RA

Mechanism: Monoclonal Antibody (IgG1k) targeted against TNF-a (chimeric); murine/human regions on same ab

Pharmacokinetics: IV, vascular compartment, T1/2 8-9.5 days

Side effects: infusion rxns, headache, nausea/vomiting, diarrheea, dizzines, etc

Contraindications: Pregnancy, breast feeding, children infections (TB etc.)

DMRAD

Mechanism: chimeric monoclonal ab (IgG); binds CD20 (B cells antigen on pre-B and mature b-lymphs-> CD20 on >90% of B-cells in NHL; 

Pharmacokinetics: IV

Side effects: infusion rxns, hypersensitivity rxns, fever, chills, rash etc.

RA

Mechanism: IgG1 monoclonal ab; specific for TNF-a; 

Pharmacokinetics: subq; 

Side effects: rash, flu like, fatigue, headache, pruritis, nausea/vomiting