• #1 drug used in pts with atrial fibrillation
• Inhibits synthesis of Vitamin K clotting factors
• + Flagyl = increased warfarin blood levels, BLEED OUT
• + Florinal (Aspirin/Barbituates) = lowers warfarin blood levels, stroke!
• MSE: bleeding out
• Low therapeutic index
• Enzyme: CYP1A2 (inhibited by erythro, cipro aka increased warfarin)/(induced aka decreased substrate by rifampin, tobacco)

- Anxiolytic/Tx of spasticity

- Enhances action of GABA-A

- Causes influx of chloride ions -- HYPERPOLARIZATION!

- MSE: sleepiness, psychomotor impairment

- Category D (cleft palate, respiratory depression)

- Parent active compound (T1/2 = 24 h), converted to Desmethyldiazepam (12hr) via phase 1 rxn (lose methyl) converted via another phase 1 rxn (add hydroxyl) to Oxazepam/Serax(R) [6hr] then via phase 2/glucuronidation to inactive compound

- Used for pulmonary hypertension

- PDE5 inhibitors (degrades cGMP which = vasodilation)
- If you have PDE5 inhibited, you won't degrade cGMP and you'll have vasodilation which helps hypertension

- MSE: priapism (erection 4 hours +)

- Absorbs glucose

- Destroyed by stomach acid

- MSE: lower blood sugar too much, hypoglycemia

- Tolbutamide is protein bumped -- action increased by other drugs

- Non-selective beta-blocker (B1 & B2)

- Antagonist

- Slows down HR, prevents angina

- Reduces liver perfusion by reducing cardiac output (B1) & constricting blood vessels of liver (B2)

- Blocks action of epi on B1/B2 -- negative chronotropic effect, negative inotropic effect, bronchoconstriction -- gives epi pure alpha 1 activity (tighten blood vessels + slow heart)
- MSE: can cause drug-induced CHF or bronchoconstriction (don't give to asthmatic)

- (Selective) Alpha-1 Blocker/Antagonist

- Lowers BP

- Reversible, competitive

- Hypotension can occur during initial dose -- first dose effect

- Opens up blood vessels

- Causes postural hypotension (pass out when get up)

- Calcium channel blocking agents

- Decrease rate and contraction force of heart

- Vasodilate (used in arrhythmias more)

- MSE: gingival hyperplasia (overgrowth of gingiva)

- Elevates mood

- Blocks reuptake of NE and SE

- Increases synaptic levels of both

- Blocks muscarinic cholinergic receptors

- MSE: dry mouth

- Metabolized by CYP1A2 (inhibited by erythro/cipro, induced by tobacco, rifampin)

- Bisphosphonate that prevents bone from demineralizing/fracturing

- MSE: osteonecrosis

- Belladona alkaloid

- Blocks ACh at muscarinic receptors (antagonist)

- Relatively selective

- Uncharged, enters CNS quickly -- penetrates BBB

- Competitive antagonist

- Decreases salivation/causes dry mouth aka xerostomia

- Increase HR, mydriasis (used in eye exam), constipation, urinary retention

- Less sweating

- Antidote to OD of cholinergic agents

- Relief of Parkinson's -- decrease fx of ACh

- Contraindicated in NARROW ANGLE GLAUCOMA & MG

- Antibiotic

- Kills anaerobic bacteria

- + Alcohol? Inhibits metabolism by blocking alcohol dehydrogenase (ANTABUSE fx)

- + Warfarin? Increased blood levels of warfarin, bleed out!

- Schedule II (NO REFILLS)

- Contains aspirin

- Give to patient with allergy - dead!

- Analgesic

- Removed from market during Phase IV trials

- Liver toxicity

- Caused valve damage in heart

- Pressure built up in lungs

- Removed during Phase IV clinical trials

- First non-sedating antihistamine (blocks H1)

- Converted to Fexofenadine(Allegra) via CYP3A4

- Tae with erytho or grape fruit juice? Enzyme inhibited -- build up causes torsades de pointes (resistant arrhythmia)

- Pulled from market during Phase IV clinical trials

- Decongestant found in many OTC cough+cold preps

- Removed during Phase IV clinical trials

- Correlation between use + strokes in young women

- Also in OTC diet aids

- CNS stimulant + anorexiant

- Decreases appetite control center in hypothalamus

- Statin

- Cholesterol lowering drug

- Removed during Phase IV trials

- High incidence of rhabdomyolysis (break down of skeeltal muscle)

- Anti-arthritis

- Selective COX-2 inhibitor

- High incidence of strokes + heart attacks

- Bextra caused serious skin rxns, too

- Increases heart contraction force without increasing rate of contraction

- LOW therapeutic index

- Inhibits sodium/potassium ATPase pump (Na in cell longer)

- Effects mirror acetylcholine -- parasympathetic side keeps rate down

- Comes from foxglove plant

- Acetylsalicylic acid
- Pregnancy category C/D -- causes fetal bleeding, delayed labor in 3rd trimester (D) and antiplatelet activity leads to complications + premature closure of DA in fetus

- Enteric coating (to lessen GI distress) so more quickly dissolved in body if dissolved in water 

- Weak acid

- Active aspirin molecule (ASA) -- only derivative with anti-platelet activity (+ analgesic, + anti-inflammatory)

- Converted to salicylic acid (no AP activity, + analgesic, + AI) which is then converted into conjugated metabolite, inactive (attached gly)

- COVALENTLY binds to COX (only take 1/day)

- Considered peripherally acting analgesic

- Blocks COX 1(endothelial cells) + COX 2(platelets) 

- Blocks more COX 1 than COX 2; reduces plaetlet ability to aggregate

- 2 diethyl 2,6 acetoxylide

- Weak base

- Taken orally? Converted to charged form - no absorption!
- T1/2 increased if propranolol also given

- Not much paresthesia

- Category B drug

- Sodium channel blocker

- Actions increased when administered with epi (local vasoconstrictor) - Used most of the time in dentistry (amide anesthetic -- no PABA breakdown product; solubilized in water)

- N-acetyl-para-aminophenol

-Pregnancy Category B

- 90-96% transformed via PHASE 2 rxn --> conjugated metabolite via glucuronidation (inactive molecule)

- 4% transformed via enzyme CYP2E1 --> NAPQI, very hepatoxic! --> transformed via Glutathione that converts to conjugated metabolite/inactive

- + Alcohol? Upregulation of CYP2E1 -- more NAPQI 

- Isobutyl-phenyl propionic acid

- Pregnancy category B/D -- fetal bleeding, delayed labor in 3rd tri

- Peripherally acting analgesic

- Operates via 1st Order Kinetics -- 50% eliminated each half life

Potent, highly efficacious narcotic analgesic

D-form isomer, Dextromethorphan(R) -- weak analgesic at best, but retains antitussive activity

- General anesthetic gases

- Dissolve in lipid rich membranes of nervous tissues -- increasing membrane fluidity (expanding membrane)

- Triggers malignant hyperthermia

- TB drug

- Reduces other drugs levels in the body (induces the enzymes aka decreases the substrate)

- Lowers BC levels (along with St Johns Wort)

- Schedule II (NO REFILLS)

- Centrally acting analgesic

- Graded dose response curve, i.e. increase dose and get increased pain relief

- Opiate receptor agonist

- K3 = 1

- Binds to receptor and activates it!
- + Naloxone? Naloxone competes for receptor sites, antagonizes -- curve shifts to the RIGHT (takes a higher dose of oxycodone + naloxone to elicit same responses as just oxycodone) 

- K3 = 0 (ANTAGONIST)

- Opiate receptor antagonist

- Classic antidote for WEAK BASE overdose

- Binds to the opiate receptor but blocks the activity site so it cannot be activated

- Opiate receptor partial agonist

- K3 = 0.7

- Binds to opiate receptor and partially activates it (competes with opiates)

- Ween off morphine, use this drug

- Nicotinic M blocker (so works at the MEP)/Anticholinergic

- Permanently charged so not absorbed well

- Blocks contraction of striated muscle (overcome by administering more ACh -- competitive inhibitor)

- + ACh? Shift curve to the RIGHT (competitive antagonist at nicotinic M receptors so takes more ACh in presence of curare to elicit same contraction strength as ACh alone)

- Potent

- Depolarizing neuromuscular blocking agent (depolarizes MEP until unresponsibe to ACh)

- Used in the OR to facilitate intubation

- Causes skeletal muscle paralysis/blocks contraction of striated skeletal muscle

- Trigger for malignant hyperthermia

- Not reversible with an agonist -- just have to wait for it to be metabolized (to succinylmonocholine)

- + ACh? Bottoms out the curve -- succinylcholine is a non-competitive antagonist at nicotinic M cholinergic receptors

-  Fasiculate after succinylcholine admin before going into blockade

- Antibiotic

- Chemical antagonism when in the presence of divalent and trivalent cations, dairy products, antacids, or iron supplements

- Antifungal drug

- Punches holes in fungal cell membrane causing death

- Inhibits AChase -- indirect acting (activates muscarinic AND nicotinic at same time)

- Cholinesterase inhibitor

- Used to overcome a curare-like blockade

- Increases ACh levels at the synapse by blocking breakdown

- Increases muscle contraction

- Also increases salivation

- Blocks MAO which inhibits breakdown of NE/SE

- Elevates a patients mood

- MAOI

- 

- Muscarinic cholinergic agonist

- Binds to and activates muscarinic cholinergic receptors

- Works like ACh -- increased salivation!

- Direct acting

- DOES NOT induce skeletal muscle contraction because devoid of nicotinic (M) cholinergic receptor activity

- Does not activate ganglionic sites (Nicotinic N)

- Schedule II (NO REFILLS)

- Increase release of NE and DO in brain and elsewhere in body

- Causes euphoria

- Increases attention in ADD patients

- Also increases BP + HR

- Dual-acting (direct + indirect) adrenergic drug

Serotonin Selective Reuptake Inhibitors (SSRIs)
 

Paroxitene/Paxil(R), Fluoxitene/Prozac(R), Sertaline/Zoloft(R)

- Block removal of serotonin elevating moods

- Inhibit CYP2D6 (enzyme that metabolizes codeine + tramadol) -- inhibits their actions

- SSRI + Tramadol = serotonergic syndrome b/c both drugs increase serotonergic activity

- Also inhibit CYP2C9 (enzyme that metabolizes warfarin, tolbutamide, phenytoin) -- causes substrate accumulation

- Muscarinic blocker

- Quarternary amine (ionized, water soluble)

- Reduce gastric acid secretions

- Results in xerostomia, papillary dilation, reduced sweating, etc.

- Just like atropine

- Cholinesterase inhibitor

- Blocks effects of cholinesterase

- Prolongs actions of ACh

- Used to overcome blockade of curare

- Alpha-1 Adrenergic Antagonist

- For reversal of soft tissue local anesthesia

- Reversible, competitive antagonism of both A1 & A2 sites

- Antihypertensive

- Depletes NE stores or prevents release from nerve terminals

- Alkaloid

- Stimulates postsynaptic ganglionic receptors -- prevents repolarization of membrane

- Direct stimulator of nicotinic receptors

- Skeletal muscle + brain

- Activates para and sympathetic systems

- Nicotine + salivary gland? NOTHING - no nicotinic cholinergic receptors, only muscarinic

- Nicotine + muscle? CONTRACT!

- Donepezil, Rivastigmine, Tacrine, Memantine/Namenda(R), Gingko Biloba

- Best treated with anticholinesterases

- Cholinergic neurons getting destroyed, want to keep ACh around long

- Drugs improve cognition and function

**Memantine - N-methyl-D-aspartate antagonist (excitatory amino acids contribute to neuronal destruction)

- Soman, Sarin, Tabun

- Organophosphates

- Cholinesterase inhibitors -- covalently bond to enzyme

- Excite parasympathetic system at ganglionic site

- SLUDGE: Salivation, Lacrimation, Urination, Defecation, Gastrointestinal Distress and Emesis (puking)

- Wellbutrin: antidepressant

- Zyban: marketed name for smoking cessation

- Inhibitor of DO, SE & NE reuptake -- stay around longer -- happy! 

- Dual selective (NE + SE) reuptake blocker

- Treatment of ADHD

- Smoking helps ADHD people --- this drug should work on smokers!
- Research being done at UPenn 

- Oral opiate receptor antagonist

- Approved for narcotic/alcohol addiction recovery

- More data needed for smoking cessation

- Blocks the pleasure systems

- Take narcotics on this? NO HIGH!

- Binds to and partially activates nicotinic receptors

- Partial agonist at alpha-4 + beta-2 nicotinic ACh receptor in brain

- More effective than bupropion aka Zyban

- Decreased dopamine release = diminished pleasure with smoking

- Drug that blocks active secretion of penicillin

- Keeps penicillin in body longer (smart move in WWII)

- Major anti-gout drug now -- excretes uric acid

- Category B (pregnancy)

- Potent antibiotic

- Penicillin G destroyed by stomach (Penicillin V is acid stable)

- Eliminated via active/tubular secretion (so quick elimination!)

- Does not change much pre-elimination; can reisolate from urine!

- Blocked by probenecid

- Penicillin V = drug of choice for odontogenic infections

- Actively secreted into kidney tubule system

- Low TI

- NSAIDs compete with lithium to get into the tubules -- take the two together and get all kinds of fucked up

- Muscarinic cholinergic antagonist

- Like Atropine

- Absorbed significantly through skin behind ear (postauricular) when transdermal patch applied

Muscarinic Blockers

Tertiary Amines

Antispasmodics

- More lipid soluble

- Wide distribution into peripheral + central tissues

- Little anticholinergic activity = minimal reduction of gastric secretion

- Nonspecific direct relaxant effect on smooth muscle

- Dicyclomine/Bentyl(R) -- for IBS

- Tolerodine/Detrol(R) -- bladder instability

- Produce mydriasis + cyclopegia for eye exam

- Atropine + Scopolamine -- long durations

- Tropicamide/Mydriacyl(R) - dilate pupil

- Not ionized (cross BBB)

- Parkinson's = deficiency of DA + excessive influence of ACh

- Benzotropine/Cogentin(R)

- Diphenhydramine/Benadryl(R) - antihistamine + anticholinergic activity; TRIAD = anticholinesterase, antihistamine + anesthetic

- Ionized, low solubility

- Reduces gastric acid secretions (especially pre-op)

- Many ADRs though -- H+ pump blockers preferred

- Glycopyrrolate/Robinul(R) - also decreases saliva + prevents bradycardia

- Propantheline/Probanthine(R)

- Non-depolarizing neuromuscular blocker aka relaxant

- Less likely to release histamine than metocurine or d-tubocurarine

- Histamine release is NOT an essential part of neuromuscular blockade

- Hypotensive effect minimal

- Rapidly inactivated in plasma

- Non-depolarizing neuromuscular blocker aka relaxant

- NOT USED ANYMORE

- Histamine release activity caused EXTREME systemic vasodilation with not enough blood to carry/cover area; drugs today devoid of histamine release

- Can be used to test myasthenia gravis -- positive test? increase muscle weakness!

- Little or no release of histamine

- Non-depolarizing neuromuscular blocking agent

- No initial stimulatory effects

- Direct-acting skeletal muscle relaxant

- Act on muscles directly to DECREASE CALCIUM RELEASE, DECREASE CONTRACTION!

- Available in oral form for tx of muscle spasticity

- Action not at the synapse

- Treat emergency case of malignant hyperthermia

- Liver damage/toxicity is possible

- Nondepolarizing NOR depolarizing

- Centrally acting skeletal muscle relaxant

- Tx of SPASTICITY: abnormalities in skeletal muscle tone due to pathological changes in descending CNS motor tracts

- Highly addictive

- Reduces monosynaptic and polysynaptic signal transmission in spinal cord

- Molecular structure similar to GABA (inhibitory NT)

- Active GABA-B -- increased K+ efflux -- HYPERPOLARIZATION!

- Reduced cell activity/decrease excitatory NTs

- Tx of SPASMS - interfere with the transmission of impulses in polysynaptic motor reflex pathways in spinal cord and brainstems (still central but acting at lower levels)

Centrally Acting Skeletal Muscle Relaxants

Anticholinergic Action
(2 Drugs) 

- Cyclobenzaprine/Flexeril(R)

- Orphenadrine/Norflex(R)

- Endogenous catecholamines

- A1 & B1 & B2 agonist

- Positive chronotropic heart effects @ B1;adrenal medulla

- Primatene Mist(R) -- used for bronchospasm (B2 agonist)

- Binds to beta-receptors -- increases activity of adenylate cyclase increasing cAMP concentrations

- Excellent vasoconstrictor used with local anesthetics -- EXCEPT mepivacaine, prilocaine, prolong duration of action of local anesthetics

- Direct activation of A & B adrenergic receptor sites

- Minimal CNS activity

- Excellent absorption through mucous membranes

- 1:100K weaker than 1:50K

- Tx of simple open-angle glaucoma + increase bronchodilation

- Potentiation may occur in TCAs + MAOIs

- More specific direct activation of alpha-adrenergic sites

- Strong vasoconstrictor

- Increases BP + coronary artery blood flow but also increases workload of heart

- Pressor action in acute hypotensive states

- Much beta activity

- Direct activation of dopaminergic receptors in renal + mesenteric vasculature = vasodilation + increased renal blood flow

- Beta-1 receptors = increased force of contraction + cardiac output

- High doses --> activate alpha --> vasoconstriction

- Primary alpha-1 adrenergic

- Anything applied to mucous membrane --> systemic (NOT BBB)

- Direct vasoconstriction reduces congestion and local blood flow

- Chronic use = rebound congestion

- Alpha-1 adrenergic nasal decongestant

- Mydriasis induced

- DOES NOT CAUSE cycloplegia or increase in IOP

- Contraindicated in narrow angle glaucoma

- Alpha 1 agonist/opthalmic decongestant

- Reduce IOP in chronic open-angle glaucoma

- Lipid soluble pro-drug of epinephrine

- Contraindicated in narrow angle glaucoma

- Potentiates analgesia

- Alpha-2 adrenergic agonist

- On presynaptic membranes

- Hypotension, sedation + analgesia

- Relatively specific

- Beta-1 agonist

- Direct activation of beta-1 receptors on myocardium

- Increases contractile force

- Acute tx of heart failure due to depressed contractility

- Bronchodilators

- Beta 2 adrenergic agonist

- Selective

- Used to treat asthma via relaxation of bronchiolar smooth muscle 

- Activate adenyl cyclase stimulated ATP --> cAMP

- Smooth muscle relaxants

- Beta-2 adrenergic agonist

- Activates B2 on uterine smooth muscle to avoid early labor, contractile response

- IV then po

- Low doses? not so selective - B1!

- CNS stimulant + anorexiant

- Control obesity

- Used by athletes for energy

- Vasoconstriction, increased BP/HR, dilate pupils/mydrasis

- Tx of ADHD

- Work out in hot weather -- BV constricted -- HEAT STROKE!

- Activates A&B receptors -- NE release presynaptic

- Directly activates alpha + beta receptors

- Indirectly releases NE from presynaptic membrane

- 

- Amino acid found in cheddar cheese and wine

- Usually inactivated in stomach by MAO

- + MAOIs? Too much NT released...DRUG INTERACTION!

- Indirect acting adrenergic agent/sympathomimetic

- Works at presynaptic end and causes release of EPI + NE

- Hits adrenergic receptors

- Same effect but doesn't work directly on the receptors 

- Non-catecholamine vasoconstrictor

- Nonselective alpha-blocker (blocks alpha 1 & 2)

- Long-acting and noncompetitive (hard to reverse)

- Forms covalent bond with alpha receptor site

- Major cause of orthostatic hypotension (excessive vasodilation of lower limbs)

- Controls hypertension associated with pheochromocytoma (adrenal gland tumor)

- Nonselective alpha blocker

- Reversal soft tissue local anesthesia

- Different from phenoxybenzamine because this is REVERSIBLE

- Competitive antagonism of both A1/A2 sites

- Alpha 1 selective blocker

- Dilation of arterioles + veins 

- Hypertension tx

- A1 on blood vessels

- Reversible, competitive

- BP lowered when patient is supine

- First Dose Effect: significant hypotension can occur during initial dose

- Selective A2 blocker

- Net increase in NT release -- increases BP (can cause strokes)

- Used for orthostatic hypotension + impotense

- Selective B1 blocker

- Cardioselective

- Used to decrease cardiac function to treat hypertension

- Decreases CO -- causes lower BP

- Anti-asthma

- Metabolized by CYP1A2

- Beta-blockers reduce bronchodilating action and clearance

- Deficiency in amount of NADH dependent reductase so spontaneous formation of Fe3+ which is the oxidized form of hemoglobin that does not carry oxygen

- Certain drugs aggravate condition: Prilocaine/Citanest(R), Benzocaine/Hurricaine(R), Nitraites + Nitrites

- Antidote: Methylene Blue

- Form excessive amounts of hemoglobin precursors, porphyrins

- Defect in liver mitochondria

- Cytochrome P-450 (liver enzymes) can increase formation of porphyrins

- Barbituates, Phenytoin, Sulfonamides, Estrogens

- Genetically transmitted

- Triggering Drugs: Halothane, Isoflurane, Succinylcholine
- Massive release of Ca from SR -- muscle rigidity -- high body temp!

- TREATMENT: Dantrolene/Dantrium(R) - inhibits Ca release, IV

- Cold IV solutions, etc. 

- Stimulates kappa receptors

- Women respond better to the drug than men

- Antagonist at mu

- Erythoxylum Coca Shrub

- 1st Anesthetic

- Local anesthetic, not a narcotic!

- Blocks sodium channels (anesthetic) and NE reuptake pump -- accumulation of NE -- elevates mood/vasoconstriction/increase heart rate + contraction force

- Also blocks reuptake of DO/increased release

- + Vasoconstrictors? Hypertension, death

- Ester anesthetic

- Anesthetic

- Promotes formation of methemoglobinemia

- No amino terminus (so no water solubility) -- can only be used topically!

- NO LONGER USED/ON MARKET!

- Long onset, did not last long -- breakdown product floated around in interstiial fluid

- Breakdown product, para-amino benzoic acid (PABA) = haptant (binds tissues and causes allergies)

- Not really used in dentistry

- Used in a spray to numb gagging reflex

- Extremely lipid soluble

- Potent

- Used in epidural

- More carbons over lidocaine = more powerful/longer lasting

- Amide anesthetic

- NO LONGER ON MARKET! 

- Amide anesthetic

- Used mainly without a vasoconstrictor

- Doesn't vasodilate as much

- Good for patients who can't have epi

- Amide anesthetic

- Added more carbons = powerful + longer lasting

- Category C (pregnancy) = bradycardia, respiratory depression

- Amide anesthetic

- Does not vasodilate as much

- Use without a vasoconstrictor

- Use in people that can't tolerate epi

- Longer lasting than mepivicaine without epi

- Paresthesias (long term numbing) reported (rarely)

- Can cause methemoglobinemia

- Amide anesthetic

- Latest local anesthetic

- Amide + ester linkage

- NO PABA!

- Totally inactive when it hits the blood

- Causes paresthesias

- Uplift mood by inactivating MAO which normally breaks down NE in nerve terminal

- + Tyramine? Too much NT release (b/c tyr = sympathomimetic)

- Atorvastatin/Lipitor(R), Lovastatin/Mevacor(R), Simvastatin/Zocor(R)

- All inhibit HMG CoA Reductase (rate limiting step of cholesterol synth)

- **Except Ezetimide/Zetia(R) -- blocks absorption from food

- LDL/HDL should be less than 2.5, i.e. 150/50 = 3 = BAD!