Block 2

Source: mast cells, basophils

Response: vasodilation, increased vascular permeability, pain

Mechanism: activation of GPCRs

Pharm: Antihistamines (H1 antagonists)

Source: endothelial cells

Response: vasodilation, increased microvessel permeability, pain

Mechanism: activation of GPCRs

Pharm: BK receptor antagonists being tested

Source: synthesized by liver, circulate in blood

Response: chemotaxis, promote release of mediators from neutrophil, increase vascular permeability, excessive activation may contribute to tissue injury

Mechanism: complement protein complexes cause osmotic lysis, activation of GPCRs

Pharm: treat rare blood disorders and prevent organ rejection

Source: Produced in liver in response to cytokines, also adipocytes

Response: Acute-phase reactant, activates complement cascade, mediates phagocytosis, marker of inflammation

Mechanism: bind to phospholipids in bacteria and damaged cells, maybe specific receptors in macrophages

Pharm: elevated CRP may be associated with increased risk of diabetes, hypertension, and CV disease.  Drugs like statins may be effective in patients with elevated CRP.

Source: all inflammatory cells

• Response:
•     TNF-alpha: Acute phase reaction, fever sepsis
•     IL-1: acute phase reaction, fibroblast and lymphocyte proliferation, fever

Mechanism: Bind to specific receptor proteins to induce gene expression of number of proteins via activation of NFkB and AP-1 - increase cycloxygenase (fever) and lipoxygenase, increase adhesion molecule expression, induce colleganse

Pharm: Etanercept, infliximab

Source: All cells

Response: increased extraceullarly during injury, anti-inflammatory, inhibit cytokine action

Mechanism: activation of GPCRs

Pharm: Adenosine A2 agonists, methotrexate for rheumatoid arthritis

Source: endothelial cells, platelets, leukocytes

Response: Leukocyte adhesion to endothelium is a pivotal event in host defense and tissue repair.  Endothelial adhesion molecules contribute to recruitment of activated platelets.

Mechanism: "contact molecules" calcium dependent

Pharm: Anti-platelet drugs, treatment of MS and Crohn's disease

Source: All cells

Response: vasodilation/vasoconstriction, pain, fever, platelet aggregation, activation of GPCRs

Pharm: NSAIDs

increased concentrations in cancer - induce cellular proliferation

Source: macrophages, neutrophils

Response: increase vascular permeability, bronchoconstriction

Mechanism: Activation of GPCRs

Pharm: 5 lipoxygenase inhibitors (Zileuton) and cys-leukotriene receptor antagonists (Zafirlukast)

Synthesized by 5-lipoxygenase

BRONCHOSTRICTOR RESPONSE TO LEUKOTRIENES PREDOMINATES IN BRONCHIAL/TRACHEAL SM

Source: Adrenal cortex

Response: inhibition of cytokines, inhibition of phospholipase A2, inhibition of COX2, inhibition of cell adhesion molecules

Mechanism: activation of nuclear receptors

Pharm: steroids

two isoforms exist

mediate production of prostaglandins, thromboxane, and prostacyclin

increased by cytokines to induce fever

inhibited by glucocorticoids

Cytokine inhibitor

Used to treat rheumatoid arthritis

mechanism: fusion protein that binds TNF

IV or SC

• T1/2 = 3 days
• onset of action = 1-2 weeks

Adverse effects: infections

cytokine inhibitor

Use to treat rheumatoid arthritis, Crohn's disease, ulcerative colitis disease

mechanism of action: chimeric IgG monoclonal antibody that binds TNF - results in cell lysis

IV infusion

Adverse effects: infection, delayed hypersensitivity, lupus like symptoms, fever, non-Hodgkin lymphoma

5-lipoxygenase inhibitor

INHIBITS SYNTHESIS OF LEUKOTRIENES

Pharmacokinetics: oral administration, half-life of 2.5 hrs, metabolized by CÁP enzymes - inhibits bronchoconstriction

Adverse effects: few, increased liver enzymes

Therapeutic Use: prophylactic treatment of mild asthma - particularly effective in aspirin induced asthma

Competitive antagonist of cys-leukotriene receptor

Pharmacokinetics: oral administration; half-life of 10 hrs, metabolized by CYP2C9/3A4

Mechanism: inhibits cys-LTs

Adverse Effects: minimal

• Use: prophylactic treatment of mild asthma
• particulary effective in aspirin induced asthma

Non-steroidal anti-inflammatory durg that inhibits the action of cyclooxygenase.  Most widely used medication in the world.

Nonsteroidal anti-inflammatory drug

Inhibitors prostaglandins

• Anti-inflammatory: in large doses
• Analgesia: low intensity pain alleviation
• Antipyretic: reduces fever by inhibiting PG production

All (except aspirin) are REVERSIBLE inhibitors of COX 1 and COX 2 (except celecoxib only blocks COX 2)

• Toxicity & Contraindications
• 1) GI: gastric irritation leading to ulcers, COX-1 inhibition prevents production of protective PGs

2) Blood: increased bleading time d/t lack of TX production

3) Hypersensitivity: bronchoconstriction, edema, d/t leukotrienes b/c of shunting of AA pathway from COX to lipoxygenase

4) Renal: decreased RBF and GFR; salt and water retention

5) NSAID use in pregnancy = decreased uterine contractions, may prolong labor

Glucocorticoid

Most potent and effective agents for controlling chronic inflammatory diseases

First-line treatment for asthma

Mechanism: binds to cytoplasmic receptors

Activated receptor-steroid complex: localizes to nucleus/binds DNA (glucocorticoid response elements) - transcription of certain target genes (induction or repression)

Small minority of patients are resistant

Limitations to use are side effects

The most abundant precursor of eicosanoids.

Low concentrations in cells, found esterified to membrane phospholipids.

Release is calcium-dependent

Phospholipase A2 hydrolyzes the sn-2 ester bond.

In brain, coupled to ethanolamine to form anadamide which binds cannabinoid receptors and displays biochemical and behavioral effects similiar to THC.

Describes the families of prostaglandins, leukotrienes, and other related compounds.

Derived from 20-carbon essential fatty acids that contain 3, 4, or 5 double bonds.

Present on mast cells and eosinophils

Mediate inflammation, asthma

Zafirlukast is the receptor antagonist

hyperalgesia

initiation and progression of labor by inducing uterine contractility and mediating ripening of cervix

vasodilator - systemic blood pressure decrease

tone of ductus arteriosus 

relaxes bronchail/tracheal smooth muscle

increases RBF b/c of vasodilation, promotes diuresis

inhibits gastric acid secretion, increases gastric mucosal blood blow, stimulates release of viscous mucus, stimulates bicarb secretion, contracts GI smooth muscle

hyperalgesia

inhibits platelet aggregation via IP receptor coupled to cAMP,  synthesized by endothelial cells NOT platelets

quiescent state of uterine activity during eary pregnancy, relaxation of uterine tone via increased cAMP

CV/Vascular SM vasodilator, profound hypotension after IV administration

relaxation of bronchial/tracheal smooth muscle

increase RBF b/c of vasodilation in kidney, promotes diuresis & naturesis

inhibits gastric acid secretion, increases gastric mucosal blood flow

made from arachidonic acid by COX-1 in response to activation of platelet membrane PLA₂

promotes platelet aggregation by stimulating TP receptor that couples to increase in intracellular calcium

pathway activated in acute coronary artery syndromes

potent vasoconstrictor in CV/Vascular SM

Constricts bronchial/tracheal muscle

mediates uterine contractility during labor

primary dysmenorrhea: concentrations increase in menstrual fluid and cause vasoconstriction, uterine contraction, pain - COX1 and COX2 involvement

CV/Vascular SM: vasoconstriction

Bronchial/tracheal smooth muscle: constrict

chemoattractant for neutrophils in inflammatory and immune response

constricts bronchial/tracheal smooth muscle

increases vascular permeability in inflammatory and immune responses

constricts bronchial/tracheal smooth muscle

increases vascular permeability in inflammatory and immune responses

Vasoconstrictor and a potent hypertensive agent

Facilitates platelet aggregation.

synthetic analog of PGE2

• Use: Cervical ripening in pregnancy
• Prep: Cervical gel
• Mechanism: promotes cervical ripening - activation of collagenase, relaxes cervical smooth muscle EP4 receptor subtype

• Use: terminate an early pregnancy/abortion
• Prep: vaginal suppository
• Mechanism: uterine contractions via EP1/3 receptors

• Adverse effects: GI-related, fever, uterine rupture
• Contraindicated: women w/ C-section or uterine surgery

PGE₁

Use: replacement therapy for prevention of ulcers caused by long-term administration with NSAIDs

Prep: oral administration/requires 4x/day dosing

Mechanism: suppresses gastric acid secretion by stimulating EP3 receptors on parietal cells; causes a decrease in cAMP, increase mucin and bicarbonate secretion, increase mucosal blood flow

Adverse Effect: diarrhea/cramping; contraindicated in pregnancy, and IBS

PGE1

• Use: Impotence and erectile dysfunction
• Prep: intravernous injection
• Mechanism: increase cAMP which relaxes smooth muscle of corpus cavernosum
• Adverse effect: pripism - prolonged erection

• Use: maintenance of patent ductus arteriosus
• Prep: IV
• Mechanism: cAMP-mediated relaxation of ductus arteriosus SM
• Adverse effect: apnea in 10% neonates

PGI₂


Effect: primary pulmonary hypertension, rare idopathic disease mainly observed in young adults; increased incidence in females leads to right heart failure, frequently fatal

Prep: continuous intravenous infusion

Mechanism: cAMP-mediated dilation of pulmonary artery vascular smooth muscle

Adverse effects: nausea, vomiting, headache, flushing

PGF2alpha

• Use: glaucoma
• Prep: ophthalmic solution
• Mechanism: increase outflow of aqueous humor
• Adverse effects: eye redness, itching, may cause permanent changes in eye colors, eyelid skin' may increase length and number of eyelashes

• Use: eyelash hypotrichosis
• Prep: ophthalmic solution
• Mechanism: increase the percent and duration of hairs in the growth phase
• Effects: excess, unwanted hair growth, brown iris pigmentation, eye redness, itching

inhibits release of histamine

inhaled anti-inflammatory agent

Mechanism: stabilizes most mast cell membranes and prevents release of histamine - prevents transmembrane influx of calcium into mast cells required for degranulation - may bind to a plasma membrane calcium channel to inhibit activity

Few side effects

Uses: preventive management of asthma, allergic rhinitis, conjunctivitis, food allergies

MUST BE USED IMMEDIATELY BEFORE EXPOSURE TO STIMMULANT OF ASTHMA ATTACK

monoclonal antibody

Mechanism: decrease amount of antigen specific IgE that normally binds to and sensitizes mast cells

Subcutaneous administration

Major adverse effects: life-threatening anaphlaxis and bleeding

Uses: allergic asthma

First generation H₁ blocker

Allergies (profound sedation)

Motion sickness (d/t anticholinergic effects)

Nonprescription sleeping tablets

Early stage Parkinson's disease

First generation H₁ blocker

Vestibular disturbances

Motion sickness (d/t anticholinergic effects)

Acts at inner ear vestibular afferents and brain stem

Side Fx: drowsiness

First generation H₁ blocker

Less prone to drowsiness for allergy treatment

First generation H₁ blocker

• motion sickness (d/t anticholinergic effects)
• Chemotherapy-induced nausea/vomiting

2nd generation H₁ blocker

Treats allergies

No CNS effects - no sedation

2nd generation H₁ blocker

Treats allergies

No CNS effects - no sedation

No associated cardiact toxicity

2nd generation H₁ blocker

Treats allergies

No CNS effects - no sedation

2nd generation H₁ blocker

Treats allergies

Higher incidence of sedation compared to other 2nd generation drugs

• H₂ blocker - reversible competitive inhibition
• -inhibits CYP - prolongs half life of other drugs
• -decreases basal/nocturnal acid secretion
• -use approrpriate dose reduction for patients w/ impaired renal fxn
• -duration of action = 4-5 hrs
• longer term use at high doses: decreases testosterone binding and inhibits a CYP enzyme that hydroxylates estradiol --> men: gynecomastia, reduced sperm count, impotence

Least potent

Used to treat Zollinger-Ellison Syndrome (non beta cell tumor of the pancreas with overproduction of gastric)

H₂ blocker

• -decreases basal/nocturnal acid secretion
• combined w/ bismuth sulfate

Inhibits CYP but with only 10% affinity of cimetidine

Minimal side effects

Medium potency

H₂ blocker

Minimal side effects

Most potent

Irreversible inhibitor of COX via acetylation of serine residue

• Pharmacokinetics: 
• -rapid absorption
• -buffered vs enteric-coated
• -hihgly bound to plasma proteins
• -crosses BBB & placenta
• -hydrolyzed to salicylic acid (still active), then to variouus less polar metabolites
• -T_1/2 is dose dependent (0 order kinetics)
• -kidney excretion

• Non-COX related effects
• 1) increased uric acid levels at low dose
• 2) decreased uric acid levels at high dose
• 3) delirium, psychoses b/c croses BBB, nausea, vomiting

4)respiration: increased RR, respiratory alkalosis, renal compensation via increased HCO3 excretion

• Adverse Reactions specific to Aspirin:
• Salicylism: slight respiratory stimluation, nausea, vomiting, tinnitus, deafness, dehydration

Reye's syndrome: illness related to viral epidemics, result in liver failure and death - affects kids often following a viral illness - perhaps d/t mitochondrial damage

T1/2 = 2 hrs

highly bound to plasma

anti-inflammatory, analgesic, anti-pyretic

Tx: rheumatoid arthritis, dysmenorrhea, pain, fever, osteoarthritis

Injection: closure of patent ductus arteriosus in premies when usual tx is not effective

T1/2= 14 hrs

highly bound to plasma

anto-inflammatory, analgesic, anti-pyretic

management of ankylosing spondylitis, osteoarthritis, rheumatoid disorders, acute gout, tendonitis, bursitis, dysmenorrhea, fever

T1/2 = 3 hrs

Tx: acute gouty arthritis, acute bursitis/tendonitis, moderate-to-severe osteoarthritis, ankylosing spondylitis

IV: alternative to surgery for closure of PDA

Off-label: pre-tern labor

• Absorbed orally and intramuscularly
• Highly plasma bound

Use: oral, injection: short term (<5 days) management of moderate-to-severe acute pain requiring analgesia at the opiod level (post-operative pain for ptx who can't tolerate narcotics)

COX2>COX1 inhibition

• converted to active metabolite
• long half life

well tolerated side effects

Tx: osteoarthritis, rheumatoid arthritis

T1/2 = 50 hrs

may offer advantage in tx of osteoarthritis b/c of long half life

• Not clear if inhibits COX
• Inhibition of production of IL-1 & TNFalpha, inhibition of lipoxygenase pathway, scavenging of free radicals and oxidants, inhibition of NF-kB

Prodrug cleaved by colon bacteria (active forms: mesalamine + sulfapyridine)

Tx: ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis

Side Fx: decreased folate absorption, sperm motility; headache, nausea, vomiting, fever, malaise

Inhibition of COX2 - specific binding site not present in COX1

Oral administration, bound to plasma proteins

Metabolized via CYP450 2C9 to inactive metabolites

Tx: rheumatoid arthritis, primary dysmenorrhea, acute pain, decrease polyps in FAP

Side FX: increase GI ulceration, bleeding, increased risk of thrombosis

Contraindications: patients w/ sulfonamide toxicity, prior NSAID hypersensitivity, pre-existing CV factors or disease, deficient CYP 2C9

mechanism not understood, no affinity for COX 1 or 2

• oral administration
• absorbed in GI tract
• T1/2=2 hrs
• little binding to plasma proteins

metabolized by CYP2E1, CYP1A2, and CYP3A4

NOT anti-inflammatory

• Adverse effects: related to excessive use
• hepatic toxicity
• treatment = N-acetylcystein
• alochol may increase risk of liver damage

Used to treat gout

Antimimotic effect: decreases crystal-induced secretion of chemotactic factors and superoxide anions by activated neutrophils

• oral administration
• metabolized by CYP 3A4

• adverse effects: GI, dairrhea
• latent period before onset of toxic symptoms great limits use of drugs

hepatic/renal disease should receive reduced doses 

treatment of familiar mediterranea fever

competitively inhibits xanthine oxidase (which produces uric acid)

concenctration of uric acid in plasma decreases and excretion increases

plasma concentrations of hypoxanthine and zanthine increase but are efficiently excreted without tissue deposition

lowers [uric acid] in plasma below the limit of its solubility

adverse effects: incidence of acute attacks of gouty arthritis may increase as a consequence of mobilization of tissue stores or uric acid (give w/ colchicine or NSAIDs)

hypersensitivity reactions

drug interactions: increase half life of probenecid, increased risk of hypersensitivity if taken with ACE inhibitors

Use: prevention of attack of gouty arthritis and nephropathy, treatment of secondary hyperuricemia

mechanism: inhibition of organic acid transport in renal tubule

competes with uric acid for the exchange so that reabsorption of uric acid decreases

oral administration

adverse effects: well tolerated, GI irritation

use: chronic gout, not in patients with kidney stones or with overproduction or uric acid because at higher doses there is increased tendency to produce uric acid stones, may need to combine with colchicine

If given with penicillin, results in increased plasma [penicillin]

Use: rheumatoid arthritis 

Mechanism: antagonist of interleukin-1

SC injection

Adverse effects: infections, should not be used in combination with tumor necrosis factor antagonists

Class of CCB that acts preferentially on cardiac cells

Verapamil

Use-dependent - binding site deep within channel, rapidly firing of action potentials in the myocardium and the SA and AV node promote binding of CCBs - effective block in myocardium and cardiac conducting cells

Class of CCB that acts preferentially on cardiac cells

Diltiazem

Use-dependent - binding site deep within channel, rapidly firing of action potentials in the myocardium and the SA and AV node promote binding of CCBs - effective block in myocardium and cardiac conducting cells

Class of CCB that bind preferentially to vascular smooth muscle to induce vasodilation

Binding site is on ouside surface of channel protein and bind to depolarized state of the channel.

Preferentially block L-type Ca channels in ARTERIES and have little effect on veins - reduce cardiac afterload NOT preload

• Nifedipine
• Amlodipine

Often used in combo with beta blockers to prevent reflex tachycardia

Contraindicated in patients with tachyarrhythmias

Higher protein binding percentages than phenylalkylamines and benzothiazepines

Side Fx: hypotension, headache, flushing, and peripheral edema

Prototype of benzothiazepine family

often used in angina- used for typical stable angina - decreases oxygen demand

• reduces cardiac workload because decreases SA firing rate
• orally to chronically tx HTN

potential dilator of coronary arteries allowing increased blood flow to myocardium

also used in supraventricular arrhythmias

Not much 1st pass metabolism

Best tolerated: less potent cardiac effects than verapamil, less dramatic peripheral vasodilation than nifedipine

reflex tachycardia but not as much as w/ other vasodilators

SE: flushing, headaches, negative inotropic effects, edema, constipation

Prototype of phenylalkylamine family

Used in supraventricular arrhthmias because reduce the firing rate of SA node and reduce conduction through AV node.  Helpful in reducing ventricular response rates if atria is firing too fast.

tx of stable angina - decreases oxygen demand

Extensive first pass metabolism

Side Fx: constipation(worse than other 2 Ca blockers). worsen CHF, AV block, flushing, headaches, negative inotropic effects, edema

Prototype of 1,4-dihydropyridine family

• Used in hypertension because potent vasodilator
• vasospastic angina d/t vascular effects
• may aggravate angina symptoms in patients with typical stable angina if they are not used in combo w/ beta blocker

Not much first pass metabolism

SE: flushing, headaches, negative inotropic effects, decreased AV conduction, edema(more than other 2 Ca blockers), constipation

slow onset, slow affect as compared to others in 1,4-dihydropyridine family

longer half life than others - so less reflex tachycardia, but harder to adjust dose

Synthesized in the zona glomerulosa

Actions: carbohydrate and protein metabolism, lipid metabolism, mineral and electrolyte metabolism, responsible for hypertension by increasing sodium reabsorption and increasing K and H+ excretion.  causes sleepiness, lability of mood.

Immune System: reduces access of cells to target tissueAnti-inflammatory activity

Uses: adrenal insufficiency, rheumatoid arthritis, osteoarthritis, allergic diseases, inflammatory diseases, cerebral edema

Synthesized in the zona fasciculata and reticularis

Actions:

carbohydrate and protein metabolism, lipid metabolism, mineral and electrolyte metabolism, responsible for hypertension by increasing sodium reabsorption and increasing K and H+ excretion.  causes sleepiness, lability of mood.

• Immune System: reduces access of cells to target tissue
• Anti-inflammatory activity

Uses: adrenal insufficiency, rheumatoid arthritis, osteoarthritis, allergic diseases, inflammatory diseases, cerebral edema

Dexamethasone

Prednisolone

Fludrocortisone

Aldosterone

Cortisol

Contraindication: existing infection (TB)

Toxicity: rapid withdrawl may cause adrenal insufficiency

Prolonged therapy: suppression of pituitary

Cushing's Syndrome

Glucocorticoid synthesis inhibitor

Blocks 11-beta hydroxylation so synthesis is stopped at 11 desoxycortisol --> plasma ACTH levels increase

Used as diagnostic test

competitive antagonist at progesterone and glucocorticoid receptor

termination of pregnancy

treat cushing disease

competitive antagonist at mineralocorticoid receptor

diuretics

treat hypertension

cardiac hypertrophy and heart failure

• Progesterone receptor agonist:
• Use with estrogen to suppress ovluation and as hormone replacement therapy in post-menopausal women

• Mineralocorticoid receptor antagonist:
• diuretic
• antagonizes the salt retaining effects of estrogen

Androgen receptor antagonist

Corticosteroid

Reduces access of cells to target tissue - redistribution of cells out fo vascular space.

Prevent neutrophil adherence to endothelium

Inhibit action of chemotactic factors

• Interference with macrophage antigen processing
• Blocks actions of lymphokines
• Inhibits binding to Fc receptors

Used in combo w/ other drugs in autoimmune diseases and to prevent graft rejection


Toxicity: supression of adrenal-pit axis.  Acute adrenal insufficiency on abrupt withdrawl, Cushing's Syndrome

Contraindicated in presence of existing infection

Cytotoxic agent

Kill rapidly proliferating cells

• Metabolized to 6-mercaptopurine
• Orally active
• Purine anti-metabolite that inhibits purine biosynthesis/DNA synthesis.
• INHIBITS DE NOVO AND SALVAGE PATHWAYS

Use: inhibits rejection of transplanted organs and rheumatoid arthritis

Side Fx: bone marrow depression, GI and hepatic toxicity

Alkylating agent that results in cross-linking of DNA to kill replicating and non-replicating cells

Toxic effect more prnounced on B-cells so more effective in suppressing humoral immunity

Orally active

Used in the tx of autoimmune diseases in combo w/ other drugs.  Not effective in preventing graft rejection

Side Fx: bone marrow depression

Inhibitor of dihydrofolate reductase - inhibits folate dependent steps in purine synthesis- inhibits DNA synthesis

Used to treat autoimmune diseases

Side Fx: Hepatic toxicity

2nd generation immunosupressant

Metabolized to active mycophenolic acid

• Mechanism: Lymphocyte selective immunosuppressant
• Inhibits IMP dehydrogenase (necessary for de novo purine synthesis) - no effect on salvage pathway

lymphocytes cannot make GMP via salvage pathway, thus selectively toxic for lymphocytes

orally active

used with cyclosporine and corticosteroids to prevent renal allograft rejection.

Used to treat autoimmune diseases - rheumatoid arthritis and refractor psoriasis

Used with caution in patients w/ active GI disease, reduced renal function, and infections

Side Fx: infection, leukopenia, anemia

No used in pregnacy

Immunosuppressant

Lipophilic peptide antibiotic

Binds receptor and inhibits Ca-dependent phosphatase - Calcineurin.  Blocks action of transcription factor necessary for IL-2 production.  Blocks T-cell helper function.  

Orally active.

Used to prevent rejection of transplanted organs.  Used in autoimmune diseases.

Nephrotoxicity is a major side effect.  Hepatoxicity may occur.

Immunosuppresant

Binds FK binding protein, a cyclophilin-related protein.  Inactivates calcineurin. Same mechanism of action as cyclosporine.

50-100 times more potent than cyclosporine.

Less nephro- and hepatotoxicity.

Immunosuppressant

Inhibits T-cell activation and proliferation downstream of IL-2.

Binds FKBP-12.  Does not affect calcineurin activity.  Binds and inhibits mTOR, kinase involved in cell cycle progression.  Blocks G1 --> S1 transition.

Side Fx: infection

• Used to prevent rejection of transplanted organs and autoimmune diseases.
• Coating of cardiac stents.

R & S isomers

Inhibits H+/K+ ATPase

Prodrugs activated by protonation 

Action longer than half life

Inhibits acid secretion

Drug for Zollinger-Ellison syndrome, ulcers, GERD

Side Fx: can reduce hepatic metabolism of other drugs. rebound hypergastrinemia

S isomer

Inhibits H+/K+ ATPase

Prodrugs activated by protonation

Action longer than half life

Inhibits acid secretion

Drug for Zollinger-Ellison syndrome, ulcers, GERD

Side Fx: can reduce hepatic metabolism of other drugs. rebound hypergastrinemia

Inhibits H+/K+ ATPase

Prodrugs activated by protonation

Action longer than half lifeInhibits acid secretion

Drug for Zollinger-Ellison syndrome, ulcers, GERD

Side Fx: can reduce hepatic metabolism of other drugs. rebound hypergastrinemia

Neutralizes HCL

(slow reaction)

Side Fx: constipation

Rapid onset of action, immediate relief, short duration of action

Often combined w/ sucralfate to protect gastric lining

Neutralizes HCl

rapid onset of action, immediate relief, short duration of action

(fast reaction)

Side Fx: constipation

HCl neutralization

(Moderate reaction)

Rapid onset, immediate relief, short duration of action

Side Fx: diarrhea - used at treatment for diarrhea - saline laxative, causes osmotic water retention to increase bulk and intestinal peristalsis - contraindicated with electrolyte imbalance, renal, or cardiac disease

octasulfate of sucrose + aluminum hydroxide

with acid it forms a polymer gel to protect the gastric lining from acid and pepsin digestion.

It also binds bile and stimulates prostaglandin production.

Side Fx: constipation, may interfere with absorption of drugs

Anti-emetic

Anticholinergic agent

Tx: motion sickness

Mechanism: blocks neural pathway in inner ear and vomiting center

Used prophylactically, injected/transdermal patch

Side Fx: muscarinic blockage stuff like xerostomia

Tx: chemotherapy, radiation or post operative nausea

Serotonin 5-HT3 receptor antagonist

Acts centrally at the CTZ and/or at vagal afferent nerves in upper GI tract

Side Fx: headache, fatigue, constipation, diarrhea

Tx: chemotherapy, radiation or post operative nausea

Serotonin 5-HT3 receptor antagonist

Acts centrally at the CTZ and/or at vagal afferent nerves in upper GI tract

Side Fx: headache, fatigue, constipation, diarrhea

Anti-emetic "general use"

Dopamine2 receptor antagonist

Some anticholinergic, antihistamine activity

side effects, concerns

tetrahydrocannabinol - natural product may mimic endogenous cannabinoid-compound

used for chemotherapy-induced emesis refractory to other treatments

SE esp. elder: dysphoria, vetigo, dizziness, lack of concentration, depersonalization

glucocorticoid

anti-emetic effect when given in conjunction with other emetics

chemotherapy, cancer

mechanism of action - decreased inflammation and PGs

substance P receptor antagonist

inhibits P/NK, receptor

Used in combo w/ other antiemetics for acute and delayed nausea and vomiting associated with chemotherapy, poster operative nausea

SE: fatigue, nausea, constipation, hiccups

prokinetic agent that promotes gastric emptying and GI motility by enhancing coordination

dopamine2 antagonist, may interact w/ serotonin receptor

has central antiemetic effects at CTZ (5-HT receptors) and promotes gastric emptying by enhancing acetylcholine release in myenteric plexus

used for mild to moderate cases of nausea and vomiting (diabetic induced gastroparesis and GERD) - best with GI dysmotility disorders

little effect on large bowel

SE: rare, dystonia, Parkinson-like symptoms

Pokinetic agent that promotes gastric emptying and GI motility by enhancing coordination

activates motilin receptors in gastric antrum and duodenum

• non-antibiotic mediated event
• stimulates duodenal motility and gastric empting

(off-label) used to treat diabetic gastroparesis

anti-diarrheal therapy

opioid derivate

OTC, best agent, poorly penetrates CNS

• anti-diarrheal therapy
• opioid derivate
• OTC
• has some CNS side effects
• active metabolite is difenoxin
• abuse potential - preparations include subtherapeutic atropine to limit abuse

• traveler's diarrhea - pepto bismol
• displacement of intestinal bacteria from mucous into lumen where lysis occurs
• also used to treat H. pylori
• some relief of gastric and intestinal cramping/discomfort
• causes black stools and tongue d/t bismuth sulfate formation

treatment for carcinoid syndrome - enterochromaffin cell tumor that makes excess serotonin, vasoactive intestinal peptide, bradykinin, and gastrin (secretory diarrhea)

somatostatin analong, physiology antagonizes hormone secretion

useful for dumping syndrome after surgery

many side effects

osmotic laxative

non-absorbed disaccharide, hydrolyzed in the intestine to organic acids, which osmotically pull water into the intestine

SE: gas and abdominal distention

useful in portal-system encephalopathy, acidifies ileum and colon causing NH3 to get trapped in lumen

long chain PEGs are poorly absorbed.

Widely used for surgical/radiological prep to cleanse the colon.  Osmotic retention of water.

anionic surfactant- lowers sufrace tension of the stool to enhance mixing.

softens stool and enhances intestinal secretion.

marginal efficacy

• stimulant laxative
• irritant
• prodrug
• acts primarily on colon
• 6 hour latent period with oral administration

Laxative

• Chloride channel activator - increasing secretions in intestine
• used for idiopathic constipation and for women w/ IBS

contraindications: undiagnosed abdominal pain and constipation b/c of intestinal obstruction

Immunosuppresive therapy used for IBD

• Corticosteroid
• Used for acute attacks, moderate to severe

Immunosuppressive therapy for IBD

enteric release steroid used to treat mild-moderate acute Crohn's

5-aminosalicylate for moderative ulcerative colitis

NOT related to cox inhibition

prodrug converted to mesalamine

• 5 aminosalicylate
• used for mild to moderate ulcerative colitis

NOT related to cox inhibition

less side effects than sulfasalazine

ACE inhibitor

Inhibits formtion of Ang. II and degradation of BK

Block actions of Ang. I and potentiates actions of BK

• Orally active
• Competitive enzyme inhibitors
• Use in treatment of hypertension and congestive cardiac failure (lowers BP w/out changing HR)
• Therapeutic effect enhanced by diuretic

SE: agranulocytosis, rash, proteinuria, angiodema, coughing

Contraindicated in pregnancy

• Should be used w/ caution in volume-depleted patients or patients on diuretics - hypotension possible
• Lowers aldosterone release so hyperkalemia may occur

• ACE inhibitor
• Inhibits formtion of Ang. II and degradation of BK
• Block actions of Ang. I and potentiates actions of BK
• Orally active
• Competitive enzyme inhibitors
• Use in treatment of hypertension and congestive cardiac failure (lowers BP w/out changing HR)
• Therapeutic effect enhanced by diuretic
• SE: angiodema, coughing
• Contraindicated in pregnancy

• Should be used w/ caution in volume-depleted patients or patients on diuretics - hypotension possible
• Lowers aldosterone release so hyperkalemia may occur

• ACE inhibitor
• Inhibits formtion of Ang. II and degradation of BK
• Block actions of Ang. I and potentiates actions of BK
• Orally active
• Competitive enzyme inhibitors
• Use in treatment of hypertension and congestive cardiac failure (lowers BP w/out changing HR)
• Therapeutic effect enhanced by diuretic
• SE: angiodema, coughing
• Contraindicated in pregnancy

• Should be used w/ caution in volume-depleted patients or patients on diuretics - hypotension possible
• Lowers aldosterone release so hyperkalemia may occur

• angiotensin receptor antagonist - block AT1 receptors
• competitive inhibitor of Ang. II 
• orally active
• Used to treat HTN w/out change in HR, effective related to PRA
• Slow onset of action
• Activity enhanced by diuretic
• Reduces BP w/out increasing HR - should be used w/ caution in patients with volume depletion or on diuretics - hypotension possible
• Contraindicated in pregnancy
• Renal function may decrease in patients with CHF or renal artery stenosis

SE: dizziness, cough, angioedema, upper respiratory infections

• Renin inhibitor
• Potent active site, non-peptide inhibitor
• Orally active
• Long acting - T1/2=24h
• Use to treat HTN w/out changing HR - effect comparable to angiotensin receptor antagonist
• Effect enhanced by diuretic, ACE, or AT1 antagonist
• Decreases plasma ang. II and aldosterone 
• Antihypertensive effect related to pretreatment PRA
• Side effects comparable to placebo

Beta blocker (non-selective)

• used for chronic tx of stable angina (may worsen vasospastic angina)
• decreases oxygen demand for myocardium

• reduces renin release
• decreased HR to reduce CO
• inhibition of norepi release from central/peripheral neurons

more effective in lowering blood pressure in young vs. old patients

effect enhanced by diuretic

SE: cardiac depression, increase airway resistance, mask symptoms of hypoglycemia, sedation, impotence, nightmares

use w/ cautions in patients w/ asthma, CHF, peripheral vascular disease.  useful in patients w/ angina pectoris.

w/drawl syndrome - supersensitivity to beta stimulation may cause angina, arrhythmias, or infarction

• Beta1 blocker
• reduces renin release

used for chronic tx of stable angina (not useful for variant vaspospastic angina and may worsen condition if used alone) - decreases oxygen demand of myocardium - decrease HR, contractility, and afterload

• decreased HR to reduce CO
• inhibition of norepi release from central/peripheral neurons
• more effective in lowering blood pressure in young vs. old patients
• effect enhanced by diuretic

SE: cardiac depression, increase airway resistance, mask symptoms of hypoglycemia, sedation, impotence, nightmares

use w/ cautions in patients w/ asthma, CHF, peripheral vascular disease.  useful in patients w/ angina pectoris.

w/drawl syndrome - supersensitivity to beta stimulation may cause angina, arrhythmias, or infarction

• Competitive aldosterone antagonist at mineralocorticoid receptor
• Diuretics
• Orally active
• Reduce cardiac hypertrophy; heart failure

• Competitive aldosterone antagonist at mineralocorticoid receptor
• Diuretics
• Orally active
• Reduce cardiac hypertrophy; heart failure

• DA1 agonist - high concentrations blocks alpha-receptors.  activates adenyl cyclate and increases cAMP
• vasodilator
• increases RBF w/out reducing GFR
• decreases FF
• weak diuretic due to compensatory sodium reabsorption in more distal segments
• limited pharm uses
• lowers systolic and diastolic blood pressure in severe hypertension - equivalent to sodium nitroprusside - dilate renal and mesenteric vascular beds
• increases intra-ocular pressure, flushing, headache, tachycardia, may precipitate angina

contrainidcated in glaucoma, angina, and heart failure

• DA1 agonist
• vasodilator
• increases RBF w/out reducing GFR
• decreases FF
• weak diuretic due to compensatory sodium reabsorption in more distal segments
• limited pharm uses

• DA1 agonist
• vasodilator increases RBF w/out reducing GFR
• decreases FF
• weak diuretic due to compensatory sodium reabsorption in more distal segments
• limited pharm uses

• osmotic diuretic
• freely filterable at glomerulus
• limited reabsorption by tubule
• not metabolized by kidney
• pharmacologically inert

mchanism of action: non-reabsorbed solute limits the reabsorptin of water from the tubule, Na is reabsorbed w/out water, reduced Na concentration diminishes, NET SODIUM REABSORPTION FALLS, enhanced K excretion occurs in distal tubule due to increased Na available for exchangee, urine flow increases as does Na, K, and Cl excretion.

Uses: IV, prophylaxis of acute renal failure, edematous conditions in which a volume load is not detrimental, glaucoma

SE: related to volume overload and expansion of intravascular fluid volume, rare hypersensitivity

• Carbonic anhydrase inhibitor
• Secreted into proximal tubule by organic transporter (OAT)
• Blockade of CA decreases carbonate reabsorption and thereby sodium reabsorption in proximal tubule causing urine pH to decrease
• K+ secretion in distal tubule increases
• Urine volume increases as does the excretion of Na+, K+, and bicarb, urinary excretion of Cl- falls

Uses: glaucoma (reduces aqueous humor formation), alkaline urine to decrease drug toxicity, treat symptoms of acute altitude sickness

SE: metabolic acidosis occurs which reduces renal response to the drug

lool/high ceiling diuretic

• mechanism:
• Na/K/2Cl symport inhibitors
• secreted into proximal tubule by organic acid transporter
• act on cortical and medullary segments of ascending limb of loop of Henle to inhibit active Cl reabsorption, reducing reabsorption of both Na and Cl by inhibiting the symporter.

• potent diuretics
• increases RBF and often GFR
• increases urine volume and excretion of Na, Cl, and K

• Uses:
• rapid onset, shurt duration
• management of edema d/t cardiac, hepatic or renal disease
• acute pulmonary edema
• hypertension

• SE:
• hypokalemia
• hyperuricemia
• hyperglycemia
• ototoxicity - deafness w/ high doses
• volume depletion

• lool/high ceiling diuretic
• mechanism:
• Na/K/2Cl symport inhibitorssecreted into proximal tubule by organic acid transporteract on cortical and medullary segments of ascending limb of loop of Henle to inhibit active Cl reabsorption, reducing reabsorption of both Na and Cl by inhibiting the symporter.

• potent diuretics
• increases RBF and often GFR
• increases urine volume and excretion of Na, Cl, and K

• Uses: rapid onset, shurt duration
• management of edema d/t cardiac, hepatic or renal disease
• acute pulmonary edema
• hypertension

• SE:
• hypokalemia
• hyperuricemia
• ototoxicity - deafness w/ high doses
• volume depletion

lool/high ceiling diuretic

• mechanism:
• Na/K/2Cl symport inhibitors
• secreted into proximal tubule by organic acid transporter
• act on cortical and medullary segments of ascending limb of loop of Henle to inhibit active Cl reabsorption, reducing reabsorption of both Na and Cl by inhibiting the symporter.

• potent diuretics
• increases RBF and often GFR
• increases urine volume and excretion of Na, Cl, and K

• Uses: rapid onset, shurt duration
• management of edema d/t cardiac, hepatic or renal disease
• acute pulmonary edema
• hypertension

• SE:
• hypokalemia
• hyperuricemia
• ototoxicity - deafness w/ high dosesvolume depletion

Thiazide diuretic

• Mechanism:
• Na/Cl symport inhibitor
• Secreted into proximal tubule by OAT
• Act on CORTICAL diluting segment of ascending limb of loop of Henle to inhibit NaCl reabsorption

• Intermediate activity (8-10%)
• Reduces GFR
• K secretion increases d/t increased Na delivery to distal tubule
• Impairs kidney's ability to produce dilute urine
• Enhance urate reabsorption in proximal tubule
• Decrease renal excretion of calcium
• Urine volume increases and Na, Cl, and K excretion - excretes a hypertonic urine

• Uses:
• diuresis is rapid with long duration
• managemnt of edema d/t congestive cardiac failure
• hypertension
• management of hypercalciuria in patients with renal calculi composed of calcium salts

• SE: 
• hypokalemia
• hyperuricemia
• hyperglycemia - d/t increased insulin secretion
• should not be used when GFR < 25 ml/min

Thiazide diuretic

• Mechanism:
• Na/Cl symport inhibitor
• Secreted into proximal tubule by OAT
• Act on CORTICAL diluting segment of ascending limb of loop of Henle to inhibit NaCl reabsorption

• Intermediate activity (8-10%)
• Reduces GFR
• K secretion increases d/t increased Na delivery to distal tubule
• Impairs kidney's ability to produce dilute urine
• Enhance urate reabsorption in proximal tubule
• Decrease renal excretion of calcium
• Urine volume increases and Na, Cl, and K excretion - excretes a hypertonic urine

Uses:diuresis is rapid with long duration

• managemnt of edema d/t congestive cardiac failure
• hypertension
• management of hypercalciuria in patients with renal calculi composed of calcium salts

• SE: hypokalemia
• hyperuricemia
• hyperglycemia - d/t increased insulin secretion
• should not be used when GFR < 25 ml/min

Thiazide Diuretic

• Mechanism:
• Na/Cl symport inhibitor
• Secreted into proximal tubule by OAT
• Act on CORTICAL diluting segment of ascending limb of loop of Henle to inhibit NaCl reabsorption

• Intermediate activity (8-10%)
• Reduces GFR
• K secretion increases d/t increased Na delivery to distal tubule
• Impairs kidney's ability to produce dilute urine
• Enhanced urate reabsorption to proximal tubule
• Decrease renal excretion of Ca
• Urine volume increases and Na, Cl, and K excretion - excretes a hypertonic urine

• Ues:
• diuresis is rapid with long duration
• management of edema d/t congestive cardiac failure
• hypertension
• management of hypercalciuria in patients with renal calculi composed of calcium salts

• SE: 
• hypkalemia
• hyperuricemia
• hyperglycemia - d/t increased insulin secretion
• should not be used when GFR <25 ml/min

Potassium sparing diuretic

• Mechanism:
• acts on distal tubule as a competitive antagonist of aldosterone
• requires endogemous aldosterone activity
• urine volume increases.  urinary excretion of Na increases while K excretion decreases

weak diuretic (2-3% of filtered Na load is excreted)

• Use:
• hypertension
• refractory edema
• Primary aldosteronism
• Used with thiazide or loop diuretic to enhance diuretic effect and reduce K loss
• long duration of action T1/2=24 hrs

• SE: 
• hyperkalemia: should not be used with K supplements and used with care in patients w/ severe renal sufficiency
• gynecomastia - weak progesterone agonist

Potassium sparing diuretic

• Mechanism:
• acts on distal tubule as competitive antagonist of aldosterone
• requires endogenous aldosterone activity
• urine volume increases, urinary excretion of Na increases while K excretion decreases

weak diuretic (2-3% of filtered Na load is excreted)

• Use:
• hypertension
• refractory edema
• Primary aldosteronism
• Used with thiazide or loop diuretic to enhance diuretic effect and reduce K loss
• long duration of action (T1/2 =24 hrs)

• SE: 
• hyperkalemia: should not be used w/ K supplements

tiny bit of gynecomastia

Potassium-sparking diuretic - Sodium channel inhibitor

• Mechanism:
• inhibit entry of Na into principal cell - Na/K exchance does not occur
• Effects independent of aldosterone
• Urine volume increases, urinary excretion of Na increases while K excretion falls
• At high doses, reduces GFR

Weak diuretic --> 2-3% of filtered Na load excreted

• Uses:
• used with thiazide or loop diuretic to enhance diuretic effect and reduce K loss
• treatment of edema or hypertension

• SE: 
• hyperkalemia - should not be used with K supplements
• mild azotemia

K sparing diuretic  - Na channel inhibitor

• Mechanism:
• inhibit entry of Na into principal cell.  Na/K exchance does not occur.  Blocks Na/H exchance at higher concenctration.

effects are independent of aldosterone

urine volume increases, urinary excretion of Na increases while K excretion falls.

weak as diuretic (2-3% of filtered Na load is excreted)

• Uses:
• thiazide or loop diuretic to enhance diuretic effect and reduce K loss
• treatment of edema or hypertension

• SE:
• hyperkalemia - don't give w/ K supplements
• mild azotemia

vasodilator that relaxes vascular smooth muscles to cause vasodilation

acts mainly at peripheral arterioles

little effect on veins

reduces peripheral resistance

• orally active vasodilator
• used in chronic tx of HTN in bombo w/ other drugs
• acts mainly on arterioles with little effect on veins
• acetylation is major route of inactivation

SE: headache, palpitations, tachycardia, dizziness, edema, and lupus-like syndrome

• orally active vasodilator
• used in chronic tx of refractory HTN
• dilates mainly arterioles
• opens ATP-sensitive potassium channels in vascular SM
• long lasting

SE: tachycardia, edema, hair growth

• Parenteral vasodilator
• Used to treat hypertensive emergencies -BP rarely falls below normal
• Dilates mainly aterioles by opening ATP-sensitive potassium channels in vascular smooth muscle
• Highly bound to plasma proteins - must be given by IV bolus

SE: reflex tachycardia, hyperglycemia, edema

Parenteral vasodilator given by IV infusion - must monitor blood pressure - can cause hypotension

Tx: hypertensive emergencies

Dilates arteries AND veins - CO decreases, venous pooling occurs

Metabolized to nitric oxide - acts by increasing cyclic GMP in vascular smooth muscle

short T1/2

SE: headache, methemoglobinemia, palpitations

Metabolized to cyanide and thiocynate - can accumulate with prolonged therapy and excreted slowly

sympatholytic drugs

irreversible atagonist of alpha 1 and alpha 2 receptors - long duration of action

orally active inhibitor used in hypertension that is refractory to conventional therapy and in pheochromocytoma  

SE: many - postural hypotension, nasal stifness, inhibition of ejaculation

competitive REVERSIBLE alpha antagonists

short acting

orally active used in hypertension that is refractory to conventional therapy in pheochromocytoma - used parenterally to treat sympathetic excess

SE: postural hypotension, gastrointestinal stimulation, inhibition of ejaculation

competitive, reversible alpha1 antagonist

treat chronic hypertension

first dose effect - extreme hypotension w/ initial dose

reflex tachycardia - less than alpha1/2 antagonists

no inhibition of sexual function

SE: headache, drowsiness

competitive inhibitor of alpha1 and beta1/2 receptors.

orally active to treat chronic essential hypertension

may be used IV for HTN emergencies

reduces CO and peripheral resistance

SE: mild orthostatic hypotension, headaches

competitive inhibitor of alpha1 and beta1/2 receptors

orally active to treat chronic essential HTN

may be used IV for HTN emergencies

reduces CO and peripheral resistance

SE: mild orthostatic hypotension, headaches

neuronal blocking sympatholytic drug

inhibits norepi release and depletes neuronal amine stores

orally active to treat severe HTN

polar compound - does not enter CNS

long acting

must enter neuron by amine pump to be effective; effect inhibited by tricyclic antidepressants

SE: numerous, limit use - orthostatic hypotension, interferes w/ sexual fxn, diarrhea, muscle weakness, edema

neuronal blocking sympatholytic drug

inhibits norepi release and depletes neuronal amine stores

orally active to treat severe HTN

long acting

must enter neuron by amine pump to be effective; effect inhibited by tricyclic antidepressants

SE: numerous, limit use - orthostatic hypotension, interferes w/ sexual fxn, diarrhea, muscle weakness, edema

depletes neuronal amine stores

orally active compound used to treat essential HTN in combo w/ other drugs.  rarely used.

enters CNS, long acting, slow onset

SE: sedation, diarrhea, orthostatic hypotension, increased gastric acid secretion

ganglionic blocking drug - blocks action of ACTH at autonomic ganglia - blockage of sympathetic ganglia produces hypotension

blockage of parasympathetic ganglia produces: dry mouth, constipation, urinary retention, inhibition of sexual function, blurred vision

rarely used b/c of erratic absorption

used to produce controlled hypotension during surgery for dissecting aneurysm

centrally acting agent - reduces BP by reducing sympathetic tone on blood veessels

must be metabolized in CNS

• alpha2 adrenergic agonist - reduces sympathetic outflow
• alpha-methyl group prevents metabolism by MAO and prolongs action

decrease peripheral resistance, heart rate, and CO

SE: sedation, flu-like syndrome, positive Coomb's test, edema, rebound hypertension w/ sudden discontinuation

alpha2 agonist that directly stimulates central alpha adrenergic receptors to reduce sympathetic outflow

• causes prolonged blood pressure lowering
• decreases HR and CO
• long acting
• rebound hypertension occurs w/ withdrawl
• SE: sedation, dry mouth, edema

alpha2-adrenergic agonist which directly stimulates central alpha2 adrenergic receptors to reduce sympathetic outflow

reduces peripheral resistance and produces a sustained reduction in blood pressure

HR decreases slightly

• hypertension occurs w/ sudden withdrawl
• SE: sedation, dry mouth, headache

• Beta blocker
• reduces renin release
• decreased HR to reduce CO
• inhibition of norepi release from central/peripheral neurons
• more effective in lowering blood pressure in young vs. old patients
• effect enhanced by diuretic

SE: cardiac depression, increase airway resistance, mask symptoms of hypoglycemia, sedation, impotence, nightmare

suse w/ cautions in patients w/ asthma, CHF, peripheral vascular disease.  

useful in patients w/ angina pectoris.

w/drawl syndrome - supersensitivity to beta stimulation may cause angina, arrhythmias, or infarction

Only cardiac glycoside available in US

• In patients w/ heart failure:
• Direct Effects:
• 1) Positive inotropic effect of failing heart d/t direct effect to increase contractile state of myocardium and increasing CO

2) Increases vagal tone (slows heart rate)

• Secondary effects d/t reduced neuroendocrine activation:
• Decreased herat rate
• Arterial and venous dilation
• Decreased venous pressure
• Normalized arterial baroreceptors

• Molecular site of action:
• Inhibition of Na/K ATPase in cardiomyocytes, indirectly results in increased intracellular concentration of Ca.  K+ competes for binding of digoxin to the Na/K ATPase.

• Electrophysiological Actions:
• Increased vagal nerve activity (decreased HR, conduction velocity in AV node, increased refractory period in AV node, heart block can sometimes develop)

ECG: increased PR interval

Kinetics: T1/2 = 36-48 hrs, orally absorbed, excreted unchanged in kidney

Adverse effects/toxicity: Low therapeutic index. GI most common (anorexia, nausea, vom., diarrhea), visual disturbances, neurological (hallucination/disorientation), muscular(weakness, fatigue), cardiac (arrhthmia).  Toxicity enhanced with hypokalemia.

dilate venous vasculature better than arterial

decreases preload via NO production

rapidly dissolvable tablet or aerosol spray both for sublingual administration

fast onset (few mins) and short duration (15-30 mins)

• acute episodes of angina and chronic tx of typical stable angina
• can also be used in acute heart failure
• available for IV administration
• used in tx of left ventricular dysfunction due to acute infarction

side effects: hypotension, orthostatic hypotension, tachycardia, throbbing headaches

tolerance develops for a few hrs, but rapidly reverses

don't give in combo w/ PDE inhibitor = hypotension

inactivated by high capacity organic nitrate reductase in liver

oral nitrovasodilator (much greater effect on venous blood vessels)

used in combination with hydralazine

• prolong life and is particularly effective in AAs
• used for acute episodes of angina and chronix tx of typical stable angina

also used for chornic therapy - long duration of action compared to nitroglycerine

extensive first pass metabolism

more expensive than nitroglycerin

no significant advantage over nitroglycerin

side effects: hypotension, orthostatic hypotension, tachycardia, throbbing headaches

tolerance develops for a few hrs, but rapidly reverses

does not undergo 1st pass metabolism

T1/2= 5 hours

used to treat acute and chronic angina

direct NO donor that dilates both arteries and veins by increasing cGMP levels in vascular SM

can be used in acute heart failure

beta adrenergic agonist

dose-dependent sympathomimetic

limited utility because vasoconstriction can lead to afterload and worsening of performance

sometimes use at low dose to increase RBF to help maintain GFR

overall affect of racemic mixture = beta agonist

agent of choice in management of severe dysfunction (doesn't increase systemic vascular resistance the way dopamine can)

increases stroke volume and increases inotropy

little effect on heart rate

tolerance develops in 4 days

used for acute heart failure

phosphodiesterase inhibitor

decreases cAMP degradation resulting in elevated cAMP in cardiac and smooth muscle

positive inotropif effect

balanced arterial and venous dilator (decrease preload and afterload)

combined effects produce a substantial increase in CO

available IV for short-term circulatory support

major adverse reactions: arrhythmias

recombinant form of the B-type natriuretic peptide normally produced by ventricles in response to stretch

counter regulates the effects of renin-angiotensin-aldosterone system

vasodilation

increases sodium excretion

net effect = decrease blood volume, BP, afterload; increases CO


used for acute decompensated heart failure mainly for reducing dyspnea

blocks specific sodium current during ischemia, results in decrease in calcium overload during ischemia

sustained release prep

used in combo w/ other agents

no hemodynamic effects

only use in effort angina patients unresponsive to standard therapy

Antiarrhythmic drug

Inhibitors of depolarization

Class I antiarrhythmic agents - Na channel blockers

Moderate phase 0 depression and slowed conductino (2+) - prolong repolarization

• Increase AP threshold
• Decrease Vmax
• Increase ERP

Indirect effects: blocks K+ channels --> early after depolarizations, vagolytic effect (unwanted)

Inhibits P450 system (metabolism of narcotics is reduced)

Proarrhthmic - not necessarily related to the arrhythmia being treated

Metabolized in liver; tolerated in patients with renal failure

Use: Atrial flutter or fibrillation, prevent ventricular tachycardia and fibrillation

Side FX: diarrhea, cramps, vagolytic (digitalize first)

Class I antiarrhythmic drug - Na channel blocker

Moderate phase 0 depression and slowed conduction (2+); prolong repolarization

Class IB antiarrhthmic drug - Na channel blocker

Minimal phase 0 depression and slow conduction (0-1+); shorten repolarization

• Increase AP threshold
• Block Na channels (decrease Vmax) at high HR and in depolarized cells (can target diseased ischemic cells)
• Decreases AP during and ERP

• Side Fx: Dizziness, seizures
• Use: ventricular tachycardia
• Digitalis- induced arrhythmias
• Safe for patients long QT syndrome

Class Ic antiarrythmic

Marked phase 0 depression and slow conduction (4+); little effect on repolarization

• Increase AP threshold
• Decrease Vmax (conduction velocity)

Side Fx: pro-arrhythmic (CAST trial) (more so than treating the arrhythmia)

Use: approved for use in life-threatening situations when supraventricular and ventricular arrhythmias are resistant to toher drugs

Class III Potassium channel blocker

prolongs repolarization (AP duration increases)

Main common effect is increased ERP.

• Potent K channel blocker
• Modest Na channel blocker
• Modest Ca channel blocker
• Modest alpha/beta adrenergic receptor blocker

Uses: effective against ventricular tachyarrhythmias and fibrillation.  Also used in the prevention of recurrent paroyxsmal atrial fibrillation or flutter.

Side Fx: triggered arrhythmias, altered thyroid function, pulmonary fibrosis(irreversible)

Class III Potassium channel blocker

prolongs repolarization

also has secondary beta receptor blocking actions

Side Fx: triggered arrhythmias

structurally similiar to HMG CoA substrate

Reversible inhibitor for active site in INITIAL RATE LIMITING STEP IN CHOLESTEROL BIOSYNTHESIS

• HMG CoA Reductase inhibitor
• isolated from mold

USE: first line therapy for those w/ increased risk of MI d/t hypercholesterolinemia

Mechanism: reduced cholesterol increases LDL receptor gene

• Administered as inactive lactone
• T1/2 = 1-4 hrs

Extensive first pass metabolism - CYP3A4

• Drugs that increase statin serum concentrations:
• Antifungal
• Macrolide antibiotics
• Grapefruit juice

SE: GI symptoms, myopathy, rhabdomyolysis, hepatoxicity

Greater risk factors when taken with gemfibrozil

Contraindications: hypersensitivity, active liver disease, WOMEN WHO ARE PREGNANT OR LACTATING

• HMG CoA Reductase inhibitor
• Administered as inactive lactone
• T1/2 = 12 hrs

Use: 1st line therapy for those w/ increased risk of MI d/t hypercholesterolinemia

CYP3A4

SE:L GI symptoms, hepatoxicity, myopathy, rhabdomyolysis

• W/ niacin = increased risk for myopathy in chinese
• Greater risk factors when taken w/ gemibrozil

• triglyceride lowering agents
• effects mediated by PPARs
• increase lipolysis and plasma clearance of TG rich lioproteins

Tx: patients w/ high TGs

example: gemfibrozil

• Peroxisome proliferator activated receptors
• Regulate gene expression to increase lipolysis and plasma clearance of TG rich lipoproteins

fibric acid/PPAR activator used to lower TGs

• use: metabolic syndrome, hypertriglyceridemia, avoid in patients w/ elevated LDL w/out elevated TGs
• inhibits uptake of active hydroxy acid forms of statins by transporter

first-pass hepatic uptake of these statins by transporter after their oral administration

activated PPAR-alpha 

• decrease VLDL production
• increase VLDL clearance
• decrease LDL particles
• increase HDL production

combination therapy: w/ statins increased myopathy and increased creatine kinase--> renal failure

• Bile acid binding resin
• Anion exchange resins that exchange Cl for bile salts in small intestine, increasing bile excretion in feces
• Less bile = increased cholesterol breakdown d/t feedback inhibitor
• Lower plasma LDL-cholester --> more LDL receptors

SE: constipation/bloating sension, gritty consistency, interferes w/ absorption of other drugs, modest increase in TG/with time returns to baseline

• Use:
• hypertriglyceridemias and elevated LDL-cholesterol (particularly in patients w/ low HDL and high LDL)
• severe hypercholesterolemias that do not respond to resin therapy
• only lipid-lowering drug that reduces Lp(a) levels

• Mechanism: not related to vitamin effects
• adipose tissue: decreases TG synthesis
• liver: decreases synthesis rate of VLDL-TG
• inhibits uptake of HDL-apoA1 - less removal from plasma

SE: intense cutaneous flush and pruitus, GI, abnormal liver function tests, uricemia, increase fasting glucose levels

Contraindicated: patients w/ peptic ulcer, gout, hepatic dysfunction, diabetes

Combined w/ statin = myopathy (especially in Chinese)

cholesterol absorption inhibitor

• uses: primary hypercholesterolemia  for patients resistant to statin therapy
• - combined with statins - simvastatin + ezetimibe - further decrease in LDL-cholesterol

• mechanism:
• protein transporter called NPC1L1
• reduced cholesterol flux from intestine to liver

• oral administration
• metabolized to active 

SE: well tolderated

Unfractionated, high MW

• Uses: 
• deep vein thrombosis
• pulmonar embolism
• unstable angina/acute MI
• surgery requiring cardiopulmonary bypass
• during/after coronary angioplasty or stent placement
• low dose used prophylactically to prevent DVT and thromboembolism

Mechanism: Catalyzes antithrombin III which inhibits coagulation proteases - catalyzes inhibition of thrombin and Xa (DOES NOT AFFECT SYNTHESIS OF CLOTTING FACTORS OR LYSE EXISTING CLOT)

• Not absorbed orally - IV infusion or subQ
• Cleared/degraded by reticuloendothelial system and liver
• Does not cross placenta - yay pregnancy!
• monitor aPTT (clotting time 1.5 to 2.5 times the normal mean aPTT is therapeutic)

SE: bleeding/hemorrhage, thrombocytopenia (decreased platelet count)

Contraindications: active bleeding, severe uncontrolled HTN, recent surgery of eye, brain, spinal cord

fragments of standard-molecular weight heparin

Enoxaparin/Dalteparin

Inhibitor of Factor X, accelerates activity of ATIII poorly catalyze inhibition of thrombin

• longer half life than standard heparin
• decreased risk of hemorrhage
• theoretically less risk of thrombocytopenia
• administered subQ

Use: acute DVT, prophlaxis of DVT, hip replacement surgery, during and following hospitalization, acute unstable angina and MI

more predictable anti-coagulant response than unfractionated heparin

low molecular weight heparin

administered sub q

Use: acute DVT, prophlaxis of DVT, hip replacement surgery, during and following hospitalization, acute unstable angina and MI

longer T1/2 than heparin

more selectively for activated factor X than thrombin

Low molecular weight heparin

• administered subq
• longer half-life than heparin

Use: acute DVT, prophlaxis of DVT, hip replacement surgery, during and following hospitalization, acute unstable angina and MI

Direct thrombin inhibitor

IV administration

Inactivates thrombin by blocking the substrate binding site in a 1:1 complex

Derived from the leech

Use: alternative to heparin in patients who have heparin induced thrombocytopenia

SE: hemorrhage

Heparin antagonist

Low MW, + charged

SE : weak anticoagulant properties in high doses, analphylactic reaction, severe pulmonary hypertension

USE: used for heparin overdose with acute bleeding that can't be controlled by stopping heparin - reverse heparin following cardiopulmonary bypass

• Fat soluble, structural analog of Vit. K 
• Highly bound to plasma proteins

Use: long-term venous thromboembolic disease, prophylaxis against thromboembolism in atrial filbrillation, prosthetic heart valves, dilated cardiomyopathy)

Oral administration

• Mechanism:
• 3 types of warfarin - racemic (administered), S (more active), and R
• Vitamin K antagonist
• **inhibits vitamin K epoxide reductase, not allowing Vit. K to be recycled and used to form clotting factors

therapeutic effect not seen for several hrs to days - delayed because active clotting factors are not degraded by warfarin

• Measure therapeutic effect via prothrombin time(PT btwn 15-26 secs) or INR (btwn 2-3)
• Inactivated by liver microsomes - CYP2C9

SE: hemorrhage, purple toe syndrome, skin necrosis/gangre

Contraindications: pregnancy, liver or kidney disease, CYP2C9 polymorphism, genetic variations in VKOR, Vit. K deficiency

Reversal: transfusion with fresh frozen plasma, vit. k would have a time delay before you would see effectiveness

• Drug interactions are common
• Interactions w/ food (increase INR: cranberries, alcohol, Vit. E) (decrease INR: green vegetables, green tea, soy beans, vit. k supplements)

Orally active reversible direct thrombin inhibitor

• Use: 
• long-term tx of venous thromboembolic disease
• prophylaxis against thromboembolism in a fib., prosthetic heart valves, & dilated cardiomyopathy

• Mechanism:
• Prodrug 
• reversible direct inhibitor of clot-bound and free thrombin - inhibit thrombin's activation of platelets

No monitoring (unlike warfarin) - little efect on PT or INR

• More predictable than warfarin 
• Rapid onset of action (don't have to wait to block synthesis of new clotting factors, directly inhibits active clotting factor)

Not substrate of CYP450

SE: increased risk of bleeding (less than warfarin), GI upset (more than warfarin)

Drug Interactions: substrate for P-gp efflux transporter - other drugs can increase elimination of drug, and also drugs that inhibit transporter to increase plasma concentration

orally active reversible Xa inhibitor - inhibits free and thrombus-associated factor Xa

Use: reducing risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation & prophylaxis of DVT in patients undergoing knee or hip replacement surgery

No monitoring required

SE: bleeding, interactions with CYP3A4 and Pglycoprotein inhibitors

endogenous activator that converts plasminogen to plasmin, synthesized by vascular endothelial cells and released at local sites of thrombosis

early stage of clot formation: little released b/c of plasminogen activator inhibitors (PAI-1 and PAI-2)

later: production increases to allow breakdown of clot and recanalization of injured vessel

Uses: acute MI, pulmonary embolism/DVT, stroke (w/in first 3 hrs)

contraindications: active bleedingrecent surgery (w/in 10 days)GI bleedingrecent CVA, intracranial surgery/mass/aneurysmknown hemorrhagic disorderknown hypersensitivitysevere, uncontrolled hypertensionrecent streptokinase therapypregnancy/postpartum period

• Exogenous plasmin activator
• Also called t-PA

Uses: acute MI, pulmonary embolism/DVT, stroke (w/in first 3 hrs)

• poor enzyme in absence of fibrin
• activates fibrin-bound plasminogen 100x more rapidly than free plasminogen

• rapid hepatic clearance (T1/2=1-4 mins)
• IV

• contraindications: 
• active bleeding
• recent surgery (w/in 10 days)
• GI bleeding
• recent CVA, intracranial surgery/mass/aneurysm
• known hemorrhagic disorder
• known hypersensitivity
• severe, uncontrolled hypertension
• recent streptokinase therapy
• pregnancy/postpartum period

Potent inhibitor of fibrinolysis

binds to lysine binding sides on plasminogen and plasmin thus blocking the binding of plasmin to fibrin

reverse states associated with excessive breakdown of fibrin

effect in decreasing hemorrhage with surgical procedures

useful for tx urinary tract bleeding (concentration in urine 100x > plasma)

glycoprotein IIb/IIIa receptor blocker

• Use: 
• prevention of cardiac ischemic complications during coronary intervention
• unstable angina not responding to conventional therapy
• intended to be used with aspirin and heparin

• mechanism:
• binds intact platelet GPIIb/IIIa receptor to inhibit platelet aggregation by preventing binding of fibrinogen, VW factor, adhesive molecules

steric hinderance

• SE:
• bleeding
• thrombocytopenia

vasodilator and inhibitor of platelet aggregation

use: primary orphylaxis of thromboemboli in patients w/ prosthetic heart valves (in combo w/ warfarin), in combo w/ aspirin for secondary prevention of MI or TIA

• inhibition of phosphodiesterase - increases cAMP,
• inhibits adenosine uptake

oral administration

SE: headache, GI upset, dizziness

• Use:
• secondary prevention of cerebrovascular disease
• myocardial infarction
• unstable angina
• coronary artery stenting
• peripheral vascular disease
• patietns w/ transient ischemic attacks; completed strokes

• Mechanim:
• act through P2Y₁/P2Y₁₂ receptors to inhibit ADP-induced platelet aggregation, decreasing levels of cAMP

prlongs bleeding time, inhibits platelet aggregation, delays clot retraction

• SE:
• serious blood dyscrasias
• neutropenia

• Use:
• Myocardial infarction prophylaxis
• Stroke prophylaxis
• unstable angina
• coronary artery stenting

Mechanism: act through P2y1/P2Y12 receptors to inhibit ADP-induced platelet aggregation, decreasing levels of cAMP

prlongs bleeding time, inhibits platelet aggregation, delays clot retraction

METABOLIZED BY CYP2C19

SE: CYP2C19 polymorphism, 

Drug Interaction: patients take it w/ aspirin and have GI irritation - prescribe PPI (omeprazole) metabolized by CYP2C19 so has less therapeutic effect

• b2 adrenoceptor agonist - bronchodilator
• long acting b/c of lipophilic tail binds to exoreceptor in vicity of adrenoreceptor - gets anchored into cell membrane

• relaxes airway smooth muscle
• stimulates mucociliary transport
• activate G protein --> cAMP
• receptors undergo desensitization - decreased effectiveness

toxicity: overrealiance, arrhythmias, don't use for HTN

short acting b2 adrenoceptor agonist - bronchodilator

• elaxes airway smooth muscle
• stimulates mucociliary transport
• activate G protein --> cAMP
• receptors undergo desensitization - decreased effectiveness
• toxicity: overrealiance, arrhythmias, don't use for HTN

importance as therapeutic agent is waning b/c effectiveness of B2 and anti-inflammatories

relaxes airway smooth muscle

• phosphodiesterase inhibition
• adenosine antagonist

narrow therapeutic window d/t stimulant effects on CNS and CV system (convulsions)

anticholinergic - bronchodilator

• quaternary ammonium derivative of atropine
• allows high dose to airway
• poorly absorbed, limiting access to CNS

• relaxes airway smooth muscle
• decreases mucus secretion
• may not be as effective b/c no sympathetic effects

long acting anticholinergic bronchodilator

• relaxes airway smooth muscle
• decreases mucus secretion
• may not be as effective b/c no sympathetic effects

glucocorticosteroid

most effective and most often prescribed anti-inflammatory drug for treatment of chronic inflammation underlying asthma

often used as first drug in newly diagnosed asthma

chronic use: reduces airway smooth muscle hyperreactivity that is caused by inflammation

used to treat inflammatory components of asthma by inhibiting leukotriene production of inflammatory mediators including PGs, leukotrienes, cytokines

permissive effect on response to beta agonists

mechanism: binding to glucocorticodsteroid receptors in cytosol, translocation of receptor-drug complex to nucleus where it binds to transcription factors leading to: increased transcription of lipocortin-1, inhibitor of phospholipase A2, decreased transcription for other inflammatory mediators, increased transcription of B2 receptor protein

kinetics: not effective in acute attcks, used chronically

SE: oropharyngeal candidiasis, hoarseness

antibiotic treatment for chronic pulmonary obstructive disease and cystic fibrosis

treats acute exacerbations, acute bronchitis, and prophylaxis to prevent bronchitis

for cystic fibrosis

reduces sputum viscosity by cleaving extracellular DNA that has been released from infiltrating neutrophils that accumulate in sputum