Pharm 1

what the body does to the drug: ADME

• what the drug does to the body
• -interactios, pt's functional state, placebo effects

• channels/pores: passive
• direct diffusion
• transport systems: active, energy dependent, ie P glycoprotein

movement from site of administration to bloodstream

• molecular weight
• lipid solubility
• ionization
• blood flow

• non ionized drugs pass through membranes easier
• -weak acids in acidic environment get absorbed, then ionize in neutral blood and stay there
• -make urine basic to excrete acids

pH at which drug will be in equilibrium b/w ionized and non-ionized

bypass barriers to absorption, introduced directly to systemc circulation

avoid 1st pass metabolism, but still subject to blood flow to site, oils can prolong absorption

• good to use if can't take PO (vomitting), but inconsistent absorption. 
• 50% bypasses liver, but some still has 1st pass

• requires highly lipophilic drug
• slow delivery to site of action
• no 1st pass
• no harsh GI environment

high blood flow areas (heart, liver, kidneys, brain) get drug 1st; bones/fat/skin are 2nd

lipid solubility and size still apply for exiting bloodstream to tissue/cells

• drugs that are highly protein bound (albumin) stay in vasculature
• - ie warfarin, NSAIDs, dilantin, benadryl
• only free drug can interact with receptors to enter cells

pts with decreased albumin may have larger response to these meds r/t higher free drug

hard for drugs to get into CNS r/t tight junctions of cells lining capillaries 

1) oxidation/reduction: done by enzymes, ie CYP

2) conjugation/hydrolysis: hydrolyze a drug to a large polar molecule to inactivate it or enhance excretion (make it water soluble)

• -changes fat soluble item to water soluble
• -comprised of multiple proteins
• -present in almost all body tissues, but liver and gut have the most

CYP3A is most common (50%)

drug with higher affinity gets metabolized, so the other one will build up

expression and activity of CYP in increased --> more rapid metabolism of substrates --> lower concentrations and effects

• drugs and dietary substances increase concentration of substrates
• -ie grapefruit

urine, bile, sweat, saliva, breast milk, lungs, and KIDNEYS

• move drugs from blood to urine
• depends on size of drug, GFR, and protein binding (protein bound stay in blood)

• passive
• most drugs here
• lipid soluble stay in blood, water soluble and ionized get excreted

• relationship b/w pharmacologic effect of the drug and the concentration of the drug in the body
• -clearance, volume of distribution, bioavailability, elimination half life

• comparing [x] in blood to rest of body/site of action. 
• large VD means well distributed (very little remains in blood), small VD means held in blood stream

• *theoretical* volume of blood that is completely cleared of a drug in a given period of time
• -vol per unit time
• NOT an indicator of how much drug is removed

• fraction of the administered dose that reaches systemic circulation
• -mostly for oral. IV would be 100%

• time required for serum plasma [x] to decrease by 1/2
• usually 5 half lives until drug reaches steady level

• receptors used by drugs are normal point of control of physiologic processes
• - normally regulated by molecules supplied by the body
• -drug doesn't give body new function, just mimic or block action of body's own regulatory molecules

usually temporary/irreversible, but there are some irreversible

reversible

irreversible

• PD of a drug can be quantified by the relationship b/w the [x] of the drug and the pt's response.
• -generally inc. dose --> inc response
• -only up to a maximum effect; further drug will not cause more response b/c receptor is saturated
• -can still --> more SE though

• lethal dose of a drug from 50% of population divided by minimum effective dose for 50% of pop.
• -wider index is safer
• -need to get serum levels of drugs w/ narrow index (warfarin, dilantin, digoxin)

influence of genetic variation on drug response by correlating gene expression or single nucleotide polymorphisms with a drugs efficacy/toxicity 

• PM: poor metabolizer
• IM: intermediate metabolizer
• EM: extensive metabolizer
• UM: ultrametabolizer

1906: prohibited manufacture of adulterated/misbranded/poisonous food,drugs, meds, liquor

• 1938: created FDA
• apprroval of drugs based on safety
• which drugs need an rx

1962: required safety and efficacy of drugs before approval

• human and animal drugs, biomedical devices, food, cosmetics, radiation products
• NOT herbals

• 1970: manufacturers, distributors, and dispensers of controlled substances need to register with DEA annualy
• 5 classes

discovered penicillin in 1928 by staph growing in halo on mold

• new chemical entities
• may lead to drug discovery

• new drug application
• -safety
• -efficacy
• -benefits>risks
• -labeling
• -manufacturing adequate to preserve strength/quality/purity

abbreviated new drug application

investigational new drug

in vivo (lab) or in vitro (animals)

• exploratory and IND
• apply to FDA to see if clinical trials should proceed

• fisrt human testing, small groups of healthy volunteers (20-100) 
• assess PK, PD, safety, tolerability

• larger groups of actual patients (300-3000)
• see how well drug works

• randomized, multicenter
• definitive assessment of efficacy of drug
• compared to current DOC, then apply for NDA

post-marketing surveillance, safety, ADRs

accelerated development and approval for serious and life threatening diseases

• disease that affects <200,000 ppl in US
• exclusive approval for this indication for 7 yrs post approval

• high abuse potential- no accepted medical use or lack of safety for use
• heroin, MDMA, psilocybin, LSD, pot?

• high potential for abuse, have accepted medical use
• -cocaine, opium, methadone, oxycodone, PCP, hydromorphone 

• less abuse potential than 1/2
• anabolic steroids, ketamine, marinol

• low potential for abuse
• benzos, ambien, phenobarb

• low abuse potential
• cough suppressant with low codeine, lyrica
• may be available OTC in some states

• A: capacity to cause error
• B: error occured, didn't reach pt
• C: reached pt, no harm
• D: reached pt, required monitoring to ensure no harm
• E: likely caused temporary harm, needing intervention
• F: required hospitalization
• G: likely caused permanent harm
• H: required intervention to sustain life
• I: likely contributed to pt death

• adequate studies showed no harm
• -folic acid/B6/synthroid

• no adequate human studies (animal studies showed no harm) OR animal studies showed adverse effect, but human studies haven't shown any risk
• tylenol, prednisone, insulin, amox, zyrtec, claritin

• animal studies showed adverse effect and no studies in humans OR no animal or human studies
• antidepressants, diflucan, cipro, compazine

• adequate human studies showed risk to fetus
• benefits of therapy may outweigh risks if needed and no safer alternative
• lithium, dilantin, valproic acid, ACEi, chemo, tetracyclines, caramazepine

• adequate studies showed fetal anomalies or risks
• cytotec, accutane

category c- dont use late in pregnancy r/t premature closure of DA

• category D- high risk in 1st tri
• long half life
• should avoid pregnancy for 12 wks after d/c

• category c
• no well controlled studies in humans, but --> cleft palates in rats.
• interferses w/ folic acid metabolism

• involuntary function: cardiac muscle, smooth muscle, secretory glands
• 2 neuron linkage: pre and post ganglionic, second one is outside CNS

• ADRENERGIC
• fight/flight
• neurons in thoracolumbar

• CHOLINERGIC
• rest/digest
• craniosacro neurons

acetylcholine (ACh)for sym and parasym

• ACh for para
• Norepi or ACh for sym (epi secreted from adrenal medulla also part of sympathetic)

• stimulated by ACh
• Nicotinic and Muscarinic

• sympathetic
• stimulated by epi or norepi
• Alpha1 Alpha 2 Beta1 Beta2 dopamine

NN: nicotinic neuronal- stimulate postganglionic neurons of PSNS and SNS, stimulate adrenal medula to --> Epi/norepi

NM: nicotinic muscular: at neuromuscular junction --> contraction of skeletal muscle

• end organs of PSNS
• sweat glands innervated by SNS

• vasoconstrict
• ejaculation
• contract bladder neck/prostate
• sensitive to: epi, norepi, dopamine

• presynaptic junction: broader effect
• minimal clinical significance
• sensitive to: epi, norepi

• heart: increases heart rate, force of contraction, velocity of AV conduction
• kidneys: renin release
• sensitive to: epi, norepi, dopamine

• bronchial dilation
• uterine relaxation
• vasodilation
• glycogenolysis
• liver, pancreas
• sensistive to: epi only

• dilate renal blood vessels
• sensitive to: dopamine only

alpha1/2 beta1/2

alpha1/2, beta1

alpha1, beta1, dopamine

• secrete: Ach
• receptor: nicotinic (cholinergic)

• secrete: norepi
• receptor: adrenergic (alpha,beta, dopa)

• secrete: ACh
• receptor: cholinergic (N and M)

• secrete: ACh
• receptor: cholinergic (N and M)

• antigen binds to IgE mast cell --> mediators (histamines/leukotrienes) 
• inflammation
• bronchoconstriction
• airway edema
• airway hyperresponsiveness: exaggerated bronchoconstrictor response to stimuli
• airway remodeling: inflammation, mucus hypersecretion, subepithelial fibrosis, smooth muscle hypertrophy, angiogenesis

• airway obstruction that is NOT reversible
• dyspnea that is progressive. 
• usually worse w/ exercise
• persistent
• DONT respond to anti-inflammatories : b/c main mediator is neutrophil which is steroid resistant --> steroids manage acute symptoms but not disease progression (bronchodilate but don't help w/ inflammation)

• most effective bronchodilators
• MOA: B2 selective increase cAMP --> dilate bronchioles
• use: in ACUTE bronchospasm, should not use regularly
• caution: CV disease r/t vasodilation, pregnancy, lactation, digoxin
• SE: hypokalemia, tachycardia, vasodilation, hyperglcemia, tremors
• administration: inhalers --> direct administration lung, usually stays there

• salmeterol, fomoterol
• onset 10-15 min
• duration 12 hr
• shouldn't be used as monotherapy: can cause B receptor downregulation r/t desensitizing, use w/ ICS which up regulates B receptors
• use: BID dosing, not for acute symptoms
• black box: can inc. asthma related deaths, only used for additional therapy for pts not controlled on other meds

• albuterol, levalbuterol (may have fewer SE)
• onset 5-15 min
• duration 4-6 hr

• theophylline, caffeine- not used much now
• MOA: bonchodilation through inhibition of phsphodiesterase --> inc cAMP
• -inhibit pulmonary edema, decrease vascular permeability, enhance mucus clearance, improve diaphragmatic contractility
• SE: Gi, CNS, CV; narrow therapeutic window, OD can cause seizure or arryhthmias
• interactions: 90% liver CYP450 metabolism

• ipatropium bromide(short acting), tiotropium(long acting), combivent (ipatropium +albuterol)
• MOA: blocks muscarinic receptors by anatagonizing ACh --> bronchodilation
• use: only approved for COPD, used in asthma too. NOT for acute
• CI: soy/peanut allergy 
• caution: urinary retention, bladder obstruction, BPH

• SLUD: salivation, lacrimation, urination, defecation
• hot hare
• mad hatter
• red beet
• dry bone
• blind bat

• budesonide, fluticasone (pulmicort/flovent)
• MOA: beta receptor upregulation --> bronchodilation, dec. mucus, prevent/reverse airway remodeling, dec. capillary permeability, inhibit leukotriene
• *improve asthma more effectively than any other long term med*
• max effect: 4-8 wks
• use: not for acute, use intranasal for allergic rhinitis
• ADR: generally not systemic- hoarse, altered taste, thrush, throat irritation, impaired growth in peds (early in tx, dose related, not progressive)
• if give iv/po --> fluid retention, muscle weakness, ulcers, malaise, impaired wound healing, N/V, HA, osteoporosis, cataracts, glaucoma, hyperglycemia

• mast cell stabilizer
• MOA: inhibits histamine release
• inhaled from capsule- peak effect in 1wk
• use: if not tolerating other meds for asthma, allergic rhinitis. NOT for acute
• caution: seafood allergy
• AE: swollen eyes, HA, dry mucosa, bitter taste, bronchospasm (can preadminister Bagonist), cough, throat irritation

• antileukotriene/lipoxygenase inhibitor
• blocks the enzyme that --> leukotrienes

• *newer* 
• zarfirlukast, mentelukast (singulair/accolate)
• leukotrienes --> mucus, bronchoconstriction, edema, and eosinophils
• MOA: improve lung fn, decrease need of short acting, preven exacerbations
• use: long term use in asthma, esp. peds
• modest efficacy in allergic rhinitis
• AE: elevated hepatic enzymes, drug interactions, HA, GI upset, churg-strauss syndome (vasculitis)
• caution: liver failure

• recombinant DNA monoclonal antibody
• MOA: binds to IgE to dec binding to mast cells and basophils --> no inflammation
• use: mod-persistent asthma resistant to other tx b/c $$$ 
• AE: HA, injection site rxn, URI
• black box: anaphylaxis

• intermittent
• 1: SABA
• persistent
• 2: lose dose ICS
• 3: lose doseICS + LABA
• 4: med dose ICS+ LABA
• 5: high dose ICS + LABA, maybe omalizumab
• 6: High dose ICS + laba + oral steroid maybe omalizumab

• uses: allergic rhinitis, conjuctivitis, acute hypersensitivity, urticaria, angioedema, sleep aid, motion sickness
• MOA: inverse agonists: bind and stabilize inactive receptor so stays inactive (when histamine binds, receptor becomes active)
• can be receptor selective ($$) or not (SE).
• *can decrease milk production, paradoxical CNS stimulation can occur in PEDS
• CI: narrow angle glaucoma, lower resp s/s, BPH, bladder obstruction
• caution: urinary retention, increased IOP, hyperthyroid, CV diease, HTN
• AE: CNS, GI, nausea, anticholinergic
• half life can be up to 28 hrs

• mediate effects on smooth muscle leading to vasodilation, increased vascular permeability, contraction of nonvascular smooth muscle
• location: endothelium, brain, smooth muscle

• mediate histamine stimulation of parietal cells of gastric acid secretion, maybe cardia stimulation
• location: mass and cells, gastric mucosa, cardia muscle, brain

• feedback inhibitors in CNS, GI tract, lungs, heart
• location: brain, mesenteric plexus

• non-selective
• benadryl
• lipophilic, small molecule --> cross BBB --> sedation
• affinity for muscarinic receptors --> anticholinergic effects

• peripheral H1 selective
• loratidine, fexofenadine, desloratadine
• large, lipophobic --> no sedation, no anticholinergic effects

• azelastine
• intranasal H1 blocker
• use: seasonal allergic rhinitis, vasomotor rhinitis
• AE: bitter taste, somnolence, HA, weight gain, myalgia, local irritation

• MOA: vasoconstrict by stimulate alpha receptors in respiratory mucosa
• pseudoephedrine, phenylephrine 3-5 days
• oxymetazoline (afrin) 3 days only to prevent rebound congestion
• AE: tachycardia, HTN, anxiety, HA, lightheaded, drowsy, tremor, insomnia
• CI: severe HTN, severe CAD, MAOI use-mimic meth

• MOA: elevate threshold for coughing, anesthetize stretch receptors in resp passages, 
• use: control non productive cough
• dextromethorphan, codeine sulfate, tessalon perles (more peripheral)
• AE: drowsiness, dizzy, nausea, GI, HA, pruritus, constipation
• abused by teens: PCP effect in high doses

• MOA: increase output of respiratory tract by decreasing adhesiveness and surface tension- promotes ciliary action
• --> productive cough
• guaifenesin
• AE: GI, n/v, drowsy, diarrhea, rash, HA

contact activation of the damaged surface with coagulation factors in the blood

damaged tissue reveals tissue factor

• where intrinsic and extrinsic meet, bottleneck --> clot
• prothrombin (II) --> thrombin (IIa), also X-Xa: this is what antithrombin works agains
• Protein C works against V-Va and 8-8a

natural endogenous anticoagulants usually regulate clotting cascade

• coumarin derivative
• works on clotting factos: 2, 7, 9, 10 (vit K dependent)
• quick absorption (1-2 hr), but effect is dependent on depletion of factors, and 2 has long half life (72hr)
• 2 enantemers- both metabolized by CYP450 --> many drug rxn
• amiodarone --> much higher INR, hold next dose of coumadin and reduce by 50%
• antibiotics (cephalosporins, bactrim, avelox, flagyl) --> less activated clotting factor b/c kill flora and alter vit K absorption
• pregnancy: category X
• stop 3-5 days before procedure and bridge with LMWH

• clotting factors require vit K for enzymatic process to convert to active form. 
• Warfarin interrupts the enzyme (epoxide reductase) from reducing vit K
• foods w/ vitK antagonize warfarin, need consistent diet

• narrow therapeutic range, but dose varies by pt from 0.5-30 mg/day
• generally start 5mg/day >65 start 2.5
• need INR to tell effective dose

• not on warfarin: 0.8-1.2
• DVT/AFib/PE: 2-3
• mechanical valve: 2.5-3.5

• elevated INR <6: hold 1-2 dose
• higher INR or bleeding: vitamin K, generally PO but can use IV for pts with absorption issues. SQ/IM not recommended 

• red, purple, green, tan, blue, orange, turquoise,  yellow, white
• (1,2,2.5,3,4,5,6,7,10)

• MOA:activate antithrombin III 
• LMWH is smaller --> greater affinity, need less, but have longer duration
• not absorbable in GI
• antiXa: monitors toxicity (target 0.4-0.7)
• ADR: bleeding, HIT, osteoporosis
• reversible w/ protamine sulfate

• prophylaxis: 5000units TID
• treatment: varies by weight

• low platelets
• interleukins see heparin as foreign body
• much lower risk with lovenox, no risk with fondaparinux

• smaller than lovenox, heparin, with more affinity for antithrombin
• very long acting (3x lovenox)
• in system 3-5 days --> only used outpt
• no reversal!
• C/I: severe renal impairement (CrCl<30), weight <50 for pts with joint replacement surgery
• caution: elderly

• prophylaxis: 2.5mg daily
• treatment: based on weight
• <50: 5mg/day
• 50-100: 7.5 mg/day
• >100: 10mg/day

• Rivaroxaban (Xarelto)/Apixaban (eliquis)
• marketed for prophylaxis in joint replacement, also approved for afib
• directly inhibits Xa
• no reversal

• argatroban(Refludan)/ bilvarudin(angiomax)/ lepirudin (prodaxa)
• competitive inhibitors of thrombin
• monitor aPTT
• weight based dosing

• direct thrombin inhibitor
• also approved for treatment of HIT
• falsely elevates INR 2-3pt, so if transitioning to coumadin, need target INR >4 before d/cing
• IV only

• direct thrombin inhibitor
• approved for afib and hip surgery
• 150mg PO BID
• fixed dose, so no lab testing, but very $$
• -do need dose adjustments in renal impairement
• no reversal- many fatal bleeds
• opening capsule increases bioavailability

• not for pts w severe hepatic disease or GI ulcers
• main se is bleeding, otherwise well tolerated

• arachidonic pathway uses COX to produce TXA2 and PGI2 
• TXA2: vasoconstriction, platelet degranulation
• PGI2: vasodilation, inhibit platelet degranulation
• opposites in balance, but net effect is platelet aggregation

• produced by platelets- induce aggregation and vasoconstriction
• platelets have no nuclei, once inhibited, cant make more

• produced by vascular endothelial cells-inhibit platelet aggregation and promote vasodilation
• endothelial cells have nuclei, can replace inhibited enzyme

• rapid onset, 15 min half life, peak level in 30min, platelet inhibition within hr
• but effect last lifetime of platelet 7-10 days
• low dose: irreversibly inhibit cox 1
• med dose: inhibit cox1 and cox 2, block prostoglandin production
• high dose: anti inflammatory, rarely used b/c of toxicity (tinnitus and GI intolerance)

• class including clopidogrel, ticlopidine, pasugrel- but different metabolism pathways
• inhibit ADP induced platelet aggregation
• prodrugs: converted to active metabolite in-vivo
• MOA: irreversible inhibition of P2Y12 receptor on platelet so ADP cant bind
• Blocks stimulated adenylyl-cyclase activity

• 1st gen thienopyridine
• rapid absorption, peak plasma 1-3 hr.
• halflife: 24-46 hrs, but increases with consisten use X 14 days to 96 hrs
• delayed antithrombotic effect: no protection for 2 wks (use for prevention, not acute)
• C/I: severe hepatic impairment (no renal adjustment needed)
• black box: neutropenia, TTP, aplastic anemia
• pregnancy: B

• 2nd gen thienopyridine
• rapid oral absorption, and permanent inhibition of P2Y12 receptor for life of platelet
• once daily dosing
• pts that are CYP2C19: won't metabolize --> never get active form "fail therapy:
• caution: renal impairment
• use: ACS/MI, recent MI, recent CVA, PAD
• ADR: rash, diarrhea, bleeding, TTP (1st 2 wks), thrombocytopenia, no neutropenia!
• plavix+aspirin: additive effects, good for PCI pts
• Pregnancy: B

• 3rd gen thienopyridine
• load 60mg then 10 mg/day, 5 if <50kg
• caution: hepatic injury, no renal adjustment needed
• better efficacy than plavix, but more bleeding
• black box: bleed risk in elderly
• use: thrombotic CV event
• not for: hx of CVA/TIA, >75yr, <60kg

• vasodilator/antiplatelet with unclear MOA, probably similar to plavix (not used much)
• half life: 10 hr, need BID 
• use: reduce risk of ischemic stroke when combined w/ ASA; no intrinsic antiplatelet activity alone
• ADR: HA, hypotension, bronchospasm, MI, arrhythmias, nausea, dizzy, rash, flishing, paresthesias

• MOA: block glycoprotein IIb/IIIa to prevent platelets from attaching to each other 
• most potent antiplatelet activity b/c don't inactivate, prevent sticking together irrelevant of activation

• dissolves intravascular clots
• tPA released from endothelial cells in response to venous stasis (and other stimuli) to convert plasminogen --> plasmin (active form)
• plasmin is non specific- digests any clot whether protective or thrombotic
• fibrinolytic drugs are also non specific --> high potential for hemorrhage; newer agents are fibrin specific --> less systemic complications

tPA released from endothelial cells in response to venous stasis (and other stimuli) to convert plasminogen --> plasmin

• tPA normally cleared from blood stream rapidly to prevent systemic effects
• also limited by circulating inhibitors (plasminogen activator inhibitor 1,2)

fibrinolytic drugs are also non specific --> high potential for hemorrhage; newer agents are fibrin specific --> less systemic complications

indications: STEMI, PE, thrombosed IV access, catheter directed thrombolysis (LE DVT)

• 1st gen fibrinolytic
• MOA: forms stable complex with plasminogen --> conformational change to allow conversion to plasmin
• no intrinsic enzyme activity
• not fibrin specific
• similar structure to streptococci so can have antibodies against it from prior infection- risk for allergic rxn

• 2nd gen fibrinolytic
• fibrin specific, only converts fibrin bound plasminogen to plasmin
• improved efficacy for ACS
• more $ than streptokinase
• shortest half life of all fibrynolytics 3-8 min

• 2nd gen fibrinolytic
• expensive as alteplase with the SE of streptokinase --> limited use

• 3rd gen fibrinolytic
• deletion mutant of tPA, less fibrin specific, but increased efficacy and similar $, similar risks
• only fibrinolytic with renal metabolism, so best choice in hepatic probs

• 3rd gen fibrinolytic
• recombinant version of tPA, more $, similar efficacy. also fibrin specific

• fat and cholesterol absorbed after a meal --> TG and cholesterol in intestinal cell, packed into chylomicrons
• CMs enter lymph and circulation --> TG hydrolyzed to FFA and glycerol
• removed from circulation by adipose and muscle tissue

• VLDL processed and secreted by liver
• in circulation, hydrolyzed by lipase --> FFA and glycerol
• 50% absorbed by fat/muscle, rest transformed in IDL then LDL, circulate 2-3 days

build up of cholesterol on arterial wall- mainly LDL, some HDL

• 0-1 risk factors
• goal <160 LDL

• 2+ risk factors
• <130 LDL goal
• * most people

• CHD
• <100 LDL goal

• MOA: inhibit HMG-CoA reductase- rate limiting enzyme in biosynthesis of cholesterol in liver
• inhibit endogenous cholesterol
• food decreases absorption for most statins, but increases for lovastatin
• monitor liver f'n 1-2 months monitor CK b/c --> aches r/t muscle breakdown
• ADR: HA, GI, rhabdomyolysis, myalgia
• take before bed
• given after MI
• each agent has different SE

• each has different reduction in LDL, cholesterol, TG and increase in HDL
• Atorvastatin and rotuvastatin are most potent

• Niacin: reduces hepatic synthesis of VLDL by decreasing release of FFA --> less LDL/TG
• also decrease HDL breakdown --> increased levels
• MOA: unsure
• caution: contains yellow dye 5
• ADR: flushing- need to gradually increase dose, take ASA prior to use, avoid hot fluids and take w/ meals

• colestipol, cholestyramine
• MOA: promote increased excretion of bile acid --> liver converts more cholesterol into bile acid --> more uptake of LDL from plasma
• dose: one packet mixed w/ liquid 30 min before during or 30 min after meal
• increase dose gradually
• ADR: severe constipation, flatulence, N/v- need stool softener. reduced folate levels with long term use
• not used much, sometimes adjunct to statin

• gemfibrozil/fenfofibrate (lopid/tricor)
• increase lipolysis of TG, also dec LDL and inc HDL
• *use low dose of fenfo in renal impairment
• ADR: rhabdo (not used w/ statin), minimal GI but do not use w/ gallstone hx

• MOA: inhibits cholesterol absorption across gut border (exogenous)
• combined with statins (vytorin=combo product)
• well tolerated but --> fatty stool

• release of renin from kidney cells in response to  dec renal blood flow/dec. BP/B1 activation
• renin: angioteninogen-->angI (weak vasconstrictor)
• ACE: angI-->ang II (potent vasoconstrictor) AngII: also promotes aldos secretion --> retain Na and H20, but lose K 

vasodilation

vasodilation

vasodilation

• baroreceptors in aortic arch/carotid sinus sense BP- if down, brainstem sends sympathetic impulse to B1 receptors (inc HR) and A1 (vasoconstriction)
• *diuresing pt wont help with this

kidney senses dec BP --> dec GFR --> retain water and Na --> inc BV--> inc CO --> inc BP

also activation of RAAS

• Thiazide are first line, in combo w/ other antihypertensives
• loop and K sparing are not often used for soley treating HTN
• drug interactions: NSAIDs block PG --> block renal blood flow; Lithium (follows ion [x], can end up w/ too much or little); bile acid sequestrants

decrease in systemic vascular resistance- unknown mechanism

• HCTZ
• MOA: inhibit Na reabsorption in distal tubule
• ADR: hypoK, hypovol, hyperuricemia/glycemia/cholesterolemia (bc dec nephron perfusion)
• don't take at night to avoid nocturia
• ineffective CrCl<30 (already not working, can't make it work harder)
• once daily
• mod-low potency

• lasix!
• MOA: inhibit Na reabsorption in ascending loop
• ADR: HypoK, ototoxic in high doses
• most potent of commonly used
• cross sensitivity w/ sulfa allergy
• dont use w/ aminoglycosides r/t ototoxic

• sprinolactone/aldactone
• MOA: antagonize aldosterone secretion in distal tubule, inhibit Na channels on aldosterone sensitive Na pump
• ADR: HyperK, gynecomastia (steroid like structure)
• mild action
• avoid in CrCl<30
• avoid use w/ ACE inhibitors

• MOA: prevent conversion of angI to ang II
• CV effects: dec BP, improve heart O2, downregulate sympathetic adrenergic activity, dec. inappropriate remodeling after MI
• also prevent bradykinin breakdown (a vasodilator)

• ex: ___PRIL (captopril)
• precaution: impaired renal f'n
• CI: renal artery stenosis, angioedema(r/t vasodilation), pregnancy
• ADR:dry cough (bradykinin buildup), angioedema, hyperK (no aldos-->no K loss)
• af am don't respond well; can use w/ diuretic to improve efficacy
• drug interactions: lithium, iron, NSAIDs (rt vasoconstriction from blocked PG --> dec renal blood flow)
• renal protective: good for DM, HF, CKD so often use even if no HTN

• ex: ___sartan (valsartan/diovan)
• only blocks angII type 1, so still get benefits of type2 (vasodilation, tissue repair, inhibition of cell growth)
• CV effects: dilate arteries, dec pre/afterload, down regulate sympathetic andrenergic activity/norepi reuptake (vasoconstriction), promote renal Na/H20 excretion, inhibit remodeling

• ADR: hyperK, orthostatic hypoten- but overall low SE 
• precaution: impaired renal fcn, renal artery stenosis, angioedema (but NOT contraindicated), drugs that raise K
• CI: pregnancy
• often used in combo with w/ thiazide diuretic

• renin inhibitor
• MOA: prevents angiotensinogen to angI
• precautions: angioedema, severe renal impairment
• ADR: hyperK, diarrhea

• CV effects: dec contractility, HR, conduction velocity
• Renal effects: dec renin release --> less vasoconstriction
• vascular effects: block B2 mediated vasodilation, but eventually --> reduced sympathetic outflow and TPR
• hepatic metabolism

• B1 selective blocker: safer for asthma, COPD, PAD
• b/c B2 blocking --> vaso/broncho constriction. 
• lose selectivity in high doses

• precautions: resp conditions, hyperlipidemia, DM (can block signs of hyper/hypoglycemia)
• CI: AV block b/c alters conduction velocity
• ADR: brady, dizzy, dry mouth, dec libido, masked hypoglycemia
• drug interactions: clonidine, OTC cold meds (inc BP/HR, vasconstrict), other antihypertensives
• use in combo w/ diuretic
• nonselective= propranolol

• carvedilol(coreg)/labetalol
• blocks A1, B1/2
• precaution: bronchospasms, hepatic impairment
• ADR: brady, dizzy, dry mouth, dec libido, masked hypoglycemia

• cardua, minipress, flomax(tamulosin)
• MOA: block A1 receptors in vasculature--> dec a/v vasoconstriction, dec PVR
• precaution: volume depletion, HF
• ADR: orthostatic (esp 1st dose postural), impotence
• drug of choice for BPH

• clonidine (catapres), guanfasine
• MOA: stimulate A2 receptors in brain --> dec HR/CO/PR, dec renin activity, dec baroreceptor reflexes
• ADR: anticholinergic, nightmares/insomia (clonidine), Na/H20 retention
• interactions: B blocers, CNS depression
• withdraw gradually to avoid rebound HTN
• give w/ diuretic to avoid too much H20 retention

Central A2 agonist- 1st line for HTN in pregnancy

• norvasc (amlodipine), nifedipene (procardia)
• peripheral Ca Chanel blocker --> preripheral vasodilator, no AV conduction effects
• ADR: flushing, HA, HTN, edema, reflex tachy, gingival hyperplasia

• verapamil, cardizem (dilatizem)
• cardiac ca channel blocker--> dec HR, slow AV node conduction, dec contractility
• ADR: brady, anorexia, nausea, edema, constipation
• CYP metabolism
• short acting and SR forms
• avoid in CHF (b/c dec contractility)

• short acting and SR forms
• more ADR with short acting

• peripheral vasodilators:only relax arterioles (no venous)
• both well absorbed orally, minoxidil has higher bioavailability since not protein bound, and lasts longer b/c has active metabolite (also more severe SE)
• interactions: NSAID (r/t PG vasoconstriction)
• ADR:activates baroreceptor reflex, Na/H20 retention, lupus like syndrome (hydralazine), hair growth (minoxidil---rogaine!)
• can use Beta blocker and thiazide diuretic to dec ADR

• Initial Drug Choice:Thiazide diuretic, ACE-I, ARB, CCB
• Compelling indications: Usually Beta-blocker, ACE-I or ARB
• Combination Therapy: Diuretic + ACE-I, BB, ARB, CCB
• Difficult to Treat HTN: Utilize alternate agents- alpha2 agonists, peripheral vasodilators

• diuretic + ACE inhibitor
• b blocker
• ARB, aldosterone antagonist

• B Blocker + ACE inhibitor
• aldosterone antagonist

• B Blocker
• ACE inhibitor, CCB, diuretic

• ACE inhibitor OR ARB
• diuretic
• B Blocker, CCB

ace inhibitor or ARB

diuretic + ACE inhibitor

• methyldopa is traditional drug of choice
• labetolol: increasingly preferred (low SE)
• clonidine: limited date, use in 3rd tri
• BBlocker --> IUGR
• CCB: limited data
• diuretics: safe in low doses if stated before conception
• ACE/ARB/renin inhibitors: CONTRAINDICATED

• cardiac glycoside: positive inotrope --> increase force of ventricular contraction
• MOA: inhibits Na/K pump --> Ca buildup in cell --> inc contractility but dec automaticity/conduction velocity of AV node *stronger but slower

• HF: dec sympathetic tone, inc urine, dec renin release
• precautions: renal impairment, lyte imbalances (hypoK hyperCa can --> arrythmias)
• CI: AV block, arrythmias
• ADR: anorexia, n/v, diarrhea, yellow vision, halo effect, brady, gynecomastia
• monitor drug levels until normalized, then not as much
• also monitor lytes, CrCl

• drugs that --> hypoK: inc dig levels (diuretics)
• drugs that --> hyperK: dec dig levels (ACE-I/ARB)
• verapamil (ccb): dec dig effects by dec contractility

• oral nitrates (similar to nitro)
• MOA: vaso dilate, reduce pre/after load, dec O2 demand b/c heart relaxes
• sig. 1st pass for oral
• precautions: volume depletion (makes heart want to work harder)
• CI: head trauma, cerebral hemorrhage (dont want to dilate more)
• interactions: anti HTN, ASA (increase nitrate [x]), may dec effect of heparin
• bidil:combo with hydralazine, shows more improvement
• *need 10-12 hr nitrate free interval
• treat HA w/ tylenol

• sym: rate of nodal discharge, rate of conduction and excitability, force of contraction
• para: rate rhythmic contraction, release ACh

• fast:
• Na in--> depol
• Ca in --> contraction
• K out --> repol

• slow:
• slower depol mediatied by Ca influx

• I: NA channel blocker
• quinidine: dec CV, inc RP, dec A
• lidocaine: 0/dec CV, dec RP, dec A
• flecanide: big dec CV, 0 R, dec A
• II: beta blockers-  dec CV, inc RP, dec A
• III: K channel blockers- o CV, big inc RP, 0A
• IV: Ca channel blockers- dec CV, inc RP, dec A

• CV- conduction velocity
• RP- refractory period
• A- automaticity

• Na channel blocker
• slow impulse conduction, delay repol (by blockin K channels), anticholinergic action
• use: long term arrythmia suppression
• ADR: prolonged QT, diarrhea, ringing ears, HA, n/v, vsion disturbance
• metabolized and inhibited by different CYP

• Na channel blocker
• slows conduction, reduces automaticity, accelerates repol (short action potential)
• *no anticholinergic
• *no ECG change
• use: short term ventricular arrythmia
• ADR: brady, asystole, dizzy, seizures, confusion

• Na channel blocker
• last line agent: very potent, use w/ discretion
• markedly dec rate of depol --> delay repol
• ADR: prolonged PR, QRS; sinus node dysfunction, reduced conduction velocity, conduction block
• interactions: amiodarone/dig increase serum levels- should dec felc dose by 50% and monitor dig levels

• propanolol, esmolol, acebutolol
• MOA: dec adrenergic activity --> dec automaticity of SA node, dec AV conduction velocity, dec contractility
• ADR: bronchospasm, AV block
• CI: 2nd/3rd def block

• delay repol of fast potential (prolong refractory period)
• dec automaticity of ventricles
• prolong QT

• K channel blocker
• but also has class I, II, IV activity; inhibiting Ca ---> node depression
• use: broad spectrum arrhythmias
• extensive liver/CYP metabolism: inhibits its own metabolism --> long half life --> toxic effects can last weeks-months; also many drug interaction
• ADR: lung damage, vision disturbance, hepatotoxicity, CNS rxn
• need baseline PFT
• interactions: can increase levels of dig, dilantin, warfarin, statins

• slow SA automaticity, delay AV conduction, reduce contractility- same effects as BBlockers
• use: SVT
• precautions: high fat/carb meals inc toxicity of cadizem; antihistamines (H2) increase CCB level, BBlocker supplement activity, CCB increase Dig levels
• highly protein bound

• use: SVT
• MOA: potent and selective Na channel inhibitor --> significant inc Ca in cell --> inc contractility, dec automaticity, dec AV conduction velocity
• suppresses s/s, but doesn't treat, not 1st line agent
• inc extracellular K reverses toxic effects (b/c pushes Na into cell)
• non CYP but extensive hepatic metabolism
• CI: av block, vfib, hypoK, severe brady, severe renal impairment
• ADR: t wave inversion/depression, prolonged PR, proarrythmic, brady, gynecomastia, encephalopathy
• antidote: digtoxin

• novel therapy for arrhythmias
• resembles amiodarone, but fewer toxicity and shorter half life
• reduces rate and stimulation of heart
• QT prolongation
• inhibits Na channels, esp SA node
• inc repolarization phase, dec HR, antiadrenergic