Pharm Test 1

8/13/2019 Pharm Test 1

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Prescriptions

be able to ID what is wrong w/ agiven Rx* Required Elements- prescribers information (nameaddress phone, etc)- Pt name, date, address- drug name- dose strength- qty- dosing- refill information- addtl information (warnings, etc)- prescribers signature- DEA number (scheduled drugsONLY)- state license number

* Abbreviations- ALWAYS use leading zeros fordecimals- NEVER use lagging zeros for

decimals- WRITE OUT the word units- WRITE OUT the wordmicrograms- ALWAYS specify dose, especiallywith IV drugs that come in amps- WRITE OUT drug names- try to use generic name- AVOID USING any abbreviations

Factors that Affect PtCompliance* cost

* cannot understand instructions* does not store meds properly

Controlled Drugs* C I- high abuse potential- no recognized medical use- prescribed for RESEARCH ONLY

* C II- high abuse potential- DEA number reqd- ONLY 30 day supply- no refills- 90 Rx expiration- no phone orders except inemergency (need script w/in 7days)- no pre-printed scripts- unless in-Pt, only 1 drub / script- some states make this moredifficult than others (statelegislation)- IMPORTANT: Pts in severe pain(especially terminal) needadequate supply of pain meds

* C III, IV and V- lower abuse potential versus C II- DEA number reqd- 5 refills- script must be re-written after 6months- no pre-printed scripts

Mechanism of Drug ActionChemical interactions

- Antacids (neutralize acid)- Disinfectants (destroy

membranes)- Methenamine (formaldehyde)- General anesthetics

Receptor Effector Concept* Drug Receptors

- molecular sites to which drugsbind to produce their effect

- drugreceptor2nd

messengereffect

* General Characteristics ofreceptors

- usually protein in nature- often located in cell membranes- frequently glycosylated- selective binding and reversible- binding can be saturated due to

limited binding sites- binding results in activation or

inhibition- magnitude of effect depends on

receptor occupancy

- drugs modulate receptors- can be up-regulated or down-

regulated

* Forces involved in receptor-druginteractions

- Electrostatic interaction(opposite charges)

- Hydrogen Bonding- Hydrophobic Interactions- Van der Waals forces (weak)- Covalent bonding* most reversible, some

irreversible (suicide inhibitors)

Receptor Signal CouplingMechanism* Intracellular receptors

- regulate gene expression- 30 min lag time due to

synthesis of new proteins- drug effects persist long after

drug has been metabolized.** Examples:- corticosteroids,mineralocorticoids, sex steroids,

vitamin D, thyroid hormone, P450inducers

* Ligand-Gated Channels- channels open and alter electricpotential of the cell by allowingexchange of ions** Examples:- nAchRNa

+IN (depolarization)

- GABAClIN

(hyperpolarization)- benzodiazepines (diazepam) Cl

-IN (enhances GABA action)

- picrotoxininhibits GABA-Rfunction (convulsants)

* cAMP as 2nd

messenger- agonist binds receptor (Rs) stimulates G protein (Gs) stimulates adenylyl cyclase (AC)ATP conversion to cAMP cAMP binds regulatory subunit (R2PKA (R2C2) splitting of C2from

bound R2C2catalyzedphosphorylation of target enzymeresponse* isoproterenolcAMP by bindingreceptor (Rs) + AC signal* clonidinecAMP by binding -2receptor (Ri) - AC signal* caffeineand theophyllinecAMPby inhibiting PDE cAMPmetabolism (to 5 AMP by PDE)

* Potential sensitive (voltagegated) Ca

2+channels

- cardiac drugs- cytoplasmic Ca

2+effects cell by

binding calmodulin** Examples of Ca

2+channel

blockers- Diltiazem, Verapamil, Nifedipine

* IP3, DAG, Ca2+

signal- agonist binds R G stimulationPLC activation splitting ofmembrane inositol phospholipidinto IP3and DAG- IP3Ca

2+release from

intracellular stores Ca2+

bindingcalmodulin Ca2+/ calmodulincomplex binding calmodulinbinding enzyme response- DAG stayed in membrane and,together with Ca

2+(released via

IP3) activates PKC substratephosphorylationresponse** Examples:- Ach on muscarinic receptors- -1 agonists (phenylephrine)- serotonin on 5-HT2receptors


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* Nitric Oxide (NO)- paracrine-type transmitter- endothelial muscarinic receptoractivation IP3/ DAG / Ca

2+

mediated calmodulin-Ca2+

activation of NO synthase- NO synthase converts arginine tocitruline and NO- NO exerts paracrine effect onneighboring cells by activatingguanylyl cyclase conversion ofGTP to cGMP PKG activationvasodilation- Viagraprolonged vasodilation(erection) by inhibition of PDV(inactivates cGMP)

* Ligand-regulated protein tyrosinekinases- ligand binding dimerization oftyrosine kinase receptors receptor autophosphorylation adapter protein mediated binding

of Ras (similar to G protein -subunit) serine threoninekinase activation MAPKphosphorylation (activation) MAPK enters nucleus phosphorylation of transcriptionfactors that regulate geneexpression growth, proliferationor differentiation- cytokine receptors act similarly(JAK STAT pathway)** Examples- insulin

- EGF- PDGF- nerve growth factor- Imatinib(Gleevec): tyrosinekinase inhibitor, one of 1

stto be

useful in new class of anti-cancerdrugs called signal transductioninhibitors (STIs)

* G Proteins- membrane protein (spansmembrane 7 times, N terminusextracellular, C terminuscytoplasm)** Examples- Gsstimulates adenylyl cyclase,opens Ca

2+channels cAMP

and Ca2+

influx (1, 2, 3adrenergic receptors, D1and D5dopamine receptors)- Giinhibits adenylyl cyclase, PLA2,opens K

+channels cAMP,

eicosanoid release,hyperpolarization (2adrenergic,D2, m2, m4muscarinic, opioid)

- Gkopens K+channels (via direct

G protein -subunit activation) hyperpolarization- Gqstimulates PLC IP3, DAG,Ca

2+signaling (m1, m3muscarinic,

1adrenergic)

Drug-Receptor binding andAgonists v Antagonists

Agonists Antagonists

ACh atropineEpinephrine

1 phentolamineB1, 2 propranolol

HistamineH1 benadrylH2 cimetidine

Drug Receptor Bind ing andAgonists / Antagonists* drug [D] + receptor [R] [DR] response

- EC50: [D] at which effect is 50%of maximum- KD: [D] at which receptoroccupancy is 50% maximum- EC50equivalent to KD- ideally, KD= KA

* Receptor occupancy & drugeffect

- reversible- one drug molecule for one

receptor- response = # of receptors

occupied- bound drug is negligible to

amount of free drug available- response is maximal when all

receptors are occupied- further addition of drug will not

produce further response

Terminology* Affinity propensity of a drug tobind a receptor- measured in KD(dissociationconstant for agonist-receptor

interaction)- 10

-7has greater affinity than 10

-6

- SO, a log dose response curvewith multiple lines, the curve to theleft represents most potent

* Potency dose required toproduce particular effect relative toreference- measured in ED50(10

-7more

potent than 10-6

)

* Efficacy biological responseresulting from drug binding to itsreceptor- by definition, antagonists have noefficacy (but they have potency)- antagonists have NO EFFICACY

because the do not elicit abiological response (they do havepotency)

* Intrinsic activity synonymouswith efficacy- agonist has affinity + intrinsicactivity- competitive antagonist hasaffinity but NO INTRNSIC

ACTIVITY

* Agonist - drug that stimulates

receptor and provokes biologicalresponse

* Partial agonists partiallyactivate receptor

- act as competitive antagonistsin presence of a full agonist

* Antagonist competitive, non-competitive, functional, chemical- drug whose interaction withreceptor blocks effect of agonistacting on the same site

* Competitive antagonist - cannotactivate the receptor effectormechanism but can occupyreceptor site and prevent agonistfrom binding- competitive antagonist effectscan be overcome by dose ofagonist- fixed dose of competitiveantagonist parallel shift of doseresponse curve to the right


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- as [competitive antagonist] es,Emax(maximum response) ofagonist DOES NOT CHANGE,despite causing ED50- intrinsic activity of competitiveantagonist = 0- as number of antagonistsincreases, higher dose of drugneeded to reach 100%

* Noncompetitive inhibitors caneither irreversibly bind to the samesite as agonist or inhibit theagonist by binding to a secondarysite on the receptor (allosteric)- in presence of non-competitiveantagonist, agonist is unable toproduce maximum effectregardless of the dose, a KEYDIFFERENCE betweencompetitive antagonist and non-competitive antagonist

* Chemical antagonists - inactivatedrug via direct interaction

* Functional antagonists act viacompletely different mechanism tocounter agonist effects (BP byhistamine reversed byepinephrine)

* Inverse agonists- in systems with constitutivereceptor activity (GABAA, 5-HT2,2), these drugs can stabilize

receptors in inactive conformationbiological activity

Dose- Response Curve*Doses needed for given responseaffected by- drug characteristics- administration, absorption,metabolism, excretion- type of Pt

* Graded response- intensity of response (%) versusdose (log)- maximum effect = efficacy- potency (more potent = to theleft)- both above are governed bydrugs inherent ability to produceeffect- Slope the steeper the slope themore potent the drug faster effectwith little increase in dosage- Variability how differentlypeople respond to same drug dose(aka biological variation)

- Threshold a dose below whichno response observed

* Quantal response- relate drug dosages to thefrequency with which desiredresponse will occur in givenpopulation- all or none response- frequency distribution plot- ED50and LD50relate to dosesthat produce desired effect in 50%of population studied

Therapeutic Index / Ratio* ED50= dose that producesdesired effect in 50% of thosetreated

* LD50= dose that produces deathin 50% of those treated

* TD50= dose toxic to 50% of

human population

* Therapeutic ratio:

TR = TD50\ED50

(use LD50for animal studies)

* Standard Margin of SafetySMS (%) = (LD1\ED99-1) x 100**Example:- 100 mg of drug causes lethality in1% of population while 10 mg is

effective in 99%LD1= 100mg, ED99= 10mgSMS = (100/10 x -1) x 100 = 900%- dose that is effective in 99% ofpopulation must be increased900% to cause lethality in 1% ofthe population- SMS = safety

Decreased Drug Activity,Tolerance- drug response es with repeatedadministration

* Pharmacokinetic (metabolic)tolerance occurs because druginduces enzymes responsible forits own metabolism** Examples:- pentobarbitalsleeping time ed inPts pretreated with barbiturates forseveral days- warfarinmust be ed in Ptsbarbiturates or phenytoin becausethese drugs induce enzymes thatmetabolize warfarin

* Pharmacodynamic (cellular)tolerance develops at cellular levelmight be due to changes inreceptor number or function**Example:- continuous exposure to -adrenergic agonists (Tx asthma)drug response- same with opiates

* Tachyphylaxis- rapidly developing tolerance** Example:- tyramine and amphetamine exerteffects by releasing monoamines- with a limited amount ofmonoamines in reserve, dosesgiven over a short time will depletethe pool and no amount ofadditional drug will increaseresponse

* Physiologic tolerance- occurs when two agents withopposing physiologic effects areadministered at the same time** Example:- histamine (vasodilator) andepinephrine (vasoconstrictor)counteract each other whenadministered together

* Competitive Tolerance- when agonist is administered withreceptor antagonist

** ExamplesAntagonist Agonist

naloxone morphineatropine (m-R) ACh

propranolol isoproterenol (-R)

Mechanisms of Tolerance* Desensitization- occurs rapidly- continuous exposure to anagonist results in a conversion of achannel to an altered state thatremains closed

**Example: succinylcholine

* Downregulation- continuous exposure of a drug(agonist) causes a ligand induceddegradation of a receptor therebydecreasing receptor numbers

Increased Drug Activity,Tolerance* Supersensitivity / hyperactivity- absence of ligand or prolongedpresence of antagonist


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receptor degradation + receptorsynthesis receptor number response

* Chemically induced- halothane (general anesthetic)can catecholamine sensitivity(via up-regulation, receptorantagonists tend to cause receptor number)

* Surgically induced- destroyed or lesioned pre-synaptic nerve endogenousagonists + receptor number

* Deficiency in degrading enzymes- drug induced = pharmacogeneticeffect- Pt genetically predisposed tocertain drug sensitivity** Examples:- abnormal serum cholinesterase

succinylcholine (musclerelaxant) sensitivity- G6PD deficiency primaquine(antimalarial) sensitivity acutehemolytic anemia

* Competition for binding sites- one drug may displace anotherdrug from a binding site increasingthe binding drugs sensitivity.** Example:- warfarin must be reduced whentaken with phenytoin

(anticonvulsant) because warfarinwill displace phenytoin

* Physiologic synergism- 2 drugs with similar effects usingdifferent receptors or mechanismsare administered simultaneouslyenhancing the response with eitheragents alone- Additive: 1+1 = 2- Synergism 1+1 = 3- Potentiation 1+ 0 = 2

Adverse Effects * Usually several dose-dependentresponses can be obtained with 1drug- due to multiple receptorsactivated at different dose levels- drugs are generally selective notspecific- selectivity can be:* beneficial (therapeutic)* toxic (adverse reaction)- do the benefits of the drugoutweigh the risks?

* Overextension of therapeuticeffect- toxic effect is mediated by thesame receptor-effectormechanism- CNS depression (sedatives),arrhythmias (anti-arrhythmics),hypoglycemia (insulin), etc

* Acceptable adverse effectsinclude:- headache, fatigue, nausea,vomiting, GI upset or dizziness thataccompanies many therapeuticdrugs

* Organ Directed Toxicities- some drugs are directly toxic tocertain organs, tissues that haveno connection to their therapeuticactions- Examples: aminoglycosides

(renal toxicity), acetaminophen(hepatotoxicity), chloramphenicol(aplastic anemia), tetracycline(tooth discoloration orphotosensitization)

* Fetal toxicity (teratogenic)- Toxicity depends on the chemicalstructure of the drug have norelation to the therapeutic effectsof the drug- Examples: thalidomide,methotrexate, phenytoin, warfarin,

acetaminophen effects fetalkidneys ( isoniazid hepatotoxicity)

Drug Induced HypersensitivityReactions

** See Table 1 **

Drug Idiosyncrasies(Abnormal Responses)* Abnormal drug response that isnot immunogenically-mediated- likely genetically determinedabnormalities of enzymes andreceptors

* Apnea caused bysuccinylcholine- in patients with abnormal serumcholinesterase- cant destroy the paralyzing drug(succinylcholine)- recipients with the abnormalserum stay paralyzed for hoursinstead of minutes.

- homozygous for abnormalcholinesterase at most risk

* Fast vs Slow acetylation ofisoniazid (TB drug )- slow acetylators have low hepaticN-acetyltransferase thus moreprone to isoniazid induced vitaminB6 deficiency- liver toxicity more associated withage versus fast acetylation-use w/ caution in Pts 35 yo

* Hemolytic anemia elicited byprimaquine- occurs in patients whose RBCsare deficient in G6PD- erythrocytes are incapable ofregenerating NADPH leaving theRBCs susceptible to oxidative lysis(anemia)

* Barbiturate-induced porphyria in

patients with abnormal hemebiosynthesis- barbituric acid mimics part of theheme structure occupying a hemesite on the protein that regulatesthe production of ALA synthetase- in this process ALA synthetase isincreased and more porphyrin isproduced causing porphyria

Placebo Effect* Placebo response is fairlyconstant, between 20% to 40% in

most clinical trials* Single blind design- experimenter knows but patientdoesnt* Double-blind design- neither the experimenter nor thepatient know

Pharmacokinetics

Modes of Drug Permeation* Key Principle- drugs have to permeate throughvarious barriers to reach receptorsites-ONLY FREE DRUG ISBIOACTIVE

* Aqueous diffusion- drugs enter or exit the cell viaaqueous pores in the cellmembrane-largest pores in glomerulus

* Lipid or passive diffusion


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- drugs pass through the lipidbilayer with the concentrationgradient- lipid solubility is required- weak organic acids are best atcrossing the lipid bilayer in acidicenvironments- weak bases are best at crossingthe lipid bilayer in basicenvironments

* Active Transport- against the concentrationgradient

- requires energy, ATP

* Facilitated diffusion- carrier-mediated process- does NOT require energy- HOH-soluble solutes pass WITHconcentration gradient

* Pinocytosis

- large molecules are engulfed intothe cell

Chemical Aspects of Drugs* Ionization properties- most drugs are either weak acidsor weak bases- they undergo ionization indifferent body fluids depending onpH

* Henderson-Hasselbachdescribes extent of ionization

pH = pKa+ log ([A-] / [HA])

NOTE:log (1) = 0log (10) = 1log (10

x) = x

log (1 / 10x) = -x

* Acidic drugs (proton donors)- protonated (HA) = non-ionized- deprotonated (A

-) = ionized

- non-ionized form is lipid-soluble- acidic drug is NON-IONIZED(protonated, lipid-soluble) in more

ACIDIC environment (pH < pKa)

* Basic drugs (proton acceptors)- protonated (BH

+) = ionized

- deprotonated (B) = non-ionized- non-ionized form is lipid-soluble- basic drug is NON-IONIZED(deprotonated, lipid soluble) inmore BASIC environment (pH >pKb)

pH = pKa+ log ([B] / [BH+])

* weakly basic drug in acidicenvironment is IONIZED(protonated, NOT lipid soluble) andwill accumulate there (vice versa)

* strong acids and bases havesmall pKaand pKb- they are ALWAYS IONIZED inthe body and are NOT lipid soluble

* CO2= pH

Dose* Enough drug for desired effect- individualized based upon organfunction, Pt age, organ pathology,liver, kidney, etc

Absorption* Solubility

- drugs administered in aqueoussolution are most readily absorbed

* Dissolution- drugs administered in solid formmust dissolve into the aqueousenvironment before they can beabsorbed- the rate of dissolution dependson the formulation of the drug andthe patient- factors involved: particle size, saltcontent, rate of disintegration, GI

pH, motility

* Concentration- drugs administered at higherconcentration (versus dilute) aremost readily absorbed

* Blood flow- blood flow at absorbing surfaceenhanced absorption (heat ormassage)- blood flow slowed absorption(vasoconstriction, cold, shock,disease, sub Q injection versus IM)

* Absorbing surface area- important determinant ofabsorption RATE- drugs are more readily absorbedfrom organs with large surfaceareas (intestines, lungs)

* pH- determines relative amount ofdrug in ionized or non-ionized form

(thus, solubility in lipid andaqueous environments)

* Contact time- long contact time greateramount absorbed

* Bioavailability- amount of active drug in thebloodstream- drug given IV is 100%- drug given oral or rectal rarelyreaches 100%

F = AUC oral/ AUCiv x 100%

* 1stpass effect

- amount of drug metabolized bythe liver upon absorption of a drug- 1

stpass more drug

metabolized by liver bioavailability- morphine, lidocaine, meperidine,

propanolol, verapamil, labetolol,INH, imipramine- 1st pass less drugmetabolized by liver bioavailability- digitoxin, phenytoin, theophylline,tolbutamide, chlorpropamide,diazepam

* 1stpass drugs cause significant

inter-patient plasma concentrationvariation- use other routes of administration

Routes of Administration* oral (enteral)- most common, safest, mostconvenient, most economical- disadvantages include emesis- susceptible to metabolism byintestinal flora- 1

stpass effect

- gastric emptying time affectsabsorption- most drugs absorbed best onempty stomach- sustained-release drugs produceslow uniform drug absorption for 8hours or longer (compliance,maintain therapeutic effect, butabsorption is irregular or erratic)

* Parenteral- IV: most direct (not good for oilysolutions or suspensions)- IM: aqueous fast, w/ oil slowrelease over time in muscle- SubQ: slow absorption, smallamounts, implantation of solid


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pellets (norplant, progestin implantfor long term contraception)- intraperitoneal: danger ofinfection, lesions and pain, 1

stpass

effect still possible (still passes viaportal vein)- intra-arterial: for high drugconcentrations to specific organs- inhalation: rapid absorption, largesurface area

* Topical- skin: absorption here proportionalto surface area and lipid solubilityof drug (epidermis is lipid barrierbut dermis is NOTabraded skinis therefore best)- transdermal (patches)- eye- buccal or sublingual, for drugsthat are self-administered butsubject to 1

stpass effect (nitro)

- rectal, when oral precluded due

to emesis or when Pt is out cold

Distribution* Volume of distribution

Vd= Div/ C0

- Div= IV drug dose (mg)- C0= plasma [drug] of the drug attime zero (mg / L)- Vd= volume of distribution (L / 70kg person)

* plasma water = 3 L* extracellular compartment = 12 L* whole blood = 5 L to 6 L* total body water = 41 L- body fat Vd(due to HOHcontent)- Vdis a conceptual figure- drugs that distribute widely orbind extensively to peripheraltissues show high Vd(vice versa)- Vdindicates drug is mostly inplasma- drugs with plasma proteinbinding have V

d

- affected by age, body weight,organ pathology and disease

Storage Depots of Drugs* Fat drugs that are lipid solubleare stored in fat- Examples: DDT, anesthetics(reason obese people are hard toanesthetize)

* Tissues many drugs bindreversibly to various tissues, the

larger the tissue, the larger thedrug reservoir

* Bone tetracyclines havechelating properties so they aredeposited in Ca

2+rich regions such

as bones and teeth (discolor anddelay bone growth)- can be harmful to children whoare still developing bones andteeth and pregnant womenbecause tetracycline can cross theplacental barrier

* Plasma protein binding- plasma protein binding drugaccumulation in plasma Vd+ [drug]plasma+ longer t1/2- a small decrease in plasmaprotein binding increasesconcentration of free drug fourfold

* Transcellular reservoirs GI tract

is a good place for drugs toaccumulate especially those thatare slowly absorbed

* Importance of blood flow totissues

- when drugs are administeredthey initially distribute to areas withthe highest blood flow such asbrain, liver and kidneys

Sites of Drug Exclus ion* CSF, ocular fluid, endolymph,

fetal fluid, pleural fluid- drugs must be extremely lipidsoluble to breech these fluids

* Plasma protein binding of drugs- drugs in vascular compartmentbind reversibly with 1 or moreproteins (albumin)- changes in binding may accountfor drug interactions that toxicity- 6% in plasma binding [freedrug] x 4

* Placental transfer of drugs- fetus most vulnerable in 1sttrimester because mother may notbe aware that she is pregnant andthis is the period of organogenesis- effects of placental crossingdrugs on the fetus is calledteratogenic effect

* Mammary transfer of drugs- drugs enter milk via passivediffusion

- since milk is more acidic thanplasma, basic drugs canaccumulate (as do tetracyclinesand lipid-soluble drugs)

* Blood Brain Barrier- selectively permeable barrier thatlimits access to the brain via tight

junctions, keeps harmful or toxicsubstances away from the brain

*Redistribution- when highly lipid-soluble drugsare administered IV, they initiallygo to blood flow areas- after this, drug is redistributed toand stored in muscle and adipose[drug]plasma- as plasma levels fall, drugdiffuses out of sites of initialaccumulation, terminating theclinical effect- ultimately drug is localized in fat

where it is slowly released,metabolized and excreted** Example:- thiopental

Elimination* First order elimination- exponential kinetics- for most drugs, a constantproportion of a drug is eliminatedfrom the blood per unit time

C = C0x eKel x t

* Zero order elimination- elimination saturated after dose(alcohol, aspirin, phenytoin) andonly a constant amount iseliminated per unit time- drug can accumulate toxicity

Clearance (CL)* Measure of bodys capacity toeliminate drug

CL = Vdx Kel

where Kel= 0.7 / t1/2

SO


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CL = (Vdx 0.7) / t1/2

t1/2= (Vdx 0.7) / CL

Vd= (CL x t1/2) / 0.7

- for most drugs, clearance isconstant over the usual plasmaconcentration range in a clinicalsetting** Examples:- EtOH eliminated at 10 g / hour- aspirin < 500 mg / day is 1

st

order, anything more than that andit will go zero order

t1/2in Pharmacokinetics* time required to change plasmaconcentration of drug in body by50%- first order elimination- exponential process that is a

constant fraction eliminated ingiven time against non-exponentialprocess where constant amount iseliminated in given time** Assumptions:- body is single compartment- size = Vd- drug distributed equallythroughout tissues- drug in plasma in equilibrium withtotal volume- time course of drug in bodygoverned by Vd, CL and t1/2

- with repetitive dosing, steadystate will develop after 5 x t1/2

* Steady State Concentration- Cssis directly proportional to doseand t while inversely proportionalto CL, Vdand dosage interval

Css= F x D / CL

F = bioavailabilityD = dose = (tau) dosing intervalCL = clearance- steady state condition is NOTsame as steady stateconcentration- Cssdevelops when steadycondition is achieved in course ofrepetitive drug administration- Csscan be reached with a loadingdose- Csswill develop when elimination= dosing- 50% of Cssis achieved in 1 t1/2- 75% achieved in 2 x t1/2

- etc etc

** Key points* Plateau state- after 5 x t1/2- time to plateau independent ofdose- level of plateau proportional todose

* Fluctuations- none w/ continuous IV- blunted by slow absorption- proportional to dosage intervaland t1/2

* Plateau concentration- proportional to dose, doseinterval, t1/2, F, CL- inversely proportional to KelandVd

* Clinical implications of t

concepts- valid ONLY for drugs w/ 1

storder

kinetics- takes 5 x tto reach Css- must wait that long to determineplasma steady state levels of adrug- takes 5 x tto eliminate most ofdrug after last dose- shortening dose interval Css- lengthening dose interval gradual plasma level and Css- time to reach CssNOT related to

dose size

* Clinical implications of drugs w/zero order kinetics- repeated administration at doses NO DEVELOPMENT ofsteady state- drugs w/ saturation kinetics(aspirin, EtOH, phenytoin) given atdoses higher than elimination rateaccumulation toxicity

* Maintenance Dose- quantity of drug administered atselected intervals to providesteady state plasma levels (targetconcentration, TC)- aka amount of drug eliminatedsince last dose that now needreplenished- dosing rate = elimination rate

both = CL x TCF

** Remember

- for IV drugs, F = 1

** maintenance dose = dosing ratex dosing interval

* Loading Dose- for immediate therapeuticconcentration

Loading dose = Vdx TC

** Remember- units for Vd(mg / 70 kg person)

Brand Name Drugs v Generics* Brand names- trade name protected forever- compound protected 20 years- few exceptions (orphan drugs)

* Generic drugs- same active ingredients- different formulation

- similar dissolution- similar bioavailability ( must bewithin 80% and 120% range)

* Orphan drugs- govt makes special allowancesfor drugs targeted at a smalldisease population

Biotransformation* Most pharmacologically activedrugs are- lipid soluble (non-ionized at

physiological pH)- strongly bound to plasmaproteins- NOT readily excreted by kidney- tend to remain in body for longtime (unless liver metabolizes and/ or kidney excretes)

* Importance of biotransformation /metabolism- promote the elimination of a drugfrom the body- designed to convert lipid solubleand non-polar compounds intopolar and water solublemetabolites- during this process, most drugsbecome inactive or less active- usually produces inactiveingredients- in some drugs, metabolite haslonger t1/2than parent- sometimes produces toxiccompound (INH, isoniazid anti-TBdrug)


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- figure below shows Phase IIactivation of INH to hepatotoxicmetabolite- slow acetylator neurotoxicity- fast acetylator hepatotoxicity

* Sites of biotransformation- occurs at some point betweenabsorption and renal or fecalexcretion- GI tract, kidney, intestinal wall,

skin, lung- most important biotransformationsite is liver

* Phase I reactions- modification of the molecule- usually convert lipid solubleparent to more polar metabolite(less lipid soluble)- often these metabolites areinactive and easily excreted- some phase I metabolites mayundergo phase II reactions beforethey are excreted- phase I reactions introduce orunmask certain functional groups- OH (oxidative reactions)- SH (acetylation)- NH2 (deamination)** Example- benzene is highly lipid soluble- add hydroxyl group (make it aphenol) less lipid soluble- conjugate it with gluconoride fairly HOH-soluble

* Microsomal mixed function

oxidase systems MFOs- liver and other tissues contain intheir ER, a group of metabolizingenzymes called MFOs- MFOs major function is oxidativedegradation of drugs and foreignmolecules- these enzymes require:

* molecular oxygen* NADPH* c P450* c P450 reductase

- result is an activated oxygentransferred to the substrateforming an oxidized end product

* P450 enzymes- CYP 3A4 metabolizes the largestnumber of drugs, over 50%- inducers of P450: Smoking,charcoaled foods, cruciferousveggies, barbiturates, rifampin,rifabutin, phenytoin,carbamazepine, glucocorticoids,St. johns wart, dioxine

* Phase II Reactions- parent drugs or phase Imetabolites undergo conjugationreactions of several types- end product almost alwaysinactive and less lipid soluble excretion in urine or bile

* Environmental Factors

- pollution, smoking, pesticides,may cause the patient tometabolize a drug more rapidlythus reducing the drugseffectiveness

* Age and Gender- very young:* BBB, liver and kidney function

may not be fully developed- elderly:* slow gastric emptying,

decreased - gastric secretion,

muscle mass, renal excretion,hepatic metabolism, increased body fat,* decrease in renal function

precedes the decline in liverfunction- Gender: sex differences forcertain drugs* Ethanol, Propanolol,

Benzodiazepines, Estrogens,Salicylates

* Drug-Drug interaction- some lipid soluble drugs induceP450 and therefore increase themetabolism of other drugs

* Effects of disease onbiotransformation of drugs- Liver diseases will adverselyaffect drug metabolism

* Excretion- synthetic products < 60 kDa excreted by the kidney

- synthetic products > 60 kDa,excreted into bile GI- non-ionized drugs will NOT beexcreted by the kidney- if the urine is acidic (as inbarbiturates) then make urinemore basic w/ HCO3

-

Inducers Inhibitors

many enzymes(including 3A4) many enzymes

rifampin,rifabutin

cimetidine

barbiturates amiodaronephenytoin paroxetine

carbamazepine fluoxetineglucocorticoids CYP3A4St Johns wart ketoconazole

CYP1A2 itraconazole

smokingHIV protease

inhibitorscharcoal broiled

foodserythromycin

cruciferousveggies

clarithromycin

dioxine diltiazemNONE for 2D6 nicardipine

verapamilgrapefruit juice

CYP2D6quinidine

SSRIs

Toxicology* Treatment in ER

1. Establish and airway

2. Breathing3. Blood circulation4. Altered mental state5. Other complications6. Clinical diagnosis7. Decontamination8. Enhanced removal

* Techniques- Gastric lavage pumping of thestomach with tube* contraindicated if> 30 minutes elapsed since

ingestion of corrosive material,ingestion of hydrocarbon solvents,coma-stupor-delirium-convulsionspresent or imminent- Activated charcoal will adsorbalmost any toxin- Induced emesis - inducevomiting via ipecac syrup- adults: 15 to 30 ml PO followedby 200 to 300 mL HOH- children 1 to 12 years: 15 mL POfollowed by 10 to 20 mL HOH


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Table 1

Type Target Organ Clinical Mechanism Example

I. Anaphylactic(immediate)

GI tractSkinLungVasculature

GI allergyUrticaria

AsthmaAnaphylactic shock

IgE many drugs

Tx with Epi, 0.5 mLof 1:1000 solution

II. Cytotoxic(autoimmune)

Circulating blood cells LeukopeniaThrombocytopeniaHemolytic anemia

Granulocytopenia

IgM, IgG penicillinhemolytic anemia

III. Arthus (immunecomplex)

Blood vesselsSkinJointsKidney

Serum sicknessVasculitis

ArthritisGlomerular nephritis

Ag-Ab complexes(immune complexes)

sulfonamidespenicillinanticonvulsantsthiouraciliodides

IV. Cell-mediated(delayed)

SkinLungsCNS

Contact dermatitisTB

Allergic encephalitis

sensitized T cells many drugspoison ivy

Pharm Test 1

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Transcript of Pharm Test 1