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Pharmacodynamics

Bodys response to Rx|Rx effect on bodyEfficacy|Potency|Affinity|Dose|R#|Genetic

Efficacy How well Rx prod pharmaco resp|yAgn|full|partial|Antg|C|NCRelative|full Agn=1|Antg=0

Antg Rev|conf|effect|Endo Agn

FullAgn

PartialAgn

C AntgReversible

NC AntgIrreversible

E/NE Pindolol Propranolol Pehnoxybenzamine

Potency Amt Rx needed for desired effect|yAffinity How tight Rx bind R|left=affinityDose EC50|CAntg|NCAntgR# Rmax|NCAntg|y|spare R|Genetics Quantal DR curve|Cumulative Q-DR

Variability|ED50|

Rx action EC50|Rmax|

Agn|CAntg EC50|Rmax|right shiftCAntg|Agn Antg EC50dep on [Agn]NCAgtg EC50C|Rmax|R#

Spare R Saturate|limited by later step|Rmax reached before all R occupiedSm dose NC Antg Rmax

R Regulation Over|reg|mlc|R#|tachyphalaxProlong|reg|dose|rebound phenpharmacodynamic tolerance

Quantal Normal curve% of pop need certain dose to respon

Cum Q Sigmoid|% of pop responding to a dosInclude those that resp to lower dose

Multi-effects Rx bind same R @ other tissue|potenRx bind other R|completely selectivR density|diff R isoforms expr

TI Rx safety|TD50/ED50|LD50/ED50

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Physicochemical propertiesIntracellular barrierlipid bilayer memRx specific carriers|not natural meta

PC PC=[Rx]fat/[Rx]H2OPC=0|soluble in fatPC=|soluble in H2O

Rx No|Weak A/B|Strong A/B

Weak Ionized|Unionized|@equilibriumHA+BH+A-+B+H+|Ka

***Ionized Rx are trapped in urine & cleared***Acidic AH|B+|Base excreted via urineBasic A-|BH|Acid excreted via urineKa [B][H+]/[HA]

HH Eq [A]/[B]=10(pH-pKa)Weak A Salicylic|ASA|0.01% No|H2O insoluble

Good PC in lipidsWeak B Diphenhydramine|Benadryl|anti-his

1% N

o

|H2O insoluble|Good PC in lipids

Strong A|B Phophate|Sulfate|Poor PC|NH4

+|always|poor PCMultiple weak A/B|act like strong

Quaternary Ipratropium|inhale|analog of atropineCOPD|deliberate poor PC|

Strong A Heparin|lots SO4-& -OH|sugar

Strong B AG|Tobra|multiple weak bases|NH3Sugar=low PC

Transportation

Diffusion Fav PC|No|E|dissipate gradient|Rate=k1(C1-C2)|@Eq, C1=C2|trans

wB conjAcross|NoB cross|[No] & PCwA conjBcross|NoA cross|[No] & PC

Diff pH Ion TrappingwB affect No|ratio of B:A|

accum in lower pH than bloodwA affect No|ratio of B:A|accum in higher pH than blood

Filtration Pores|size|Phydrostaticgrad|BFCapillaries|glomerulus|NH4

+Liver sinusoid & spleen real endoSuccinylcholine|tubocura|pancuroHep too big|trapped in plasma

Active E|up [Rx] grad|SLC|ABC|Compete|Rx interaction|

FacilitatedInto cells |OCT1,2,3|Uniport|OAT1,3|AntiportGrad|Na+pump|KG2-

Out of cells |MATE-1,2|Antiport Rx+/H+1|Na/K pump|est Grad2|Na/H|est H+Grad3|Rx/H|dissipate H+Grad

ATP driven Kidney|Hepato|GI|Vasc endo brainChoroid plexus|Testis|Placenta

Rx

+

/Rx

o

P-glycoprot|MDR1|Rx

+

|large Rx

o

Rx- MRP2|BCRP|amphiphilic |ConjMRP2 Glucuronide|Glutathione|SulfateBCRP Rxo/Rx-|

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Pharmacokinetics

Absorption GI|Lungs|Skin (barrier)|Injection sitesSA|Thickness|Perfusion

Oral GI|exclude most Rx|Passive non-ionic diffusion|No|PC||wA/B|PC|pK|pHFixed charge|poorly abs-but still does

**Abs from GI complexed by the presence of Rxtransporters & Rx meta enz in epithelial cells**Stomach designed for Abs|wBabs|wA may

Sm Int Lg SA|major abs site|GI & Liver metaP-gp|Rx back into lumen|HepPortal v1stpass |Rx uneffective

Bioavailability (f)fraction of Rx into Sys circRx w/f=0 still useful if metabolite is active agentSource of Rx interaction|more important for Rx withlow f as interaction can f

Liver Sublingual|NTG|isosorbide dinitrateRectal|unconscious|V|unpredict abs50% enter sys circ b/f passing liver

Parenteral IV|IM|SubQ|Topical|Inhale|Nasal|Eye

IV Bypass abs|rapid|best control of []pVein dmg|Aq soln|reverse

IM capillary pore|lymphatic|BF|amt fatCtrl abs rate|slow but sustained|use during anticoagulant Tx

SubQ capillary pore|lymphatic|Aq soln~fastInsoluble Rx slow abs|sustained effectSolid pellets implant|abs for mo/yruse for Rx that irritate tissue

Topical Local|minimize sys exposure|patchesPotent & VERY fav PC|tolerance|Site of admin|scrotum best|sole worstBF|inflame Abs rate

Distribution [Rx]pBF Heart|Liver|Kidney|Brain|min

Muscle|Skin|Viscera|Fat|min/hrBloodECF [Rx]p=Rxadmin/(Vp+VEF)|pores|~rapidECFCells Vd=Vp+VEF+VIF|Vd=Vapp|ICF|cell***if Rx lipophilic, Distr limited to ECF***BBB pores|Cap endo Rx transporter|P-g

Cap surr by glial cells,ECF|Very good PC|guarantee|P-gpInflame vasc perm|meningitis|PCN

BBB|ChemoR trigger zone|HThChoroid plx Blood-CSF|3rd& 4thLat Ventricles|CS

Tight Jxn|enter only thru passive dff1/1000 SA of BBB|active trnsptr|enz

Placenta pores|Lg or charged cross|Lipophilic crosses readily|simple dffsP-gp|pH7-7.2|pH than mom|

***Fetus is exposed to some extent all Rx taken***

Testis/prost sertoli|tight Jxn|pore|limited distrSynovial pores|perm if inflamedLungs large cap SA|Rx meta|*Dapto

Blood from all organs pass thru lungsBodily fluid passive non-ionic dffsn|ion trapping

Distr can be limited by prot bindingAlbumin|acidic Rx|1-gp|basic RxOnly free Rx can cross|enz meta|filtReversible|buffering

Rx interxn two Rx compete|transient [Rx]|eli***Duration & significance of effect dep on t1/2***

Storage prot bound=storage|accum in tissueFat soluble|accum in adipose

Affinity for Ca or |accum bn & teet

Diseases

plasma prot|Rx bound|free Rx in bloodo synthesis|liver|albumino prot excretion|renal neprhititis

plasma prot|Rx bound|free Rx in bloodo Acute phase response|prot syno CA|arthritis|Crohns|MI

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Elimination H2O soluble mlc|KidneysMW|Prot bnd|Charge|PC

Glom Filtration|MW

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LIVERHPV & HA to central v|GI Rx|HPV|Rest of body|HALiver sinusoid extract Rx via transporters & passivedffsnRx transported out of liver by

1. Into sys circ|kidney excretion2. Bile canaliculus|GB|bile duct|Sm Int

Sinusoid mb (SLC) OAT|OATP|OCT

Pm|Na/K pumpCanaliculi mb(ABC) P-gp(MDR1)|MRP2|BRCPATP hydrolysis

Blood (ABC) via sinusoid mb|MRP1,3,4ATP hydrolysis

Enterohepatic cycling

DDI due to t1/2Most Rx in the cycle ultimately elim by kidneysRxcycle byreabst1/2|source of Rx interactio

ABt that kill bacteria in GI Non-abs polymers|cholestyramine|fiber

Biliary ExcretionRx

Poor PC

Remain in GI

Stool

Fav PC

Reabs via passivedffsn

Back to liver

(via blood)

Liver

Conjw/glucuronic

Very bad PC

Bact in colon rmvglucuronic

Free Rx w/Fav PC

Back to Liver

Free Rx w/BadPC

Stool

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Rx Response Variation

Genetic variation Metabolism|Transporters

Rx Meta P450|UGT|NAT|Cholinestease|TPMTP450 2D6|4 phenotypes|/Rx metabolism

Poor/P|intermed/IM|Extnsv/NL|ultrarpd/UP

Poor allele|CYP2D6*4|Ccsn|Afrc|Asn

Ultrarpd multiple gene copies|13|Ethiopn|Spaniards|Swedes

Rx Trans ABC|SLCABC P-gp|BCRP|MRP2SLC OCT|OAT|MATE

CYP2D6Affected Rx Tricyclic|-blocker|||tamoxifen|Tamoxifen by CYP|poor=poor resp to tamox

MEC & MTC but ptsability to metabolize codeine

influence the effects of the Rx. For instance, P maynot have enough active morphine in blood to reachMEC for analgesic effects whereas UR would have toomuch morphine surpassing MTC to prod toxic effects.

Poor Ultra rapid

Codeine Cmax CmaxMorphine Cmax Cmax

CYP2C19

1 2,3 4,5,6,7,8

Max activity activity /activity

4 Pheno P|IM|NL|URP 2 defective|2% Ccsn|14% Chinese|Affected Rx Omeprazole|ClopidofrelOmeprazole Prilosec|f=30-40%|stom acid scr

2C19|demethylation|hydroxylation

Clopidofrel Plavix|2C19 oxi|esterase40%|Hlysis3A4 oxi|CES1 esterase 90%|6%

DDI Ome2C19|clop|effective

CYP2C9 1,2,3 metabolic activityAffected Rx Warfarin

CYP3A4 2,7 Ccsn|16,18 Asn|low clnc signifcDual pathway|3A5|diff meta rate

NAT2 2 pheno|rapid|slow|5A,6A,7AAffected Rx Hydralazine|INH|Carcinognc arylamiHydralazine active Rx lvl|SLE-like SxINH t1/2|1hr3hr|periph neuropathyCA arylamine CA risk after prolonged exposure

UGT1A1 glucuronidation|bilirubin|*6|20%|Jpn|Chn|neonatal jaundiceCrigler-Najjar-I|CrNj-II|Gilberts

CrNj-I conj bilirubin|early childhood deatCrNj-II conj bilirubin|jaundiceGilberts promoter mutation|expr**GI & Bn tox to Colorectal CA Rx irinotecan(proRx|enterohepatic cycling) due to glucuronidation of active metabolite**

Rx Trans MRP2|BCRP|OAT

MRP2 ABC|Rx- out|hepatocytebile|Dfcn| transport from liverbile weGI tox of irinotecan|BM tox thoug

BCRP Gln141Lys|activity|biliary excretio30-60% Asn|5-10% Ccsn & AA

Rosuvastatin HMG-CoA reductase|chol syn90% bile CL|mutation effect & toxAsn|2xAUC|2xCmax|5mg|Ccsn20mg

OATP1B1 Rx- into|Simvastatin ProRx|N0lactone|fav PC|1stpass

Liver|H-lysis|acid|low PC|OATEnterohepatic cycle|MRP2OATP1B1|get in liver well|[Rx]p[simva acid]p|myopathy|efficacy

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DDI Physiologic|PharmacologicPharm DDI Rx1 directly aff PharmDyn/Kin of Rx2

Abs pH|trapping|solub|trans|motility|bac meta

Rx that pH Rx affected by pHAntacidNaHCO3Mg(OH)2

CaCO3H2 Antg|cimetidineH+pump|omep

PCN GKetoconazol|itraconazol|ampFe supplement (FeSO4)

Bisacodyl coated laxativeDigoxin (10%in f)Atazanavir (protease )

Trapping Rx that interact with another absNon-abs Rx|bind other Rx|fiberCharged polymer|antacids multivalentTetra|FQ|Cipro

Transporter P-gpabs & elimCyclosporine|quinidine|clarith|itraco

Cyclosporine Target T|immsupp Rx|prev renal rjct

Sirolimus GI abs=limited by P-gp|CSA siro absAdmin 4hr apart to minize DDI

Motility motilityabs|clnc significantstom emptying=delay abs

DistrLiver BF -blocker|hepatic BF|Rx meta

rpd meta Rx|deliv to liver=RLS

Prot bnd compete|transient on free []|warfLvl of eff dep on Vd|clnc signfcnt

BBB Loperamide opioid|cross BBB|Quinidine coadminCNS eff|P-gp

Elim Biotransformation|ExcretionBiotrans biotrans|compete|Irrev|CYP3A4Compete Rx meta by same pathwayIrrev Cimetidine|irrev bnd CYP|Rx elim

Wafarin|Diazepam|Chlordiazepoxide

3A4 Inhibitor

Antifungal Ketoconazole

ItraconazoleImmunosuppressant CyclosporineAntibiotics Erythromycin

ClarithromycinHIV protease Inhibitor Ritonavir

IndinavirFood/drink Grapefruit juice has

furano-coumarins whichintestinalCYP3A4proteolyticdegradation

Transporter

INDUCTION***the purpose of biotransformation is to protect thbody against xenoBt and other foreign sub; when yoare exposed to a large amount of xenoBt, its logicato induce biotransformation***

NR|TFprot syn|p450|RLSDDI|Low selectivity|induce meta of >1 Rx

Nuclear R Ligands InducesPXRPregnane

RifaminPhenobarbitalCarbamazepinePhenytoinRitonavirPaclitaxelStatinsCCBGlitazoneSt. Johns Wart(hyperforin)

CYP3A4SULTsUGTsP-gp

CARConstitutive

Pehnobarbital CYP2B6CYP2C9CYP3A4UGTsSULTsGSTs

AHRAryl hydrocarbon

OmeprazoleCigarette smoke(polycyclic AHs)

CYP1A1CYP1A2CYP1B1

Pharmacokinetic Tolerancewhen Rx induces itsown metabolismCarbamazepine Antiepileptic|t1/2|36-8/12hBosentan Endothelin antg|Tx pulm HTN*even though t1/2 of rosentan is 5hr, it takes 3-5d treach steady state when given 62.5mg twice daily*

Renal Excrtn Compete trans|pHu|passive reabs

2ndRxelim[1stRx]p1stRx dose

2ndRxelim|reabs|Rx meta|[1s Rx]pD

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Age pharmKin|body fat:H2O|BodFat:H2O with age|/Vd|Rx H2O or fat solub

Vddetermines Dload|t1/2|oscillation[Rx]p=Xadmin/Vd|

Peds sens to Rx|immature organ devclnc trial|unpredictable abs

Stom acid scrt Stom emptying

& peristalsis

Bile level

Low @ birth|hrs/d/2yr

SlowerIrregularSlows abs|Amt

Low bileabs or lipidsoluble Rx

Biotrans P450 peak @ 2-6mo|faster than adultsCYP1A2 peak @2yr|@puberty

*P450 can be induced by mom taking phenobarbital***Glucuronidation takes 3-4yr to reach adult lvl*****Bilirubin accumulates in newborns***

Renal excretion in pedsLow renal BFNeonate GFR=30-40% adult value3wk GFR=50-60%6-12mo GFR=100%GFR of kids continue to above adult values

Geriatrics >75yo|many Rx|SE/DDI|complianceNutritional prob|limited $|diff Rx respRx sens|homeostatic mech less effcnt

Diff resp Wt|muscle mass|H2O|fatrenal fxn|CO|lung capacity

Abs GI motility|tempty|stom scrt|GI BFSlower abs but extent unaffectedDistr/Elim Alb|fat:H2O|/Vddep on Rx solub

live size|BF|CYP450|Rx t1/2Renal elim All : BF|GFR|PT secretion|#nephron

Monitor renal fxn via creatinine CLRule: use lower doses in geriatric pt

Diseases Impair: p450|Rx excretion|BF to liver

TOLERANCE

Pharmacodynamic Rx resp|[Rx]p|tachyphylaxisOpioids DR right shift|dev rapidlyBenzodiazepine antiepileptic-adr Agonists bronchodilator|asthma

persistent -R in lungs|regShortterm PKA,-ARK,-arrestinLongterm R#

-adr Antagonists HTN|Angina|Prolong|R#Rebound phenomenon|upon Rx w/d

Pharmacokinetic Metabolic|Dispositional[Rx]pdue to cont admin

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Toxicology

Toxicology is governed by the same principles aspharmacology. HOWEVER, overdose characteristicsmay be different from those of therapeutic doses.

Abs rate|extent|stom emptying|bezoarDistr BPrt saturate|free Rx|%bnd|Vd

pH|distr wA & wB|Rx induced

hypoperfusion|distr|delay elimElim f|Rx meta enz saturate|Elim t1/2|1st order|pump saturateDmg liver/kidn|blood pH|perfusion

General Tx Principles

1stKEEP Pt ALIVEABCD airway|breathing|circulation|dextrose

2ndMinimize ToxicityMinimize absorption

(GI decontamination)

Maximize elimination

Induce emesisGastric lavageActivated CharcoalCathartics & LaxativesWhole-bowel irrigation

Renal excretion Forced diuresis Elim wA Rx Elim wB Rx

MDACBiotransformationHemodialysis|perfusion

Consider WBI if Rx is:

Slowly absorbed Fe tablet (Fe2+ not abs by charcoal) Poisons not adsorbed by charcoal Cocaine-filled condoms

Enhance Rate of Elimination

Forced diuresisGive large volume of IV diuretic (furosemide) toincrease urine production. The procedure is obsole

Alkalization of urine|Weakly acid RxElimination of weakly acidic drugs by alkalinizing thurine. As salts and water are reabsorbed in thetubules, the concentration of drugs in urine increas

to generate a favorable gradient for reabsorption. IRx is uncharged and have a favorable PC, it will bereabsorbed passively. The rate of reabsorption depon PC, pKa, and urine pH.Alkalination of the urine will resulting in ion trappinthus, inhibiting reabsorption and promoting excreti

NaHCO3o IV|pH7.5-8.5o Nonionic reabsorption of CO2

alkalinizes the urineo pH in blood relatively small due to

greater volume & buffering powero Useful for ASA& Phenobarbital

Other barbiturates aremetabolized rapidly so Renaexcretion play enough arole for this to be used

ASA 138Da|80%bound|pKa=3.0|wA|active scrtGood PC|reabs|

PhBbt CNS depressant|anticonvulsant|antiepileptic232Da|50%bound|pKa=7.3|wA|active scrtVery fav PC|almost all uncharged @ urine pHExtensively & efficiently reabsorbed

Acidification of urine|Weakly basic RxSame principle as alkalization for weakly acidic druNote that this only works if there is significant non-ionic reabsorption of Rx in DT thus, significantamount of Rx must 1stby filtered or actively secret

NH4Cl|VitCo [NH4]u& [NH4]p|generate gradiento Nonionic reabsorption of NH3 acidify

urineo Enhance elim of MDMA & PCP

Urine is usually acidic anyways & furtheracidification can exacerbate renal complications ofrhabdomyolysis often associated with amphetamineoverdose. RARELY USED

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