general concepts

pH where acid is 50% ionized, 50% non-ionized

• NH4Cl
• vit C
• cranberry juice

• (ex) overdose on PCP, amphetamines
• (ex) hepatic encephalopathy- give lactulose--> gut bacteria-->lactic acid--> NH4+--> eliminate ammonia this way

• NaHCO3
• acetazolaminde

(ex) Aspirin ovordose

how much of the drug gets into the blood

f= area under curve (PO)/ area under curve (IV)

w/ oral--> portal circ--> rapid hepaitc metabolism decrease bioavailability

(ex) Lidocaine (IV vs PO)- huge first pass, no point of giving PO

(ex) Nitroglycerin- give sublingual, bypass first pass, also fast onset

• - how much of drug gets from blood to target organs
• -b/c high protein binding capacity, free fraction gen constant!
• -only unbound drugs cross mem--> effect!!!

• (ex) sulfonamide displace bilirubin from albumin--> jaundice
• (ex) sulfonamide displace warfarin (98% protein bound)--> bleeding

• water soluble
• large
• highly protein bound

3L

5L

12-14 L

• 1/3 of total body water
• within ECF, plasma volume is 3L, rest is ICF

TBW= 40-42L

• volume of the compartment that drug gets into from plasma!
• -where is the drug? blood or tissue? --> look at Vd

• -Low Vd (4-8L)= distrubue in blood, high protein bound. High MW= protein bound, High charges (hydrophilic) = stay in plasma
• -Medium Vd= distribute to extracellular space or body water (ex) high charge but small MW--> interstitial fluid outside plasma, intravascular. so Vd ~ ECF 14
• -High Vd (>body wt)= go to tissues! highest Vd= small MW, lipophilic

Vd is needed to calc loading dose

• Vd= Dose/C⁰
• = amount of drug in body/ plasma drug conc at time zero (usu given for each drug)

• -experimentally determined. So use it to calc dose
• -changing Vd will affect half life!
• -increase Vd-->increase half life
• -increase Clearnce--> decrease half life

oxidation, reduction, hydrolysis

-yield slightly more polar, water soluble metabolites

• -Cyp P450- in smooth ER
• -need O2, NADPH

-Geriatric patients lose phase I first

Cyp 2C9- Phenytoin, Warfarin

• Cyp 2D6- many CV, CNS drugs
• (inhibited by Haloperidol, Quinidine)

No genetic polymorphism for Cyp 12A, 3A4

Cyp 3A4- most active one

macrolide inhibit Cyp--> increase theophylline toxicity

Hydrolysis- pseudocholinesterases genetic polymorphism

• MOA- DA, NE, EPI, 5-HT
• -exogenous compounds (ex) Tyramine

Alcohol metabolism

Acetylation, Glucuronidation, Sulfation

• -yield very polar, inactive mtabolites
• -Glucuronidation- inducible, reduced activity in neonates (ex) Chloramphenicol--> gray baby syndrome!

• -Acetylation- fast vs. slow acetylators
• (ex) drug induced SLE by slow acetylators w/ Hydralazine> Procainamide> Isoniazid

-GLutathione conjugation- deplete GSH, acetominophen toxicity!

elimination= termination of drug action. NOT same as excretion

-property of 1st order kinetics

• - volume of blood cleared of drug per unit time
• -relate rate of elimination of drug to plasma concentration
• -constant in 1st order kinetics
• -same as GFR when no reabsorption/secretion, no plasma protein binding
• -protein bound drug not clearde!

CL= rate of elimination of drug/ plasma drug conc

= Vd x Ke (Ke= elimination constant)

=Free fraction x GFR

constant AMOUNT of drug eliminated per unit time, regardless of Cp.

• -saturation kinetics (ex) drug metabolizing rxn has reached its Vmax.
• -elimination is constant.
• -half life is variable!
• -Cp decreases linearly with time

(ex) phenytoin, ethanol, aspirin (at high dose)

• Elimination rate is proportional to drug conc Cp!
• -constant % (fraction) eliminated per unit time

• -Cp decrease exponentially with time
• -half life constant!
• -clearance constant!
• -elimination rate is variable! (depends on Cp)

half life= 0.7x Vd/Cl

= 0.7 xVd/Cl

= 0.7/ Ke (elimination constant)

= GFR + active secretion - reabsorption

• Clearance= Free Fraction x GFR
• = Vd x Ke

GFR= inulin clearance

-achieve and maintain steady state plasma level of drug that's above minimal effective conc, even at it's lowest Css

rate in= rate out

• -time to reach steady state depends ONLY on elimination half life!
• -independent of dose or frequency of administration!
• -takes about 4~5 half lives to reach steady stat

• Regardless of the rate of infusion, it will take the same amount of time to reach steady state!
• -but Dose affects plasma conc Cp, so although it doesn't affect time to reach SS, it'll affect the DOSE AT steady state!

-give more drug--> reach higher plasma steady state level, but won't get there any faster.eeee

Ko= Cl x Cp (at ss)

use in situations when you can't wait 4~5 half lives to reach steady state (ex) Digoxin half life- 2 days (2x5= 10 days to reach SS!)

• -give one time only loading dose + subsequent maintenance dose.
• -loading dose- usu target plasma level at steady state!

LD= Cp x Vd/ bioavail

Cp= target plasma level

MD= Cp x Cl/bioavail

Cp=target plasma level

Efficacy= max effect a drug can produce

Potency= amount of drug needed for a given effect

• -shift curve to R--> decrease potency, no chnange in efficacy.
• -same Vmax
• -increase Km

(ex) Diazepam + Flumazenil on GABA receptor

• shift curve down--> decrease efficacy!
• -decrease Vmax
• -same Km

(ex) NE + phenoxybenzamine on alpha-receptors

• shift curve to LEFT!
• -increase potency!

(ex) BZDs on GABA potency

• agonist on its own,
• antagonist w/ the endogenous agonist

• -decrease efficacy
• -potency variable

(ex) Morphine + Buprenorphine

substance that produces opposite physiologic effect of an agnist but does not act at the same receptor

(ex) Phenylephrine + Nitroglycerin

measurement of drug safety

LD50/ ED50

want a drug with high TI, steep curve (low variability!)

B1, B2, D1, H2, some 5-HT, Prostacyclin

• also..
• FSH, LH, ACTH, TSH, CRH, PTH, hCG,
• ADH (V2), MSH, Calcitonin, GHRH, Glucagon

Alpha2, M2, D2, Opioid (mu), some 5HT

M1, M3, Alpha1

• also..
• -GnRH, Oxytosin, ADH (V1), TRH

Nitrates, ANP, BK, His (some)

• Estrogen
• Testosterone
• Cortisol
• vitD

T3,Tx

Insulin, IGF-1, FGF, PDGF

Prolactin, GH, Cytokines, EPO, Somatostatin

• vascular SM contract
• pupillary dilator (mydriasis)
• bladder sphincter contract
• increase glycogenolysis (increase glucose)
• decrease renin release

• decrease NE release
• decrease insulin release
• platelet aggreation

• increase HR
• increase heart contractility
• increase Renin release
• increase Lipolysis

• vasodilate
• bronchodilate
• increase heart rate
• increase contractility
• relax uterus
• increase glycogenolysis (glucose in SKM--> tremor!
• increase lipolysis!
• also increase insuline release! (alpha2 decreases it)
• (so tissues take up the released glucose)

• contract GI muscle
• CNS effects

• decrease HR
• decrease contractility

• -increase secretion! (sweat, salivate, lacrimate, GI)
• -increase gut peristalsis
• -increase bladder contract
• -bronchoconstrict
• -pupil constrict (miosis)
• -ciliary muscle contract (accomodate)

relax kidney vascular smooth muscle!

increase renal RBF, GFR, increase Na secretion!

• modulate neurotransmitter release
• esp. brain

• increase nasal, bronchial mucus production
• contract bronchioles
• pruritis
• pain

Parietal cell gastric acid secretion!

ADH--> vasoconstrict

ADH--> Vs-->cAMP--> aquaporin mobilize--> increase water permeability--> concentrate urine

• increase HR, decrease BP! increase PP
• (increase CO--> increase sys BP, vasodilate--> decrease dias BP--> increase PP, decrease MAP)

• alpha1--> increase BP
• beta1--> increase HR, CO, PP
• reflex bradycardia!

• NO effect on B2
• NE NEVER decrease BP!!

• Ganglionic blockade!
• Hexamethonium
• Mecamylamine

• beta1--> increase HR, CO, PP
• beta2--> decrease BP

-looks like Isopreterenol!

• beta1--> increase HR, CO, PP
• beta2--> decrease BP
• alpha1--> increase BP

antagonistic effect on BP cancle--> same MAP, just increase PP, HR!

• alpha1> beta 1, 2
• looks like NE!

increase HR, PP, BP--> reflex tachycardia

• -bronchodilate
• -glucose increase
• -fat breakdown
• -increase insulin

• EPI reversal!- at high doses B1, alpha1 predominate, NE, EPI look same. Give alpha1 blocker-->
• if pt on NE--> HR still high, but no increase in BP
• if pt on EPI--> HR kept high, but BP drops! (unmask beta2)