-
pKa
pH where acid is 50% ionized, 50% non-ionized
-
weak acid better absorbed in acidic environ,
better excreted in basic environ !
-
To acidify urine
- NH4Cl
- vit C
- cranberry juice
- (ex) overdose on PCP, amphetamines
- (ex) hepatic encephalopathy- give lactulose--> gut bacteria-->lactic acid--> NH4+--> eliminate ammonia this way
-
-
Bioavailability
how much of the drug gets into the blood
f= area under curve (PO)/ area under curve (IV)
-
First pass effect
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
-
Distribution (what affects it?)
- - 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
-
Traits of drug safe in pregnancy?
- water soluble
- large
- highly protein bound
-
approximate fluid compartment volumes (70kg)
-plasma volume?
3L
-
approximate fluid compartment volumes (70kg)
-blood volume?
5L
-
approximate fluid compartment volumes (70kg)
-ECF volume?
12-14 L
- 1/3 of total body water
- within ECF, plasma volume is 3L, rest is ICF
-
approximate fluid compartment volumes (70kg)total body water?
TBW= 40-42L
-
Volume of distribution (Vd)
-what is it?
-what do low, high values mean?
- 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
-
Volume of distribution (Vd) equation?
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
-
Biotransformation: Phase I, PhaseII
Phase I metabolism
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 P450
-which ones have genetic polymorphism?
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
-
pt w chronic bronchitis on bronchodilators, antibiotics
(ex) theophylline, macrolides
macrolide inhibit Cyp--> increase theophylline toxicity
-
Non microsomal metabolism
Hydrolysis- pseudocholinesterases genetic polymorphism
- MOA- DA, NE, EPI, 5-HT
- -exogenous compounds (ex) Tyramine
Alcohol metabolism
-
Phase II 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
definition of half life?
elimination= termination of drug action. NOT same as excretion
- half life= time to eliminate plasma level of drug by 50%
- -property of 1st order kinetics
-
Clearance
- - 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
-
Zero order elimination kinetics
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)
-
1st order elimination kinetics
- 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
-
half life equation?
= 0.7 xVd/Cl
= 0.7/ Ke (elimination constant)
-
Renal elimination
rate of elimination?
= GFR + active secretion - reabsorption
- Clearance= Free Fraction x GFR
- = Vd x Ke
GFR= inulin clearance
-
Steady state
GOAL?
-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
-
Infusion rate and steady state?
- 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
-
Infusion rate equation?
Ko= Cl x Cp (at ss)
-
Loading dose
-what is it?
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!
-
Loading dose equation
LD= Cp x Vd/ bioavail
Cp= target plasma level
-
Maintenance dose equation
MD= Cp x Cl/bioavail
Cp=target plasma level
-
in renal or liver disease, decrease maintenance dose!
loading dose unchanged.
-
Efficacy vs Potency
Efficacy= max effect a drug can produce
Potency= amount of drug needed for a given effect
-
Competative antagonist
- -shift curve to R--> decrease potency, no chnange in efficacy.
- -same Vmax
- -increase Km
(ex) Diazepam + Flumazenil on GABA receptor
-
Noncompetative antagonist
- shift curve down--> decrease efficacy!
- -decrease Vmax
- -same Km
(ex) NE + phenoxybenzamine on alpha-receptors
-
Potentiator
- shift curve to LEFT!
- -increase potency!
(ex) BZDs on GABA potency
-
Partial agonist
- agonist on its own,
- antagonist w/ the endogenous agonist
- -decrease efficacy
- -potency variable
(ex) Morphine + Buprenorphine
-
Physiological antagonism
substance that produces opposite physiologic effect of an agnist but does not act at the same receptor
(ex) Phenylephrine + Nitroglycerin
-
Therapeutic index
measurement of drug safety
LD50/ ED50
want a drug with high TI, steep curve (low variability!)
-
Gs--> cAMP--> PKA--> CREB
ANS receptors?
B1, B2, D1, H2, some 5-HT, Prostacyclin
- also..
- FSH, LH, ACTH, TSH, CRH, PTH, hCG,
- ADH (V2), MSH, Calcitonin, GHRH, Glucagon
-
Gi--> decrease cAMP
ANS receptors?
Alpha2, M2, D2, Opioid (mu), some 5HT
-
Gq--> PLC--> IP3, DAG--> Ca, PKC
ANS receptors?
M1, M3, Alpha1
- also..
- -GnRH, Oxytosin, ADH (V1), TRH
-
cGMP, NO signaling
who?
Nitrates, ANP, BK, His (some)
-
Cytosol steroid receptor
- Estrogen
- Testosterone
- Cortisol
- vitD
-
-
RTK--> Ras/MAP kinase path
Insulin, IGF-1, FGF, PDGF
-
Receptor associated tyr kinases--> JAK/STAT
Prolactin, GH, Cytokines, EPO, Somatostatin
-
alpha1--> Gq
-smooth muscles, liver, kidney
- vascular SM contract
- pupillary dilator (mydriasis)
- bladder sphincter contract
- increase glycogenolysis (increase glucose)
- decrease renin release
-
alpha 2 --> Gi
presynaptic, platelets, pancreas
- decrease NE release
- decrease insulin release
- platelet aggreation
-
B1--> Gs
-heart, kidney, fat
- increase HR
- increase heart contractility
- increase Renin release
- increase Lipolysis
-
B2--> Gs
blood-->EPI--> all BV, broncial, uterine smooth muscle, heart, liver, pancreas
- 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)
-
M1--> Gq--> Ca
-CNS, GI
- contract GI muscle
- CNS effects
-
M2--> Gi-->dec cAMP
Heart
- decrease HR
- decrease contractility
-
M3--> Gq--> Ca
smooth muscle (except vascular), glands
(sweat, piloerector m. is SNS, but Ach-->M3)
- -increase secretion! (sweat, salivate, lacrimate, GI)
- -increase gut peristalsis
- -increase bladder contract
- -bronchoconstrict
- -pupil constrict (miosis)
- -ciliary muscle contract (accomodate)
-
D1--> Gs
kidney vascular, GI vascular, Coronary vascular
relax kidney vascular smooth muscle!
increase renal RBF, GFR, increase Na secretion!
-
D2--> Gi
presynaptic? CNS
- modulate neurotransmitter release
- esp. brain
-
H1--> Gq
- increase nasal, bronchial mucus production
- contract bronchioles
- pruritis
- pain
-
H2-->Gs
Parietal cell gastric acid secretion!
-
V1--> Gq
-vascular smooth muscle
ADH--> vasoconstrict
-
V2--> Gs
-collecting duct kidney
ADH--> Vs-->cAMP--> aquaporin mobilize--> increase water permeability--> concentrate urine
-
Drug tracings
-nonselective beta agonist (ex) Isopreterenol
- increase HR, decrease BP! increase PP
- (increase CO--> increase sys BP, vasodilate--> decrease dias BP--> increase PP, decrease MAP)
-
Drug tracing
-NE
- alpha1--> increase BP
- beta1--> increase HR, CO, PP
- reflex bradycardia!
- NO effect on B2
- NE NEVER decrease BP!!
-
Drug tracing
-how to block reflex tachycardia, bradycardia?
- Ganglionic blockade!
- Hexamethonium
- Mecamylamine
-
Drug tracing
low dose EPI
- beta1--> increase HR, CO, PP
- beta2--> decrease BP
-looks like Isopreterenol!
-
Drug tracing
medium dose EPI
- beta1--> increase HR, CO, PP
- beta2--> decrease BP
- alpha1--> increase BP
antagonistic effect on BP cancle--> same MAP, just increase PP, HR!
-
Drug tracing
High dose EPI
- alpha1> beta 1, 2
- looks like NE!
increase HR, PP, BP--> reflex tachycardia
-
when you can't tell apart high dose EPI and NE,
look for Beta2 specific signs!
OR EPI reversal!
- -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)
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