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Down-Regulation
  • Receptor Dynamics
Decreases the max. response produced-->reduction in "responding units"

Ex. Heart failure, hyperadrenergic state-->down-regulation of B-adrenergic receptors--->receptor desensitization & internalization-->decrease in B-adrenergic receptors open to interact w/ adrenergic agonists on cardiomyocytes
Up-Regulation
  • Receptor Dynamics
cells create spare receptors & only a fraction of available receptors requires engagement to provide max. response

Presence of spare receptors increases sensitivity to the agonist because there is more likelihood of an interaction
Presence of Spare Receptors
EC50 < Kd means spare receptors exist

(concentration for 50% of max. effect is less than concentration for 50% of maximal binding)
Quantal Response
differences in drug responsiveness bet. individuals across the population

administer [increasing] of drug to elicit a fixed quantal response
Cumulative frequency distribution
production of response: distributed according to log of [ligand] as a freq. distribution

Cum. freq. dist = sum. freq. @ each [] = pharmacodynamic variability w/in a population
Effector Mechanisms: Signal Transduction
ligand induces change in receptors-->initiation of effector cascades--> biologic response
Signal Transduction: transcriptional regulation
Ex. Corticosteroids & their receptors

when ligand binds, receptor acts as transcriptional regulator--> alteration of regulated genes-->altered expression of proteins
Signal Transduction: Enzyme Receptors
Ex. NSAID (aspirin) inhibit cyclooxygenase, stopping production of prostaglandins

Ligand binds enzyme-->alteration of activity
Signal Transduction: Ion channel receptors
Ex. Calcium channel blockers interrupt calcium influx, inducing sm. m. relaxation in HTN & extracellular matrix remodeling in CT diseases

ligand binds & alters ion channel conductance
Signal transduction: cell surface protein receptors
cell surface receptor-->2nd messenger--> response from cell

2nd messengers:
cAMP: through guanine nucleotide binding proteins-->adenylyl cyclase: B-adrenergic receptors

cGMP: activate guanylyl cyclase

Phos. tyrosines: kinase activators: growth factor receptors
Orally Administered Drug
  • Pharmacokinetics
what the body does to the drug
  • dissolution(stomach)
  • solubilization (dissolved particles into solution)
  • absorption across GI mucosa into portal circulation
  • first pass metabolism in liver
  • systemic circ. distribution
  • further metab. in organs
  • excretion: sweat, urinary, fecal, exhaled
Absorption of Drugs
  • Transport across cell membranes
  1. Passive diffusion: lipid cell membrane, better for unionized (more lipophillic), can NOT be limited
  2. Active transport: against [gradient], ATP-transporters (Ex. multidrug resistance p-glycoprotein)
  3. Endocytosis; large molecules
Absorption Rate
  • General determinants
dissolution, flow, SA @ absorption site, lipophillicity, [gradient] (Fick's law)

Best absorption = lipid, small, non-polar, nonionized
If oral: want weak acid
First Order Kinetics
  • absorption
rate of elimination is proportional to the amount of drug in the body

+[]=+ elim/time

  • [drug] decreases exponentially w/ time
  • rate of elim. proportional to [drug]
  • T1/2= constant regardless of [drug]
Volume of Distribution: Vd
  • 1st orer kinetics
=amt of drug in body/plasma[drug]

high lipophillicity = high Vd & high T1/2 (stays in tissues)
low lipo = low Vd= stays in blood (Neuromuscular blockers)

can exceed the total volume of the body Ex. digoxin Vd=5,000L

Completely retained in plasma: Vd=plasma vol. (4% body wght.)

high Vd can be altered by liver disease (less albumin) & kidney disease (+proteinuria)


Clearance (Cl)
  • 1st order kinetics
=rate of elim/plasma[drug]

volume of plasma from which the drug is completely removed/unit time

amount eliminated is proportional to [drug] in plasma
Zero Order Elimination
rate of elimination is constant, regardless of []

pathways rapidly saturated & work to their limit

constant amt. of drug eliminated/unit time

[drug] decreases linearly
rate elim. = constant
no true T1/2
  • EtOH (only w/ true 0 order)
At high doses
  • Phenytoin (dilantin)
  • Salicylates
  • Theophylline
  • Thiopentone (very lg. doses)
  • Warfarin
  • Herparin
  • Aspirin
  • Tolbutamide
Distribution of Drugs
Blood flow: most rapid in tissues w/ high blod flow; lungs, kidneys, liver, brain
Capillary Permeability: tissue dependent, slow into CNS bc of tight junction, liver & kidney more porous

Accounting for differences in tissue/blood @ equilibrium
  • distribution
  • Lipid solube drugs can dissolve in adipose tissue
  • Drugs can bind to intracellular sites: increase [drug] in the tissue compartment
  • Plasma protein binding: a bound drug has no effect (but if unbound they're succeptible to metabolizing enzymes)
Plasma Protein Binding
  • Distribution
  • Differences in tissue/blood @ equilibrium
most drugs bind to proteins: usually Albumin or Alpha-1-acid glycoprotein (AAG)

More highly bound= longer duration of action & lower volume of distribution

Binding: reduces free drug availabe for distribution bc of restricted diffusion out of the vascular compartment
Plasma Protein Binding
  • Distribution
  • Differences in tissue/blood @ equil.
High extraction ratio drug = high Cl (bc low protein binding)

Low extraction ratio =  Cl very dependant on amt of protein binding

Highly bound = give much higher dose to get therapeutic effect
Free Drug: Interactions w/ Plasma binding
Highly protein bound drug (warfarin, diazepam, propranolol, phenytoin) + another drug competing for binding site--> increase in amt. of free drug

Ex. Drug A is 97% bound & if 3% of it is displaced by another drug, then the free [drug] doubles, but if a drug is 70% bound & 3% is displaced, this will make little difference
% bound
% bound = bound/(bound+unbound)
Elimination of Drugs
Clearance & T1/2
Cl: depends on blood flow to the organ

T1/2 is inversely prop. to total Cl
+ total Clearance = short half-life
Half-life
  • Elimination
time req'd for amt. of drug to fall to 50% of an earlier measurement

4 T1/2 = 94% eliminated

T1/2= (0.7 x Vd)/Cl
Multicompartment Model
  • Distribution
body doesn't just contain blood (which Vd is based on), there is fat, muscle, brain tissue....

graphically [] vs time: rapid fall in [blood] (rapid redistribution)-->plateau ([blood]=[tissue])-->slower gradual fall (elimination)
Delivery of drugs to different compartments
high blood flow = quick delivery: brain, liver, spleen, kidney

low Q = slower delivery: fat, muscle
(graphically); much lower [] & longer time
Tissues involved in drug metabolism
Liver: most metabolism; smooth ER
First pass metabolism

GI: contributes to first pass clearance
Kidneys
Skin: if topical application
Biotransformation
route of drug clearance involving metabolism of lipophillic drugs-->hydrophillic derivatives (for kidney elimination)

products may have greater, lesser, or different activity from parent compound

Variation in rate: chemical exposures (drugs, diet, supplements, smoke), genetics, age, disease
Pathways of Hepatic Biotransformation
Phase I: formation of product susceptible to phase II conjugative reaction. Oxidation, reduction, deamination, hydrolysis

Phase II: synthetic reactions, conugation of subgroups to other func. groups on drug.  Generates more water soluble product that can be excreted
Phase I
  • hepatic biotransformation
Oxidation, Reduction, Deamination, Hydrolysis
  • Functionalization rxns. (can add new -OH grp. or expose a group by hydrolysis)
  • Catalyzed by oxidases in ER, mainly cytochrome P450 enzymes
  • CYP450s are mainly in hepatocytes, also in kidney, lung, intestine, skin, testes, brain
Require: 1. P450 2. P450 reductase 3. NADPH 4. Oxygen
CYP450 nomenclature
ex. P4502E1

"2": CYP family (>40% homology)
"E": subfamily (>60% homology)
"1": particular isoform
Major human cytochrome P450s (aka hepatic mono-oxygenases)
  • CYP1A2
  • CYP2C9/10 & CYP2C18/19**antiseizure
  • CYP2D6**opiates
  • CYP2E1
  • CYP3A4** 50% of drugs
CYP1A2
  • universal in liver
  • induced by: smoking, eating grilled meats
  • metabolizes: caffeine, theophylline, phenacetin by dealkylations
CYP2C9/10 & CYP2C18/19**
  • 2C family very important
  • Antiseizure meds: Phenytoin, taxol, diclofenac, piroxicam, diazepam, cycloguanil, imipramine
  • Polymorphism: 2C9 (Tolbutamide) & 2C19 (Mephenytoin)
CYP2D6**
  • expressed mainly in liver
  • Opiates: Codeine, debrisoquine, propranolol, captopril, dextromorphan, nortryptiline
  • Polymorphism: Sparteine: 10% caucasions, 2% mongoloids

CYP2E1
  • mainly in liver, also in peripheral lymphocytes
  • Induced: EtOH (role in alcoholic metabolism)
  • Industrial chemicals: benzene, styrene, vinyl chloride, carbon tetrachloride, chloroform, ethyl carbamate
CYP3A4****
metabolizes 50% of drugs
  • must abundant human isoform (liver, intestine)
  • Induced: barbituates, rifampicin, glycocorticoids
  • Most important CYP450 in drug metabolism: nifedipine, quinidine, taxol, erythromycin, contraceptives, warfarin, cyclosporin, midazolam, lidnocaine
Phase II
  • biotransformation
Synthetic Conjugation Rxns.

hydrophillic
endog cofactor + drug = more polar, cleared by kidney/bile

Mainly in liver, rxn:cofactor:substrate
  • glucuronidation:UDP-glucuronic acid:acetominophen, diazepam, morphine
  • Sulfation: PAP-sulfate:acetaminophen, estrone, methyldopa
  • Acetylation:acetyl coA:clonazepam, mescaline, sulfonamides
  • Glutathione conjugation:glutathione:ethacrynic acid (metabolite of acetaminophen)
  • Methylation:transmethylases:NT & Hormones****
Phase I & II integration
  • biotransformation
Phase I enzyme must introduce the appropriate functional group in order to be metabolized by phase II conjugation

drug in plasma-->oxidized metabolite-->conjugated metabolite

product of phase I can be excreted in urine/bile IF it is polar enough
Pharmacological Deactivation
  • Biotransformation
most drugs: action of metabolite is less than action of drug

Amphetamine: inactivated by deamination
Pharmacological Activation
  • Biotransformation
few drugs: inactive prodrugs-->active drugs

Sulindac (NSAID): phase I produces active metabolite in gut contents (NOT GUT WALL)

Codeine:req. CYP2D6-catalyzed-O-methylation-->morphine (which later)-->potent analgesic (via glucuronidation)*

It is unusual for phase II metabolites to be active
Hepatic Drug Clearance Rate
Rateelimination depends on
  • liver ability to metabolize: age, disease, gender, genetic factors*
  • presence of other drugs: Enzyme induction & inhibition, inhibitors of intestinal P-glycoprotein
  • Hepatic Blood flow
Genetic Factors affecting liver clearance
  • Elimination
  • Hydrolysis of esters
  • Acetylation of amines: 50% of white & AA people in US=slow acetylaters
  • Oxidation
Enzyme Inducers
  • Elimination:presence of other drugs
results from selective increase in synthesis of CYP450 dependent drug-oxidizing enzymes in the liver
Enzyme Inhibition
  • Elimination: presence of other drugs
most likely inhibitors involved in serious drug interactions:
  • amiodarone
  • cimetidine
  • furanocoumarins (grapefruit juice)
  • ketoconazole
  • Ritonavir (HIV protease inhibitor)

Suicide Inhibitors
drugs metabolized to products that irreversible inhibit the metabolizing enzyme
Inhibitors of intestinal P-glycoprotein
  • Enzyme inhibition
P-gp is important modulator of intestinal drug transport & typically functions to expel drugs from the mucosa into the lumen...failure = buildup
Hepatic Blood Flow
  • Affects rate of elimination
High blood flow = less time to metabolize-->extraction ratio falls, especially if intrinsic clearance is low
Low Extraction Ratio drugs
kinetics (how the body deals w/ the drug) depends on enzymatic activity

(enzyme inducer-->single apple picker w/ 4 arms!)
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