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Pharmacokinetics

Absorption
 Transfer of drug from site of administration to the bloodstream
 Rate and extent of absorption: depends on environment, chemical characteristics of drug, route of administration

Mechanisms of Absorption
a. Passive diffusion
 concentration gradient from higher to lower concentration
 No need for carrier
 Not saturable
 Low structural specificity
 Water soluble drugs: penetrate cell membrane through aqueous channels or pores
 Lipid soluble drugs: readily move across most biologic membranes

b. Facilitated diffusion
 Specialized transmembrane carrier proteins facilitate passage of large molecules
 Carrier proteins undergo conformational changes
 Still from higher to lower concentration of drug
 No need for energy
 Saturable
 May be inhibited by compounds that compete for the carrier

c. Active transport
 Involves special carrier proteins
 Energy dependent (hydrolysis of ATP to produce energy)
 Against a concentration gradient
 Saturable
 Selective
 May be competitively inhibited by other substances na active transport

d. Endocytosis and exocytosis


 To transport exceptionally large drugs
 Endocytosis: engulf the drug by the cell membrane, transport into the cell by pinching off the drug-filled vesicle
 Exocytosis: done to secrete substances (ex norepinephrine) out of the cell through vesicle formation

1. Effect of pH on drug absorption


 Drug passes through membranes if uncharged
 If weak acid, it has to be protonated para maabsorb siya
 If weak base, it has to be deprotonated
2. Blood flow to the absorption site
 Intestines = more blood flow = greater absorption (compared sa stomach ache)
3. Total surface area for absorption
 High surface sa intestine (bc of microvilli brush borders) = more efficient absorption
4. Contact time at the absorption surface
 If walang laman yang tiyan mo, your drug’s not that well absorbed bc dirediretso lang siya
 If you eat, madedelay gastric emptying mo into the intestine and babagal yung absorption ng drug
5. Expression of P-glycoprotein

• P-glycoprotein: transmembrane transporter protein


• It moves substances (like drugs) from tissues to blood so it pumps drugs out of the cell
• High expression of P-glycoprotein: drug absorption is reduced

• Rate and extent to which an administered drug reaches the systemic circulation

• How to determine: compare plasma levels of the drug after a route of administration (except IV!) with the plasma levels of the drug
after IV administration.

Factors that influence bioavailability o First pass hepatic metabolism


If drug is rapidly metabolized by liver or gut wall, bago palang dumating siya sa systemic circulation, magkakaproblema na tayo
diyan kasi the drug is decreased

NTG – >90% ay metabolized na sa first pass metab kaya transdermal or sublingual route siya
o Solubility of drug

Hydrophilic drugs: poorly absorbed kasi di carry magcross ng lipid bilayer of the cell membrane

Lipophilic drugs: poorly absorbed kasi insoluble sa aqueous body fluids so di siya makakapunta dun sa near nung lipid bilayer kasi
aqueous place (ECF) then lipid bilayer then aqueous place ulit (cytosol) basta ganun u get the point :----)

Drug should be largely lipophilic w some solubility in aqueous solutions kaya most drugs ay WA or WB
o Chemical instability
• Some drugs (penicillin G) unstable sa pH of gastric contents
• Others naman (insulin) they get destroyed sa GI tract
o Nature of drug formulation

• Particle size, salt form, crystal polymorphism, enteric coatings, excipients


Bioequivalence
• 2 drug formulations mej mej same bioavailability and time to reach peak blood concentration
Therapeutic Equivalence

• Same dosage form, same API, same route of administration, same clinical and safety profiles (clinical effectiveness – max serum
drug concentration and time required to reach peak conc)
• Bioequivalent drugs, not always therapeutically equivalent

Drug Distribution

• Process by which drug reversibly leaves the bloodstream and enters interstitium (ECF) and the tissues

• If IV route, wala nang absorption absorption pa, distribution na agad at time 0 (distribution is immediately after administration to
rapid fall in drug concentration sa blood kasi nga the drug goes na to tissues)

a. Blood flow
• High blood flow = rapid distribution to tissues

• High blood flow sa liver, kidney, brain and heart. Low blood flow sa skeletal muscles, skin, adipose tissue

b. Capillary permeability

• Depends on structure of the capillaries like are there slit junctions or like are there pores where the molecule can pass through
ganun

• Depends din on chemical nature of drug cause yay babalik na naman sa lipid soluble water soluble blahh
c. Binding of drugs to plasma proteins and tissues
• Increased binding = decreased free drug concentration

• Reversible binding to plasma proteins of the drugs eh if nakabind na siya, it can’t diffuse into our out of membranes kasi gets big na
nga yung protein idadagdag mo pa yung size ng drug

• Albumin: major drug-binding protein; acts as drug reservoir (habang naeeliminaet the drug, albumin’s there to release the bound
drug para constant yung amount ng drug na nasa plasma)

• Drugs naman can also bind sa tissue proteins, so if bound sila sa tissues proteins, maproprolong yung action niya wc may lead to
local drug toxicity

d. Lipophilicity
• Lipophilic durgs dissolve in the lipid membranes and penetrate the entire cell surface

• Hydrophilic durgs gotta pass through slit junctions cause they can’t penetrate nang ganun ganunan lang
e. Volume of Distribution
• Fluid volume required to contain the entire durg in the body at the same concentration measured in the plasma

• Amount of drug in the body divided by plasma concentration at time zero


• Distribution into water compartments
• Plasma compartment

• Malaki drug mo or or like super bound siya sa protein, it can’t pass through slit junctions so trapped na siya sa plasma compartment
so di na siya madisdistribute so low Volume of distribution

• Ex Heparin
• Extracellular fluid

• Drug has low MW pero hydrophilic: can pass through the slit junctions nung capillary into the ISF

• Prob: hydrophilic siya so di siya pweds dumaan sa lipid membranes so di sila makakapasok sa ICFso either nasa plasma lang sila
or nasa interstitial fluid (ECF = plasma + interstitial fluid)

• Total body water


• Low MW drug + lipophilic pasok sa banga hanggang Intracellular fluid
!!!!!!
• Ex Ethanol
• How to determine volume of distribution
• Lam mo na yan Dose over concentration at time zero
• Effect of Vd on drug half-life

• Drug elimination depends on amount of drug delivered sa place na mamemetabolize siya per unit time

• If high yung volume of distribution, half-life of drug is increased and extended yung duration of action nung drug. High Vd means
drug is nasa extraplasmic

space and not sa excretory organs.

• Major routes of elimination: o Hepatic metabolism o Biliary elimination o Urinary elimination

• Elimination decreases plasma conc exponentially – constant fraction of drug is eliminated


• Most are eliminated na first order kinetics (zero-order: phenytoin, ethanol, aspirin)

o First order: constant fraction of drug is metabolized per unit time

o Zero order: rate of metabolism is constant over time; rate elimination is constant and doesn’t depend sa drug conc
• Metabolism production of products with increased polarity so naeeliminate the drug
• Clearance

o Estimates the amount of drug cleared from the body per unit of time

o Cl = 0.693 x Vd/t1/2

Reactions of drug metabolism

• Kidney can’t eliminate lipophilic drugs that readily cross cell membranes and are reabsorbed sa
DCT
o Lipid soluble agents have to be metabolized first into more polar substances (sa liver)
Phase 1
• Functionalization Reactions

• Convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group like –OH or NH2

• Involve reduction, oxidation or hydrolysis


• May increase, decrease or no effect on pharmacologic activity
a. Phase I reactions using the P450 system

• Cytochrome P450 system aka microsomal mixed-function oxidases do the whole drug metabolism thing pag phase I

• Superfamily of heme-containing isozymes located primarily sa GI tract and liver

• Important for metabolism of endogenous compounds (steroids, lipids) and of exogenous substances (xenobiotics)

• CYP1A2 – 1 is the superfamily, A is the subfamily, 2 is the specific isozyme bonggels


• Genetic variability
• P450 system exhibit variations among individuals and racial groups
• Variations – hello altered drug efficacy and hello adverse events

CYP2D6 exhibits genetic polymorphism – if mutated CYP2D6 mo, mababawasan capacity to metabolize substrates
• Ex if no CYP2D6 enzyme, parang no effect codeine for u

• CYP2C subfamily - if u take clopidogrel (anticoagulant to prevent blood clots), tas mej wala kwenta CYP2C19 mo, at risk ka pa rin
for stroke or

MI kasi it’s a prodrug (like it’s inactive and u have to metabolize it first para maging active metabolite)

• Specificity

• So like there’s lots of isoforms ng mga P450 enzymes and these many isozymes can metabolize different substrates (drugs)

• Then one drug can like be the substrate for metabolism ng many P450 enzymes

• CYP3A4: found in the intestinal mucosa, accounts for first pass metabolism of drugs like chlorpromazine and clonazepam

• Inducers
• Promote activity of CYP isozymes
• Increase synthesis of one or more CYP isozymes
• Increased drug metabolism:
Decreased plasma drug concentration

Decreased drug activity if the metabolite is inactive

Increased drug activity if metabolite is active

Decreased therapeutic drug effect


Inhibitors

• May lead to serious adverse events

• Most common form of inhibition: competition for the same isozyme

• Some drugs can inhibit reactions na di naman sila yung substrate so like gets epal and it leads to drug drug interactions

• Warfarin: super daling mainhibit ng other drugs yung metabolism niya (ex Omeprazole is a potent inhibitor nung 3 CYP isozymes
that metabolize warfarin so if Omeprazole + Warfarin, mas di mamemetabolize the warfarin hello bleeding)

• Other CYP inhibitors – erythromycin, ketoconazole, ritonavir

• Grapefruit juice naman, it inhibits CYP3A4 wc metabolizes nifedipine, clarithromycin and simvastatin so hello toxicity

b. Phase I reactions not involving the P450 system


• Amine oxidation (ex oxidation of `catecholamines or histamine)
• Alcohol dehydrogenation (ex ethanol oxidation)
• Esterases (metabolism of aspirin in the liver)
• Hydrolysis (procaine metabolism)

Phase II
• Conjugation Reactions

• If polar naman na yung phase I metabolite, pweds na iexcrete ng kidneys. BUTTTTT marami pa ring phase I metabolites na
lipophilic so di mahirap maexcrete

• Conjugation as in magdadagdag ka ng endogenous substrate sa metabolite like glucuronic acid, sulphuric acid, acetic acid, amino
acid hello water soluble compounds na pwede na iexcrete + di na active or wala na magigign effect sa bodehh

• Except !! Morphine-6-glucuronide wc is more potent than morphine

Drug Clearance by the Kidney


• Most important route of elimination is sa kidney into the uring

• If u have a bad kidney, it’s hard to excrete drugs so u r at risk for drug accumulation and adverse effects huhu

• Glomerular filtration, active tubular secretion, passive tubular reabsorption

1. Glomerular filtration

• Glomerular filtration rate: 125 mL/min yung normal but mas mababa if u got a bad kidney

• Free drug flows through the capillary slits into the Bowman’s capsule as part of the glomerular filtrate

• Lipid solubility and pH do not influence filtration


2. Proximal tubular secretion
• Some of the drugs na nasa glomerular filtrate can be secreted
3. Distal tubular reabsorption

• As the drug goes here, its concentration increases and is now greater than yung conc niya sa perivascular space. If the drug is
uncharged (so di siya super water soluble) it can diffuse out of the nephric lumen (kasi diba high yung conc niya sa filtrate so diffusion, high to
low concentration) and back into the systemic circulation

• Manipulate pH of urine para maionize yung drug and maminimize yung pagbabalik into the systemic circulation of the drug and to
increase drug clearance

• Ion Trapping
o Weakly acidic drugs: alkalinize the urine to eliminate it
o Weakly basic drugs: acidify the urine

o Ex Phenobarbital (weak acid) overdose: give sodium bicarbonate to alkalinize the urine and di na marereabsorb yung drug sa DCT and
maeeliminate na siya !!!!

Role of drug metabolism in drug clearance

o Most drugs are lipid soluble and If di siya minetabolize, wala magdidiffuse lang ulit siya out of the lumen pag higher na yung conc ng
drug sa filtrate compared sa perivascular space
o To minimize reabsorption, ya gotta biotransform the drugs to make them polar
o Pag polar na or ionized na yung drug, di na yun magbaback diffuse out of the kidney lumen

Clearance by Other Routes


o Intestines, bile, lungs, breast milk, skin, sweat, saliva, tears

o Drugs not absorbed after oral administration or drugs secreted directly sa intestines or bile are eliminated in the deces
o Lungs: elimination of anesthetic gases like isoflurane

o Do not breast feed If you’re taking drugs right now kasi your baby will drink the eliminated drug or its metabolites
o Total Body (Systemic) Clearance (CLtotal)

o Sum of all clearances from the drug-metabolizing and drug-eliminating organs o Kidney: major organ of elimination
o Liver: major organ of metabolism (plus excretion into the bile)
Situations na increased yung drug half life mo (like mas matagal maeliminate or mametabolize the drug) so u gotta decrease the dosage or
make the intervals less frequent
o Diminished renal or hepatic blood flow

o Decreased ability to extract drug from plasma (like in renal diseases) o Decreased metabolism or in hepatic insufficiency