linear

• How most drugs are eliminated
• Constant proportion (fraction) of total  amount of drug is eliminated per unit of time ( amount will vary proportionately with [drug])
• [drug] in body diminishes logarithmically over time
• elimination rate constant
• steady state
• half life

• fraction (or %) of the amount of drug in the body removed per unit of time
• applies only to 1st order pharmacokinetics
• K_e of 0.3 hr^-1 means 30% of the total amount of drug in the body will be eliminated every hr

equilibrium between the rate of elimination and the rate of administration

• takes 5 half lives of a constant infusion to reach (occurs at 6th dose)

• the amount of time required for the plasma drug concentration to decrease by 1/2
• applies only to 1st order pharmacokinetics

• Takes 5 half lives to eliminate from system
• 1 t1/2 = 50 %
• 2 t1/2 = 25%
• 3 t1/2 = 12.5%
• 4 t1/2 = 6.25%
• 5 t1/2 = 3.123%

Zero order pharacokinetics

elimination

non-linear

• changes in clearance, volume of distribution and t1/2 as a fxn of dose or [drug] is due to sat. of absorption, protein binding, metabolism, or active renal transport of durg
• elimination becomes saturated as the dose or [drug] increases

• capacity-limited elimination
• saturable kinetics
• dose-dependent kinetics
• concentration-dependent kinetics
• Michaellis-Menton kinetics

changes in parameters such as clearance, volume of distribution and t1/2 as a fxn of dose or [drug] is due to sat. of absorption, protein binding, metabolism, or active renal transport of durg

• parameters may vary depending on administration dose
• may be at different kinetic levels of absorption, distribution and/or elimination

decreased bioavailability at higher doses

•  
  • amoxicillin
  • metformin
  • calcium products 
  • methotrexate

shown with the antibacterial agent dicloxacillin

• has saturable active secretion in the kidneys, resulting in a decrease in renal clearance with an increase in dose

Phenytoin has saturable metabolism

• increase in the dose would result in a decrease in hepatic clearance and a more proportionate increase in the drug levels

1st order vs. zero order

kinetics

1st order

1. [drug] ↓ exponentially with time
2. rate of elimination is proportional to [drug]
3. graph of log [ ] vs. time is linear
4. t 1/2 is constant regardless of [drug]

1.      [drug] ↓ linearly with time    
2. Rate of elimination is constant
3.     Rate of elimination is independent of [drug]
4. No true t 1/2

• saturable nonlinear elimination
• free serum [ ] can substantially ↑ for a prolonged period, despite a total serum [ ] in or below the therapeutic range. 
• possible causes of altered protein binding:

1. hypoalbuminemia
2. displacement by exogenous compounds

 C _adjusted =      C measured       

                      [0.25 x albumin] + 0.1

One compartment model

Two compartment model (TCM)

Assumes the drug is evenly distributed throughout the body into a single compartment

• appropriate for drugs that rapidly and readily distribute from plasma into the tissue (peripheral) compartment

Two compartment model

(TCM)

represents rapidly equilibrating volume consisting of plasma and organs of high blood flow

• ex. heart and CNS

equilibrates with central compartment after a long period of time

• ex. myocardium

In a graph, concentration of drug over time peaks then consists of 2 phases (as it falls)

1. Rapid distribution α phase
2. Elimination β phase

in a two compartment model

• occurs when drug is moving form central compartment to the tissue compartment
• immediately follows peak [drug], seen in a graph as a sharp drop of [drug]

in a two compartment model

• equilibrium phase where blood and tissue [ ]'s are equal and drug is being eliminated from the body
• seen in graph as a long slow drop in [ ]

drugs dosed differently if drug behaves as if it is the central or peripheral compartment...

• If central behaving, administer loading dose slowly or in repeated small boluses to avoid toxicity (ex. lidocaine)
• If peripheral behaving, plasma levels obtained before distribution is complete will not reflect tissue levels at equilibrium (ex. digoxin)

Study of the ...

Absorption

Distribution

Metabolism

Excretion

of drugs

the passage of the drug from the site of administration into the systemic circulation. 

• example, orally-administered medications must pass through the various layers of the GI tract where they enter capillaries

Unless given IV, a drug must cross several semipermeable cell membranes before it reaches the systemic circulation or site of action

• passive diffusion
• facilitated passive diffusion
• active transport
• pinocytosis

• oral
• buccal
• sublingual 
• rectal
• parenteral (IV, IM, SC)
• topical
• inhalation
• epidural

• molecular size and shape
• degree of ionization
• lipid solubility (↑ abs in CNS)
• binding to serum and tissue proteins

When the pH 4.0 solution is injected, most of insulin glargine precipitates and is not bioavailable. A small amount is immediately available for use, and remainder is sequestered in SC tissue. 

• small amounts of precipitated material will move into solution in the bloodstream, and the basal level of insulin will be maintained up to 24 hrs.

IV

SC

IM

Advantages:

absorption bypassed

immediate effects

suitable for large volumes and irritation substances

Disadvantages:

↑ risk of adverse effects

not suitable for oily or poorly soluble substances

Advantages:

Suitable for poorly soluble suspensions

sustained absorption

self-administration

Disadvantages:

Slow or delayed absorption

volume restriction

local reactions

Advantages:

Suitable for moderate volumes, oily or some irritating substances

Disadvantages:

Not suitable with full anticoagulation

Pain and local reactions

Advantages

Convenient 

economical

Disadvantages

Variable absorption

requires compliance

the fraction of a dose of drug that reaches the systemic circulation

1. Absorption is reduced
2. drug undergoes metabolism or elimination prior to entering the systemic circulation

Gut wall and bioavailability

Cytochrome P-450 3A

(CYP3A)

the primary metabolizing enzyme system of the small intestine

• plays a part in the first-pass metabolism with specific orally administered drugs

deals with comparative bioavailability

(used to compare generic drug with standard)

• the absence of a significant difference in the rate and extent to which the drug becomes available at the site of drug action when administered at the same dose under similar conditions in an appropriately designed study
• 2 products have neither clinically nor statistically different AUC, max serum [ ]'s (C_max), and the times that C_max occurs (T_max)
• extent, Cmax, & Tmax must be with in 10-15% of one another

1. Exhibit the same time-dependent drug [ ]'s (rate and extent of drug absorption)
2. Have same safety and efficacy

When drug in the vascular system moves into various tissues and organs (ex. muscle or heart)

• a reversible process where the drug transfers form one compartment to another

Extent of distribution

• theoretical volume distributed 
• can vastly exceed any physical volume in the body
• range of drugs varies from 0.04-500 L/kg

• Drugs with very high Vd have much higher [ ] in extravascular tissue than in blood
• lipid soluble drugs have a high Vd

Drugs ability to:

•  bind to proteins in the blood and tissue
• cross tissue membranes
• lipid solubility

• Drugs that mostly bind to plasma proteins tend to have high plasma [ ]'s and low Vd

• drugs may bind endogenous proteins
• usually reversible
• equilibrium created between bound and unbound drug
• Albumin, α1-acid glycoprotein, and lipoproteins responsible for protein binding
• drugs compete for binding and displace each other from binding sites

• Unbound drug
• pharmacologically active moiety b/c can exert its effects on the receptor site
• more susceptible to metabolism first

• low albumin seen with chronic renal failure, chronic liver dysfunction, burns, catabolic states, malnutrition, pregnancy
• highly protein bound drugs may have low total drug levels but therapeutic free drug levels

occurs by enzymes in organs such as the liver, GI tract wall, and lung

• resulting metabolite may be pharmacologically active or inactive
• blood contains esterases, which cleave ester bonds in drug molecules and generally render them inactive 
• liver is primary organ of drug metabolism

after oral absorption, some drug metabolism may start here. 

• CYP3A plays an important part

Metabolic reactions classified into one or both of 2 types of reactions:

1. Phase I
2. Phase II

• polar group added, such as hydroxyl (-OH), thiol (-SH), or amine (-NH2), or oxidation, reduction and oxidation 
• makes drug more water soluble (rapidly eliminated)
• mostly involves cytochrome P-450 isoenzyme subclasses (all liver enzyme reactions)
• metabolites are often inactive 
• usually precede phase II reactions
• generally result in loss of pharm activity, there some ex. of retention or enhancement of activity
• Rare: metabolism associated with an altered pharm activity
• account for most drug metabolism

• P450 followed by the # of P450 enzyme family, capital letter of the subfamily, and an additional # to identify the specific enzyme
• ex) P450 3A4
  • 3 = isoenzyme family
  • A = isoenzyme subfamily
  • 4 = specific enzyme

Phase I = liver enzymes

• CYP3A4/5 metabolize 50% of drugs metabolized by liver

Phase II = Transferases

• UGTs, GSTs,...

• conjugation with acetate, sulfate, amino acids, glutathione, and sugars (mainly glucuronic acid to form glucuronides) All are more hydrophilic 
• inactivate the pharm activity,and make drug more prone to elimination by kidney
  • exceptions: morphine, glucuronide
• occur independently of Phase I red/ox rxns

some conjugation rxns. are important clinically in neonates

• have not yet fully developed the capacity to metabolize drugs 

Liver enzymes can be induced or inhibited by different compounds

• mediated by effects on enzyme transcription, translation, or degradation

Can result in:

• drug increases its own metabolism 
• drug increases the metabolism of a coadministered drug (inducer causes 1st drug to be metabolized more)
• production of toxic levels of reactive drug metabolites

Can result in:

• decreased metabolism of drugs that are metabolized by the inhibited enzyme
• increased drug [ ]s to toxic levels and prolong the presence of active drug in the body

Substrate: Statins

Inhibitor: grapefruit juice, clarithromycin

Inducer: Rifampin, Phenobarbital

Substrate: Carvedilol 

Inhibitor: Propafenone

Inducer: Rifampin

Substrate: Warfarin

Inhibitor: Amiodarone

Inducer: Rifampin, Carbamazepine

Substrate: Theophylline

Inhibitor: Amiodarone

Inducer: Phenobarbital

First pass effect

Occurs when an orally administered drug passes through the GI tract and portal circulation and is partially metabolized before entering the systemic circulation

• decreases oral bioavailability (F)

1. Drug absorbed from GI tract
2. passage through portal circulation
3. liver metabolism 
4. systemic absorption

Have a decreased oral bioavailability, F (fraction of drug that is absorbed)

• hard to dose such drugs in patients with liver failure 
• examples: Verapamil (F=0.22), Propranolol (F=0.26), morphine (F=0.24)

High extraction ratio = BAD for patients with liver dysfunction. Can lead greatly increased plasma [ ]s and result in toxicity 

Low extraction ratio = plasma [ ]s remain the same as normal healthy patients 

• can occur by glomerular filtration or by such active processes as proximal tubular secretion
• renal elimination through urine is most common route of excretion

decreased excretion results in accumulation of the drug and toxicity

• dosage adjustments are necessary to prevent drug toxicity

Carvedilol (Coreg)

Morphine

Metoprolol (Lopressor, Toprol-XL)

Meperidine- metabolized by the liver to normeperidine (renally excreted). 

• Normeperidine is neurotoxic and can cause nervousness, hallucinations, tremors, myoclonus, and generalized seizures
  • need to look at both liver and kidney fxn

• occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into bile, or both

• after phase II metabolism
• conjugates excreted into bile come into contact with intestinal bacteria
• bacteria hydrolyze the bond between the drug and conjugate, which restores its lipid soluble, pharmacologically activity form
• active form is reabsorbed back into the blood stream ad return to the liver by enterohepatic circulation
• can extend the duration of the drugs action

Ezetimibe (Zetia)

• an anti-hyperlipidemic agent 
• rapidly absorbed  and glucuronidated in the intestines before secreted into the blood
• avidly taken up by lifer from portal blood and excreted into bile, results in low blood   [ ]s  
• the glucuronide conjugate is hydrolyzed and absorbed and is equally effective in inhibiting sterol absorption
• results in a t 1/2 of more than 20 hrs

theoretical volume of distribution completely cleared of drug per unit time (ex. L/hr, ml/min) (NOT volume of drug cleared from body)

• intrinsic ability of the body/organs of elimination (kidney, liver) to remove drug from blood or plasma

• estimated from prediction equations that take into account the serum creatine [ ] as well as  age, gender, race and body size
• Use of measured creatine clearance with timed urine collections does NOT improve estimate of GFR over equations

Adults: MDRD (modification of Diet in Renal Disease) or Cockroft-Gault equation

Children: Schwartz or Couna han-Barratt equations

• Use of measured creatine clearance with timed urine collections does NOT improve estimate of GFR over equations

•  estimation of GFR in those with exceptional dietary intake (veg. diet. creatine supplements) or muscle mass (amputation, malnutrition, muscle wasting)
• assessment of diet and nutritional status
• need to start dialysis

• GFR (ml/min/1.73m²) = (Scr)^-1.154 x  (age)^{-0.203 x} (0.742 if female) x (1.212 if African-american)
• does not require weight b/c results are reported normalized to 1.73 m² of body SA
• Reported automatically by many hospital labs as "estimated GFR" (eGFR)

GFR= (140-age) x IBW x 1.73

            72 x SCr           BSA

(multiply results by 0.85 for females)

if SCr < 0.8 and age ≤65, use SCr 0.8 mg/dl

if SCr < 1 and age > 65, use SCr of 1 mg/dl

• Muscle mass
• Body size and composition
• Diet (amount of protein eaten)
• Exercise and activity level (more exercise ↑ creatine)
• special populations (ex., elderly, amputees, spinal cord injury, advanced CKD, liver cirrhosis, unstable renal fxn.)
• Serum creatine assay and instrument
• increased age (and CKD) there is a ↓ in GFR and slight increase in creatine tubular secretion and non renal clearance

at 20-29 estimated GFR > 100 ml/min

30-39 = 90 etc

General rule that for each decade, 10 ml/min in GFR is lose

120-60 = normal

60-15 = kidney disease

15-0 =  kidney failure

Stage               GFR(ml/min/1.73m²) 

           1                            ≥90                       2                           60-89          

3                           30-59        

4                           15-29        

           5                           < 15 (or dialysis)        

Therapeutic Index (TI)

• the ratio of toxic to therapeutic dose
• the further the toxic dose is from the therapeutic dose the better
• In humans, TI of a drug is almost never known with real precision. (TDM becomes critical)

• There is less than a 2-fold difference in median lethal dose and median effective dose values, or
• there is less than a 2-fold difference in the minimum toxic [ ]s and minimum effective   [ ]s in the blood, and safe and effective use of drug products require careful titration and patient monitoring

• may require a small increase in dose to produce toxic effects
• Therapeutic drug monitoring (TDM) is critical

Warfarin

Digoxin

phenytoin

lithium

theophylline

aminoglycosides

cyclosporine

Needed for drugs with:

• Low TI or narrow therapeutic range
• Unpredictable dose/response relationship
• significant toxicity
• established correlation between serum drug levels and efficacy or toxicity
• readily available assays

• administration times not recorded accurately
• dose administration error
• blood drawn at incorrect time (ex. distribution phase) (if level is high, always question time blood was drawn)
• blood drawn before steady state
• blood drawn from wrong site
• lab assay error
• pharmacy dispensing error