Wednesday, July 20, 2016
Pharmacokinetics:General prenciples.
A)PHARMACOKINETICS is the study of movement of drugs into and out of the body, including absorption(bioavailability),distribution,metabolism(biotransformation) and elemination.(ADME).
B)Clinical pharmacokinetice,which involves the mathematical description of the process of ADME, is useful to predict the serum concentration of drug under various concedrations.
C) PHARMACOKINETICS can be defined as what the body does to the drug.
PHARMACOKINETICS: ADMINESTRATION AND ANSORPTION OF DRUGS.
Drugs can be adminestered through many route.
1) oral route(PO) is usually preffered.
Advantages include.
a) Convenience(self medication is easy everyone can take easily)
b) Large surface area for the absorption of drug.
c) fewer abrupt changes of serum drug concentration than parenteral adminestration.
DESADVANTAGES INCLUDE.
i)First-pass metabolism by the liver
a) All the blood flow from the intestinal tract goes initially to the liver
through the portal vein; therefore the drug may be metabolized
before being distributed to the other tissues in the body.
(b) First-pass metabolism of a drug can be avoided by parenteral administration
of the drug and partially avoided by rectal administration.
ii. Systemic exposure to the drug.
2. The parenteral routes of administration are technically more difficult and usually
must be performed by a health care professional. Common methods are inhalation,
sublingual, intravenous (IV), intramuscular (IM), and subcutaneous (SQ)
administration.
a. Advantages include:
i. A faster onset (usually)
ii. More reliable absorption
iii. No first-pass metabolism
b. Disadvantages include:
i. More difficult administration
ii. Pain or necrosis at the site of infection
iii. Possibility of infection
iv. Toxicity from a bolus intravenous (IV) injection
v. Necessity of dissolving the drug if given intravenously
B. Some drugs are actively or passively transported by carrier proteins, but the movement
of drugs across cell membranes usually occurs passively by diffusion.
C. THE RATE OF DIFFUSION IS HIGH IF:
1. The unionized form of a drug has a high lipid solubility.
a. Lipid solubility is related to the oil-water partition coefficient.
b. Cell membranes are basically lipoidal in nature, and only lipid soluble substances
will diffuse through them.
2. A large proportion of the drug is present in the unionized form.
a. Only the unionized form can cross cell membranes, because the ionized
form will have a very low solubility in lipids.
b. The equilibrium between the ionized (A ) and unionized (HA) forms of a weak acid is:
3. The membrane is thin.
4. The membrane is porous. Porosity is especially important for water-soluble drugs.
5. The surface area of the membrane is large.
6. The difference in concentrations on the two sides of the membrane is large.
7. The diffusion constant, based on molecular size, molecular shape, and
temperature, is large.
D. At the basic pH in the small intestine
1. Weak bases are well absorbed because most of the drug is unionized.
2. Weak acids are poorly absorbed because most of the drug is ionized.
3. The opposite scenario occurs in the acidic environment of the stomach; however,
the stomach does not have a very large absorptive capability.
E. ION TRAPPING occurs with weak acids and weak bases if there is a difference in pH
on the two sides of a membrane.
1. The ionized form of the drug will be trapped on one side.
a. The ionized form of a weak base will be protonated and trapped on the side
with the lower pH.
b. The ionized form of a weak acid will be deprotonated and trapped on the side
with the higher pH.
2. Figure 1-1 illustrates ion trapping for a weak acid with a pKa of 6.4. At equilibrium,
the unionized concentrations on either side of the membrane will be equal, but
91% of the drug will be in the compartment at pH 7.4.
F. STRONG BASES AND STRONG ACIDS are totally dissociated or ionized in solution;
thus, they are poorly absorbed at any pH. Quaternary ammonium compounds are
completely ionized at physiological pHs and therefore are also poorly absorbed.
G. ABSORPTION OF A DRUG IS USUALLY FAST, as compared to the elimination; thus,
it is often ignored in kinetic calculations. The rate of gastric emptying can affect the
absorption and bioavailability of a drug.
H. BIOAVAILABILITY is the fraction of drug administered that reaches the systemic
circulation without being metabolized.
1. Bioavailability (F) equation:
F = [drug] in the systemic circulation after oral administration/
[drug] in the systemic circulation after IV administration
a. The bioavailability after oral administration depends on
i. The disintegration of a tablet
ii. The dissolution of the drug in the intestinal contents
iii. Gastrointestinal and first-pass metabolism
b. A drug that is administered by IV will be 100% bioavailable.
2. Bioequivalence occurs when drugs with equal F have the same drug concentration
versus time relationship (i.e., similar rate and extent of drug absorption).
3. Therapeutic equivalence (TE) is commonly said to occur when two drugs have
the same maximal response; it may be different than bioequivalence. (Note that the
FDA defines TE as having the same ingredients, dosage form, route of administration,
and concentration.)
PHARMACOKINETICS:Distribution of drugs.
A. THE INITIAL DISTRIBUTION of a drug to the tissues is determined by the relative blood
flows to the tissues. Sites with high blood flows will initially receive more of the drug.
B. THE VOLUME OF DISTRIBUTION Vd is an approximation of the hypothetical fluid
volume that a drug appears to distribute in.
1. It can be very large, even larger than the total body volume, if a drug is highly bound
to tissues. This makes the serum drug concentration very low and the Vd very large.
2. The Vd must be calculated at the time of administration
a. Apparent volume of distribution equation:
Vd= amount of drug administered/serum [drug]
3. The loading dose for a drug is based on the Vd.
Oral loading dose = Vd multiplied C/F
where C is the desired or target serum drug concentration and F is the bioavailability
(fraction of administered drug in the blood).
C. The final apparent volume of distribution (Vd) will be affected by
1. The lipid solubility of a drug, which, if high, will result in good penetration into
cells and a high Vd
2. Plasma protein binding and tissue binding
a. Plasma protein binding, especially to albumin, will reduce the Vd.
b. Tissue binding will increase the Vd.
c. Both types of binding act as reservoirs for the drug, as only the unbound drug
can activate pharmacological receptors. Thus binding will
i. Slow the onset of drug action
ii. Prolong the duration of drug action, if the drug is eliminated by glomerular
filtration in the kidney
3. Competition for binding sites on albumin between two drugs A and B can raise
free levels of A in the blood if
a. The concentration of B exceeds the number of albumin binding sites
b. B is able to displace A from the albumin binding sites
C. PHASE 1 metabolic reactions usually lead to the alteration or inactivation of the
drug’s activity. Often, new functional groups are introduced that make further metabolism
possible.
1. Oxidation by cytochrome P450 (CYP) enzymes (also known as mixed function
oxidases [MFO], microsomal enzymes, mono-oxygenases) occurs in the smooth
endoplasmic reticulum (ER).
a. Nicotinamide adenine dinucleotide phosphate (NADPH), cytochrome P450
reductase, and elemental oxygen (O2) are required.
b. Many reactions can be produced, including:
i. Hydroxylation
ii. Dealkylation
iii. Deamination
iv. Sulfoxidation
v. Oxidation
c. Highly lipid soluble drugs are more readily metabolized by CYPs.
2. Reductive reactions can occur in the ER or the cytosol.
3. Hydrolytic reactions do not occur in the ER.
D. PHASE 2 metabolic reactions are conjugative, adding highly polar groups to the drug
to increase renal elimination.
1. Glucuronidation occurs in the ER. Glucose is used to form uridine diphosphate
glucuronic acid (UDPGA), which then transfers a glucuronide to the drug in the
presence of glucuronyl transferase.
2. Other substances can be conjugated (by transferases primarily in the cytosol) to
drugs. These conjugates generally reduce the drug’s activity and increase its polarity,
including:
a. Sulfate
b. Acetyl
c. Methyl
d. Glutathione
e. Amino acids, especially glycine
E. Many drug interactions are due to changes in CYP activity in the liver.
1. Induction of CYPs results from increased levels of CYPs in the ER.
a. The onset of induction is slow (days) and the duration is long (taking a week
or more for recovery after the drug is withdrawn).
b. Many drugs that are metabolized by the CYPs also induce the CYPs, including:
i. Barbiturates, phenytoin, rifampin
ii. Alcohol
iii. Cigarette smoke
c. This induction hastens the metabolism of the inducing drug along with other
drugs metabolized by the same CYPs.
2. Inhibition of drug metabolism occurs if there is competition between drugs at the
CYP, or if a drug tightly binds to the CYP.
a. Potent CYP inhibitors include cimetidine, ritonavir, and azole antifungals.
b. Grapefruit juice has a similar inhibitory effect.
F. Liver enzymes are polymorphic in the population, such that individuals with different
enzyme forms may metabolize a drug at different rates.
G. The rate of metabolism is first order for most drugs
1. First-order metabolism is proportional to the concentration of free drug.
2. A constant fraction of drug is metabolized per unit of time (i.e., the metabolism of
the drug has a half-life.
3. The loading dose for a drug is based on the Vd.
Oral loading dose = Vd multiplied C/F
where C is the desired or target serum drug concentration and F is the bioavailability
(fraction of administered drug in the blood).
C. The final apparent volume of distribution (Vd) will be affected by
1. The lipid solubility of a drug, which, if high, will result in good penetration into
cells and a high Vd
2. Plasma protein binding and tissue binding
a. Plasma protein binding, especially to albumin, will reduce the Vd.
b. Tissue binding will increase the Vd.
c. Both types of binding act as reservoirs for the drug, as only the unbound drug
can activate pharmacological receptors. Thus binding will
i. Slow the onset of drug action
ii. Prolong the duration of drug action, if the drug is eliminated by glomerular
filtration in the kidney
3. Competition for binding sites on albumin between two drugs A and B can raise
free levels of A in the blood if
a. The concentration of B exceeds the number of albumin binding sites
b. B is able to displace A from the albumin binding sites
PHARMACOKINETIC Metabolism of drugs.
A. The liver is the primary site of drug metabolism.
B. Metabolism can change a drug in several ways.
1. The polarity is usually increased, enhancing the water solubility and renal excretion
of the drug metabolite.
2. The activity of the drug is reduced. Exceptions are the prodrugs, which are drugs
that are inactive in the form administered but are metabolized to their active forms.
3. A drug metabolite usually has a smaller Vd due to its increased water solubility.
C. PHASE 1 metabolic reactions usually lead to the alteration or inactivation of the
drug’s activity. Often, new functional groups are introduced that make further metabolism
possible.
1. Oxidation by cytochrome P450 (CYP) enzymes (also known as mixed function
oxidases [MFO], microsomal enzymes, mono-oxygenases) occurs in the smooth
endoplasmic reticulum (ER).
a. Nicotinamide adenine dinucleotide phosphate (NADPH), cytochrome P450
reductase, and elemental oxygen (O2) are required.
b. Many reactions can be produced, including:
i. Hydroxylation
ii. Dealkylation
iii. Deamination
iv. Sulfoxidation
v. Oxidation
c. Highly lipid soluble drugs are more readily metabolized by CYPs.
2. Reductive reactions can occur in the ER or the cytosol.
3. Hydrolytic reactions do not occur in the ER.
D. PHASE 2 metabolic reactions are conjugative, adding highly polar groups to the drug
to increase renal elimination.
1. Glucuronidation occurs in the ER. Glucose is used to form uridine diphosphate
glucuronic acid (UDPGA), which then transfers a glucuronide to the drug in the
presence of glucuronyl transferase.
2. Other substances can be conjugated (by transferases primarily in the cytosol) to
drugs. These conjugates generally reduce the drug’s activity and increase its polarity,
including:
a. Sulfate
b. Acetyl
c. Methyl
d. Glutathione
e. Amino acids, especially glycine
E. Many drug interactions are due to changes in CYP activity in the liver.
1. Induction of CYPs results from increased levels of CYPs in the ER.
a. The onset of induction is slow (days) and the duration is long (taking a week
or more for recovery after the drug is withdrawn).
b. Many drugs that are metabolized by the CYPs also induce the CYPs, including:
i. Barbiturates, phenytoin, rifampin
ii. Alcohol
iii. Cigarette smoke
c. This induction hastens the metabolism of the inducing drug along with other
drugs metabolized by the same CYPs.
2. Inhibition of drug metabolism occurs if there is competition between drugs at the
CYP, or if a drug tightly binds to the CYP.
a. Potent CYP inhibitors include cimetidine, ritonavir, and azole antifungals.
b. Grapefruit juice has a similar inhibitory effect.
F. Liver enzymes are polymorphic in the population, such that individuals with different
enzyme forms may metabolize a drug at different rates.
G. The rate of metabolism is first order for most drugs
1. First-order metabolism is proportional to the concentration of free drug.
2. A constant fraction of drug is metabolized per unit of time (i.e., the metabolism of
the drug has a half-life.
PHARMACOKINETICS:Elimenation of drug metabolites.
A. The kidney is the primary organ that excretes drugs and drug metabolites.
1. If the drug is excreted in the unmetabolized form, the kidney also decreases that
drug’s pharmacological activity.
2. Polar drugs and drug metabolites are readily eliminated by the kidney.
B. GLOMERULAR FILTRATION of the unbound molecule accounts for the excretion of
most drugs.
1. Drug molecules bound by plasma proteins will not be filtered by the
glomerulus.
2. Hydrophilic substances are most efficiently eliminated by the kidney, because
they are not readily reabsorbed across the nephron tubule after they are filtered.
3. If a drug is a weak base, administration of ammonium chloride will acidify the
urine and increase the amount of the base that is in the ionized form.
a. The excretion of the weak base will be increased.
b. This will be most effective if the pKa of the drug is near the physiological pH.
4. The excretion of a weak acid can be increased by alkalinizing the urine with
sodium bicarbonate.
C. ACTIVE TRANSPORT of a few drugs occurs in the proximal tubule.
1. It usually involves secretion of strong acids or strong bases.
2. P-glycoprotein is an important transporter in renal and other cells.
3. Characteristics of active transport are
a. Competition between substrates for the carrier
b. Saturability of the carrier
c. Being unaffected by plasma protein binding
4. Active reabsorption can also occur.
5. A few substances are both actively secreted and actively reabsorbed (e.g., uric acid,
aspirin).
D. BILIARY EXCRETION occurs in the liver.
1. Large polar compounds, often conjugated metabolites, are actively excreted into
the bile.
2. Enterohepatic cycling occurs with a few drugs that are eliminated in the bile,
reabsorbed from the intestine, returned to the liver and again eliminated in the bile.
a. Glucuronidase in the intestine can cleave off the glucuronide, so the free drug
can be reabsorbed (Figure 1-3).
b. Digitoxin, a cardiac glycoside, undergoes enterohepatic cycling.
c. This may increase the half-life of the drug.
4. With reduced liver function, there is no good predictor of the oral maintenance
dose for drugs that are cleared by the liver.
a. If the extraction ratio for a drug passing through the liver approaches 1, then
Cl equals hepatic blood flow (BF).
i. Reduced hepatic BF or reduced cardiac output (CO) will reduce the
hepatic Cl of a drug with a high hepatic extraction ratio.
ii. An example is lidocaine, which has a lower Clhepatic in patients with congestive
heart failure. As a result, the maintenance dose of lidocaine should
be reduced in these patients.
b. If the hepatic extraction ratio is near 0, hepatic BF is unimportant. Intrinsic metabolic
rate and the amount of plasma protein binding become important factors.
5. If a drug follows first-order elimination kinetics, doubling the dose will double
the Css, but it does not change the amount of time need to reach Css (i.e., it does
not affect t1/2).
F. The above equations do not apply to drugs that have zero-order elimination kinetics
(i.e., those for which a constant amount of drug is eliminated per unit of time rather
than a certain fraction of drug per unit of time).
1. It is very difficult to predict and control the Css for these drugs because the fraction
of drug being eliminated does change with the concentration of drug present.
2. Drugs which follow zero-order kinetics include:
a. Ethanol
b. Heparin
c. Phenytoin
d. Aspirin at high concentrations.
