Pharmacokinetics (1.1)

100問 • 1年前

問題一覧

The processes of a drug from the systemic circulation to organs and tissue involve its permeation through membrane barriers and are dependent on its solubility (recall that only nonionized drugs cross biomembranes), the rate of blood flow to the tissues, and the binding of drug molecules to plasma proteins.

Distribution

What are the factors affecting distribution?

Rate and Extent Distribution

-Membrane permeability - Capillary wall structure - Drug’s pKa and blood pH - Blood Perfusion

Rate of distribution.

- Lipid solubility - pH-pKa - Tissue localization - Plasma-protein binding

Extent of distribution.

DRUG MOLECULES are carried by the blood to the target site (receptors) and to nonreceptor tissues

Distribution.

DRUG + PROTEIN (ALBUMIN) = DRUG ALBUMIN COMLEX (pharmacologically inactive)

Protein binding capacity.

drug that is unbound to plasma proteins. Only the “unbound” or free drug is available to distribute out of blood vessels and act on the body cells to elicit the desired effect

Free drug.

- Major plasma protein component . - Reversible drug binding . - Acidic drugs.

Albumin.

Alpha-1 Acid Glycoprotein (AAG) and Globulin

Basic drugs.

- macromolecular complexes of lipids + proteins - Binds drugs when albumin sites become saturated

Lipoprotein

May bind both endogenous and exogenous compounds

RBC

May be responsible for the transport of certain endogenous substances such as corticoste

Globulin

The most abundant protein in human blood plasma

Albumin

produced in the liver. soluble and monomeric.

Albumin

Responsible for maintaining the osmotic pressure of the blood.

Albumin

Elimination half life 17 – 18 days Reversible binding Synthesized in the liver

Albumin

MW 44,000Da Low plasma concentration(0.4- 1%) binds primarly basic (cationic) drugs.

A-acid glycoprotein

Macromolecular complexes lipids and protein Classified accdg. to their density and separation in the ultracentrifuge.

Lipoprotein

Responsible for the transport of plasma liquids to the liver. Resp. for binding if albumin is saturated

Lipoprotein

45 % of the total volume May bind both endogenous and exogenous compounds.

Erythrocytes

Αβγ globulins Transport certain endogenous subs (corticosteroid) Ppt in both distilled water and 50% sat. Ammonium SO4

Globulins

-Physicochemical nature - Concentration in the body

Drug

- Qty available for binding - Quality of protein synthesized - Affinity between drug & protein

Protein

- Competition at binding sites - Alteration of the protein by a substance that modifies the affinity of a drug for the protein

Drug interactions

Tissues with decrease regional blood flow (bones, adipose tissues, middle ear)

Blood flow

Areas of high blood flow

Heart, liver, kidney and brain

Areas of low blood flow:

Muscle, skin, fat and bone

BBB and PLACENTAL BARRIER Allows only non-ionized, unbound drug to enter brain.

Ability to cross membranes.

The chemical process by which the body converts an agent from its original form to a more water-soluble form that can be excreted

Metabolism

most important site of drug metabolism, but it may also occur in renal tissue, lungs, plasma or intestinal mucosa.

Liver

the major site of metabolism for the majority of drugs

Liver

hydrolysis, mainly of esters

Plasma and body fluids

metabolism of endogenous transmitters and drugs with similar structures

Nerve terminals

responsible for pre-systemic metabolism of many drugs

Mucosal cells

metabolize some drugs

Kidney, lungs and muscle

capable of glucuronidation of morphine

Brain

metabolism of several drugs and hydrolysis of glucuronide metabolites.

Intestinal bacteria.

metabolic conversion of drugs, generally to less active compounds but sometimes to isoactive or more active forms.

Biotransformation.

the phenomenon whereby drugs may be metabolized following absorption before reaching systemic circulation

First pass effect

Include oxidation (especially by the cytochrome P45- group of enzymes also called mixed function oxidases), reduction, deamination and hydrolysis

Phase 1

Reactions that convert the parent drug to a more polar (watersoluble) or more reactive product by unmasking or inserting a polar functional group such as -OH, -SH, or -NH

Phase 1.

Polar functional groups are introduced into the molecule or unmasked by

Oxidation, reduction and hydrolysis

-loss of electrons - reducing agents - dehydrogenation - increase in oxidation state

Oxidation

A heme protein with iron protoporphyrin IX as the prosthetic group

Cytochrome 450

These enzymes require a reducing agent (NADPH) and molecular oxygen (one oxygen atom appearing in the product and the other in the form of water)

Microsomal oxidation

Mono Amine Oxidase (ex. Serotonin, Epinephrine, Norepinephrine, Dopamine, Tyramine)

CYP independent oxidation

Xanthine oxidase

CYP independent oxidation

-gain of electrons - oxidizing agents - hydrogenation - decrease in oxidation state

Reduction

Nitro reduction (ex)

Chlorampenicol

Carbonyl reduction (ex)

Naloxone

Azo reduction. (ex)

Protonsil (Sulfonamides).

Dehalogenation.( ex)

Halothane

Splitting of large molecule involving water as solvent

Hydrolysis

Examples of hydrolysis.

Amide and Ester.

Hydrolysis used for?

Local anesthetic

Synthetic reactions that involve addition (conjugation) of subgroups to -OH, -NH 2, and -SH functions on the drug molecule.

Phase 2.

The subgroups that are added include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups.

Phase 2.

Most of these groups are relatively polar and make the product less lipid-soluble than the original drug molecule.

Phase 2.

This metabolism phase reaction is responsible for the formation of the final metabolic product of the drug to be excreted

Phase 2.

relatively water soluble and readily excretable biologically inactive and nontoxic

Phase 2.

Do not generally increase water solubility but mainly to serve to terminate or attenuate pharmacological activity.

Phase 2.

a condensation of the drug or its primary metabolite with glucoronic acid.

Glucoronidation

The reaction requires activation of glucoronic acid by synthesis of UDPGA

Glucoronidation

Drugs that compete for glucuronidation or reduce the already low glucuronyl transferase activity can precipitate Kernicterus.

True.

Caused by Chloramphenicol given to neonates

Grey baby syndrome.

Caused by Chloramphenicol given to neonates

Grey baby syndrome.

The human newborn is already capable of sulfate conjugation but this pathway becomes easily saturated due to limited sulfate pool

Sulfation.

The sulfate pool in the organism is limited and easily depleted. PAPS transfer the sulfate to the drug molecule in the soluble fraction of the cell.

Sulfation.

Birth.

1st week

Oxidation and reduction.

1 month .

acetylation

2 months.

Glucoronidation

3 months.

Glycerin conjugate.

most common endogenous amine for conjugation with organic acids.

Glycerin

Takes place usually in the mitochondrial fraction. However, bile acids are conjugated with glycine in the microsomal fraction

Glycerin conjugation.

Newborns and aged have a reduced glycine pool

Glycerin conjugation.

available in man for conjugation with organic acids, such as phenylacetic and related acids.

Glutamine

for glutamine conjugation is localized in the liver and kidney

Acylating enzyme.

Conjugation by acetylation of aromatic primary amines, aliphatic amines, amino acids, hydrazines (-NHNH2), hydrazides (-CONHNH2) and sulfonamides occurs in many tissues

True.

The newborn is not capable of acetylation. The presence of the various acetyl transferases is genetically determined (slow acetylation and fast acetylators

True.

Side effect of Procainamide SLE (systemic lupus erythematosus

Butterfly rash.

It is only a minor pathway for conjugating drugs and xenobiotics.

Methylation.

It generally does not lead to polar or water-soluble metabolites, except when it creates a quaternary ammonium derivative.

Methylation.

Most methylated products tend to be pharmacologically inactive except for some.

True.

Drug or chemical-stimulated increase in enzyme activity.

Enzyme induction.

Alteration in the enzyme activity in liver microsomes resulting in a faster rate of metabolism not a disease; it is an adaptation of the body to exogenous material

Enzyme induction.

A drug that stimulates its own metabolism

Auto induction.

Phenobarbital is given repeatedly its metabolism is increased

Auto induction.

Types of emzye induction.

Auto and foreign.

one enzyme inducer stimulate the rate of metabolism of another drug

Foreign induction.

If a dose of hexobarbital is then given its metabolism is also increased

Foreign induction.

May be due to substrate competition or due to direct inhibition of drug metabolizing enzyme

Enzyme inhibition.

↓enzyme↓ metabolism ↑ effect

Enzyme inhibition.

↑enzymes ↑ metabolism ↓ effect

Enzyme induction.

the final elimination of the drug substance or its metabolites from the body such as through: 1) The kidney (urine) 2) intestines (feces) 3) skin (sweat) 4) saliva, and/or milk

Excretion

Located in the peritoneal cavity and most important organ for excretion

Kidney

-maintain normal fluid volume - maintain salt and water balance with 2 endocrine function

Kidney

Responsible for the removal of metabolic waste and the maintenance of water and electrolyte balance

Nephrons

Anions, cations, non-ionized molecules with lipophilic polar groups & those with MW>500

Biliary excretion

100

- For drugs poorly absorbed in the intestines - Organic acids & organic bases à active transport - Consider biliary recycling

Biliary Excretion

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問題一覧

Distribution

What are the factors affecting distribution?

Rate and Extent Distribution

-Membrane permeability - Capillary wall structure - Drug’s pKa and blood pH - Blood Perfusion

Rate of distribution.

- Lipid solubility - pH-pKa - Tissue localization - Plasma-protein binding

Extent of distribution.

DRUG MOLECULES are carried by the blood to the target site (receptors) and to nonreceptor tissues

Distribution.

DRUG + PROTEIN (ALBUMIN) = DRUG ALBUMIN COMLEX (pharmacologically inactive)

Protein binding capacity.

drug that is unbound to plasma proteins. Only the “unbound” or free drug is available to distribute out of blood vessels and act on the body cells to elicit the desired effect

Free drug.

- Major plasma protein component . - Reversible drug binding . - Acidic drugs.

Albumin.

Alpha-1 Acid Glycoprotein (AAG) and Globulin

Basic drugs.

- macromolecular complexes of lipids + proteins - Binds drugs when albumin sites become saturated

Lipoprotein

May bind both endogenous and exogenous compounds

RBC

May be responsible for the transport of certain endogenous substances such as corticoste

Globulin

The most abundant protein in human blood plasma

Albumin

produced in the liver. soluble and monomeric.

Albumin

Responsible for maintaining the osmotic pressure of the blood.

Albumin

Elimination half life 17 – 18 days Reversible binding Synthesized in the liver

Albumin

MW 44,000Da Low plasma concentration(0.4- 1%) binds primarly basic (cationic) drugs.

A-acid glycoprotein

Macromolecular complexes lipids and protein Classified accdg. to their density and separation in the ultracentrifuge.

Lipoprotein

Responsible for the transport of plasma liquids to the liver. Resp. for binding if albumin is saturated

Lipoprotein

45 % of the total volume May bind both endogenous and exogenous compounds.

Erythrocytes

Αβγ globulins Transport certain endogenous subs (corticosteroid) Ppt in both distilled water and 50% sat. Ammonium SO4

Globulins

-Physicochemical nature - Concentration in the body

Drug

- Qty available for binding - Quality of protein synthesized - Affinity between drug & protein

Protein

- Competition at binding sites - Alteration of the protein by a substance that modifies the affinity of a drug for the protein

Drug interactions

Tissues with decrease regional blood flow (bones, adipose tissues, middle ear)

Blood flow

Areas of high blood flow

Heart, liver, kidney and brain

Areas of low blood flow:

Muscle, skin, fat and bone

BBB and PLACENTAL BARRIER Allows only non-ionized, unbound drug to enter brain.

Ability to cross membranes.

The chemical process by which the body converts an agent from its original form to a more water-soluble form that can be excreted

Metabolism

most important site of drug metabolism, but it may also occur in renal tissue, lungs, plasma or intestinal mucosa.

Liver

the major site of metabolism for the majority of drugs

Liver

hydrolysis, mainly of esters

Plasma and body fluids

metabolism of endogenous transmitters and drugs with similar structures

Nerve terminals

responsible for pre-systemic metabolism of many drugs

Mucosal cells

metabolize some drugs

Kidney, lungs and muscle

capable of glucuronidation of morphine

Brain

metabolism of several drugs and hydrolysis of glucuronide metabolites.

Intestinal bacteria.

metabolic conversion of drugs, generally to less active compounds but sometimes to isoactive or more active forms.

Biotransformation.

the phenomenon whereby drugs may be metabolized following absorption before reaching systemic circulation

First pass effect

Include oxidation (especially by the cytochrome P45- group of enzymes also called mixed function oxidases), reduction, deamination and hydrolysis

Phase 1

Reactions that convert the parent drug to a more polar (watersoluble) or more reactive product by unmasking or inserting a polar functional group such as -OH, -SH, or -NH

Phase 1.

Polar functional groups are introduced into the molecule or unmasked by

Oxidation, reduction and hydrolysis

-loss of electrons - reducing agents - dehydrogenation - increase in oxidation state

Oxidation

A heme protein with iron protoporphyrin IX as the prosthetic group

Cytochrome 450

These enzymes require a reducing agent (NADPH) and molecular oxygen (one oxygen atom appearing in the product and the other in the form of water)

Microsomal oxidation

Mono Amine Oxidase (ex. Serotonin, Epinephrine, Norepinephrine, Dopamine, Tyramine)

CYP independent oxidation

Xanthine oxidase

CYP independent oxidation

-gain of electrons - oxidizing agents - hydrogenation - decrease in oxidation state

Reduction

Nitro reduction (ex)

Chlorampenicol

Carbonyl reduction (ex)

Naloxone

Azo reduction. (ex)

Protonsil (Sulfonamides).

Dehalogenation.( ex)

Halothane

Splitting of large molecule involving water as solvent

Hydrolysis

Examples of hydrolysis.

Amide and Ester.

Hydrolysis used for?

Local anesthetic

Synthetic reactions that involve addition (conjugation) of subgroups to -OH, -NH 2, and -SH functions on the drug molecule.

Phase 2.

The subgroups that are added include glucuronate, acetate, glutathione, glycine, sulfate, and methyl groups.

Phase 2.

Most of these groups are relatively polar and make the product less lipid-soluble than the original drug molecule.

Phase 2.

This metabolism phase reaction is responsible for the formation of the final metabolic product of the drug to be excreted

Phase 2.

relatively water soluble and readily excretable biologically inactive and nontoxic

Phase 2.

Do not generally increase water solubility but mainly to serve to terminate or attenuate pharmacological activity.

Phase 2.

a condensation of the drug or its primary metabolite with glucoronic acid.

Glucoronidation

The reaction requires activation of glucoronic acid by synthesis of UDPGA

Glucoronidation

Drugs that compete for glucuronidation or reduce the already low glucuronyl transferase activity can precipitate Kernicterus.

True.

Caused by Chloramphenicol given to neonates

Grey baby syndrome.

Caused by Chloramphenicol given to neonates

Grey baby syndrome.

The human newborn is already capable of sulfate conjugation but this pathway becomes easily saturated due to limited sulfate pool

Sulfation.

The sulfate pool in the organism is limited and easily depleted. PAPS transfer the sulfate to the drug molecule in the soluble fraction of the cell.

Sulfation.

Birth.

1st week

Oxidation and reduction.

1 month .

acetylation

2 months.

Glucoronidation

3 months.

Glycerin conjugate.

most common endogenous amine for conjugation with organic acids.

Glycerin

Takes place usually in the mitochondrial fraction. However, bile acids are conjugated with glycine in the microsomal fraction

Glycerin conjugation.

Newborns and aged have a reduced glycine pool

Glycerin conjugation.

available in man for conjugation with organic acids, such as phenylacetic and related acids.

Glutamine

for glutamine conjugation is localized in the liver and kidney

Acylating enzyme.

Conjugation by acetylation of aromatic primary amines, aliphatic amines, amino acids, hydrazines (-NHNH2), hydrazides (-CONHNH2) and sulfonamides occurs in many tissues

True.

The newborn is not capable of acetylation. The presence of the various acetyl transferases is genetically determined (slow acetylation and fast acetylators

True.

Side effect of Procainamide SLE (systemic lupus erythematosus

Butterfly rash.

It is only a minor pathway for conjugating drugs and xenobiotics.

Methylation.

It generally does not lead to polar or water-soluble metabolites, except when it creates a quaternary ammonium derivative.

Methylation.

Most methylated products tend to be pharmacologically inactive except for some.

True.

Drug or chemical-stimulated increase in enzyme activity.

Enzyme induction.

Alteration in the enzyme activity in liver microsomes resulting in a faster rate of metabolism not a disease; it is an adaptation of the body to exogenous material

Enzyme induction.

A drug that stimulates its own metabolism

Auto induction.

Phenobarbital is given repeatedly its metabolism is increased

Auto induction.

Types of emzye induction.

Auto and foreign.

one enzyme inducer stimulate the rate of metabolism of another drug

Foreign induction.

If a dose of hexobarbital is then given its metabolism is also increased

Foreign induction.

May be due to substrate competition or due to direct inhibition of drug metabolizing enzyme

Enzyme inhibition.

↓enzyme↓ metabolism ↑ effect

Enzyme inhibition.

↑enzymes ↑ metabolism ↓ effect

Enzyme induction.

the final elimination of the drug substance or its metabolites from the body such as through: 1) The kidney (urine) 2) intestines (feces) 3) skin (sweat) 4) saliva, and/or milk

Excretion

Located in the peritoneal cavity and most important organ for excretion

Kidney

-maintain normal fluid volume - maintain salt and water balance with 2 endocrine function

Kidney

Responsible for the removal of metabolic waste and the maintenance of water and electrolyte balance

Nephrons

Anions, cations, non-ionized molecules with lipophilic polar groups & those with MW>500

Biliary excretion

100

- For drugs poorly absorbed in the intestines - Organic acids & organic bases à active transport - Consider biliary recycling

Biliary Excretion