Basic Principles of Pharmacology IV

Question 1

Biotransformation of Toxicants

Answer 1

• can have a widespread influence on drug use
• route of administration
• dose
• effectiveness
• toxicity, safety
• duration of effect

Question 2

Purposes of Biotransformation

Answer 2

• one method of cleaning drug from the plasma
• rate will depend on endogenous enzyme systems
• Drug detoxification- change the structure thus change activity
• prepare drug for excretion- reduce the drug characteristics that made it easy to absorb- make drug larger, add positive or negative charges, make drug more water soluble- especially important- transofrm drug from lipid soluble form to water soluble form

Question 3

Sites of Biotransformation

Answer 3

• liver- on cellular structural components, smooth endoplasmic reticulum- lipid environment- enhances equilibrium with lipid soluble drugs
• cytoplasm in liver
• anywhere else in the body

Question 4

Hepatic Microsomal Drug Metabolizing systems

Answer 4

• both phase I and phase II processes
• induction- increase metabolism of the primary drug or other drugs
• inhibition- use a drug to block the metabolism of another drug or endogenous compound
• saturation

Question 5

Non-microsomal Systems

Answer 5

• other organs, plasma, red cells
• usually phase I- eg: acetyl cholinesterase, alcohol dehydrogenase
• inhibition
• saturation
• the enzyme systems can be relatively specific for certain drugs or endogenous compounds or more likely nonspecific and have a broad range of activity for classes or types of molecules
• they follow concepts of mass action- the accumulation of products from phase I become the substrates of Phase II

Question 6

Drug Oxidation

Answer 6

• phase I reaction
• add oxygen or change the proportion of oxygen in the molecule
• very important- the most common metabolic transformation
• endoplasmic reticulum of liver cells: phenobarbital to hydroxyphenobarbital
• cytoplasm of liver cells: ethanol to acetaldehyde
• mitochondria of adrenergic nerves: norepinephrine to 3,4 dihydroxymandelic aldehyde

Question 7

Hepatic Mixed Function Oxidase System

Answer 7

• NADPH
• Cytochrome P450 reductase (flavoprotein)
• Cytochrome P450 (hemoproteins)
• Mg++
• phospholipids
• O2

-they usually metabolize lipid soluble drugs- the drug as a substrate will concentrate in the SER

Question 8

P450 groups

Answer 8

• some for toxins (drugs)- others for endogenous compounds
• low specificity
• very large genetic variations
• catalyzes reductions and oxidations
• ratio of P450 to reductase is 10:1, 3D dimensional function
• CYP2D6- has the largest degree of identified genetic variations- 70, inactive enzyme or reduced catalytic activity
• phenotypes: poor (potential toxicity), intermediate, extensive, ultrarapid (potential no effect- high first pass metabolism)
• variation by race- Caucasians 5-10%, SE Asian 1-2% poor
• 65 commonly used drugs metabolized by CYP2D6

Question 9

Drug interactions and cytochrome P450

Answer 9

• potential drug interactions when various drugs are metabolized by the same type of cytochrome P450 enzymes- slow metabolism
• competition with inhibition- potential toxicities
• induction - decrease effectiveness for a given dose
• system also influenced by: disease factors- liver disease, liver perfusion
• age and sex- fetal to geriatric

Question 10

Type of Biotransformation by Hepatic Mixed Function Oxidase System

Answer 10

• aliphatic oxidations
• aromatic oxidations
• oxidative N-dealkylations
• Oxidative O-demethylations
• Oxidative S-dealkylations
• oxidative deaminations
• N-oxidations
• N-hydroxylations
• Sulfoxide formations
• Oxidative desulfurations

Question 11

Drug Reductions

Answer 11

• add hydrogen or change the proportion of hydrogen in the molecule
• reductions of aromatic nitro compounds in liver microsomes
• reductions of aromatic azo compounds in hepatic microsomes
• reductions by enzymes in cytoplasm or mitochondra of liver cells

Question 12

Drug Hydrolysis

Answer 12

• cleave a molecule by the addition of a water molecule
• ester to an acid and alcohol
• amide to RCOOH and RNH2

Question 13

Activities of Drugs vs Activities of Metabolites

Answer 13

• phase I may have variable results on activity
• both in the target tissue on secondary receptors in other tissues- toxicity
• hydrolysis of procaine to p-aminobenzoic acid (inactive products)
• oxidation of phenacetin to acetaminophen which is an active produce
• reduction of prontosil to sulfanilamide which active product and p-diaminobenze which is inactive

Question 14

Phase II reactions

Answer 14

• liver
• conjugation- synthesize a new molecule by combining the drug or metabolic product of phase I with a molecule provided by the cell
• metabolic energy is used and covalent bond is formed
• resulting molecule is large, charged, water soluble, inactive

Question 15

Types of Conjugation

Answer 15

• glucuronide formation
• glycine conjugation
• glutamine conjugation
• acetylation, acylation
• sulfate conjugation
• methylation
• riboside and riboside phosphate formation
• mercapturic acid formation

Question 16

Enzyme system with rate limiting step

Answer 16

• the enzyme systems may be a rate limiting step in the clearance of drug from plasma
• when metabolism is more important than renal elimination- lipid soluble drugs
• when enzyme is relatively slow
• V= Vmax[D]/Km = Constant [D] first order if [D] &laquo_space;Km then: efficient enzyme systems
• V= Vmax[D]/[D]= Vmax zero order, if [D]» Km then inefficent enzyme systems

Question 17

What is the result of biotransformation?

Answer 17

drug molecules having an increase in + or - charges

• becoming larger
• becoming more water soluble
• phase I may be sufficient or may prepare the drug molecule for phase II
• phase II- conjugation by a covalent bond to an endogenous molecule

Question 18

Drug Excretion

Answer 18

• Renal Excretion- most important route of elimination of drug or metabolites
• amount of drug excreted= Amount entering tubule - amount reabsorbed

Question 19

How does a drug enter a nephron

Answer 19

• glomerular filtration- only free drug molecules are filtered, amount filtered depends on glomerular blood flow are free drug concentration
• active tubular secretion- active transport, one system for acids and one for bases, exists for endogenous compounds like uric acid or choline
• inhibition usually competitive
• saturation- can occur at therapeutic doses or with overdoses- changes 1 to 0 order

Question 20

Drugs are reabsorbed by?

Answer 20

• passive reabsorption- especially for lipid soluble drugs. After free water absorption these are concentrated in the loop of Henle. Reverse concentration gradient occurs
• active reabsorption- active transport, for endogenous compounds, works for some drugs

Question 21

Amount of drug excreted

Answer 21

(glomerular filtration +active tubular secretion) - (passive reabsorption +active reabsorption)

Question 22

Urinary Excretion of Drugs by the Kidneys

Answer 22

• small blood vessels carry plasma-containing drugs to the glomerulus of the kidney for filtration
• lipid soluble drugs are capable of diffusing across the cell membranes of the proximal tubules
• and thereby escape excretion (tubular reabsorption)
• water soluble compounds do not diffuse across the kidney tubules and are eventually excreted in the urine
• some drugs and metabolites are secreted from the plasma and are thereafter eliminated from the body in the urine

Question 23

Enhancing Renal Excretion

Answer 23

• forced diuresis
• manipulate the pH of the urine- trapping of ionized drug
• usual urine pH= 5.5
• alkalinization- change urinary excretion by 4 fold to 6 fold

Question 24

Biliary Excretion

Answer 24

• amount of drug excreted = (amount of drug entering bile) - (amount of drug reabsorbed)
• enter bile by: secretion- active transport system- acids or bases, passive diffusion (small and lipid soluble)
• reabsorbed by: passive diffusion and the original absorption mechanism- enterohepatic cycling can occur
• other routes of elimination- lung, sweat, saliva, tears, breastmilk

Question 25

Elimination of Drugs from Site of Action

Answer 25

• decrease the concentration in the plasma
• redistribution- changes the location of the drug
• biotransformation- primarily hepatic, metabolically changes the drug to metabolites and causes a clearance of the drug from the plasma
• excretion- primarily renal, produces a clearance of the drug from the plasma and from the body

Question 26

Clearance

Answer 26

• a combination of biotransformation and excretion, the contribution of each process will vary for different drugs
• a volume of plasma that is cleared of drug per unit of time
• Clearance total = Clearance Metabolics + Clearance Renal
• in hepatic disease: metabolic clearance is reduced
• in renal disease: renal clearance is reduced

Question 27

Factors influencing clearance

Answer 27

• body surface area
• protein binding
• cardiac output
• renal function
• hepatic function
• blood flow to systemic organs