Basic Principles of Pharmacology IV Flashcards
1
Q
Biotransformation of Toxicants
A
- can have a widespread influence on drug use
- route of administration
- dose
- effectiveness
- toxicity, safety
- duration of effect
2
Q
Purposes of Biotransformation
A
- 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
3
Q
Sites of Biotransformation
A
- liver- on cellular structural components, smooth endoplasmic reticulum- lipid environment- enhances equilibrium with lipid soluble drugs
- cytoplasm in liver
- anywhere else in the body
4
Q
Hepatic Microsomal Drug Metabolizing systems
A
- 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
5
Q
Non-microsomal Systems
A
- 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
6
Q
Drug Oxidation
A
- 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
7
Q
Hepatic Mixed Function Oxidase System
A
- 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
8
Q
P450 groups
A
- 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
9
Q
Drug interactions and cytochrome P450
A
- 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
10
Q
Type of Biotransformation by Hepatic Mixed Function Oxidase System
A
- aliphatic oxidations
- aromatic oxidations
- oxidative N-dealkylations
- Oxidative O-demethylations
- Oxidative S-dealkylations
- oxidative deaminations
- N-oxidations
- N-hydroxylations
- Sulfoxide formations
- Oxidative desulfurations
11
Q
Drug Reductions
A
- 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
12
Q
Drug Hydrolysis
A
- cleave a molecule by the addition of a water molecule
- ester to an acid and alcohol
- amide to RCOOH and RNH2
13
Q
Activities of Drugs vs Activities of Metabolites
A
- 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
14
Q
Phase II reactions
A
- 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
15
Q
Types of Conjugation
A
- glucuronide formation
- glycine conjugation
- glutamine conjugation
- acetylation, acylation
- sulfate conjugation
- methylation
- riboside and riboside phosphate formation
- mercapturic acid formation
16
Q
Enzyme system with rate limiting step
A
- 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] «_space;Km then: efficient enzyme systems
- V= Vmax[D]/[D]= Vmax zero order, if [D]» Km then inefficent enzyme systems
17
Q
What is the result of biotransformation?
A
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
18
Q
Drug Excretion
A
- Renal Excretion- most important route of elimination of drug or metabolites
- amount of drug excreted= Amount entering tubule - amount reabsorbed
19
Q
How does a drug enter a nephron
A
- 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
20
Q
Drugs are reabsorbed by?
A
- 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
21
Q
Amount of drug excreted
A
(glomerular filtration +active tubular secretion) - (passive reabsorption +active reabsorption)
22
Q
Urinary Excretion of Drugs by the Kidneys
A
- 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
23
Q
Enhancing Renal Excretion
A
- 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
24
Q
Biliary Excretion
A
- 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
25
Q
Elimination of Drugs from Site of Action
A
- 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
26
Q
Clearance
A
- 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
27
Q
Factors influencing clearance
A
- body surface area
- protein binding
- cardiac output
- renal function
- hepatic function
- blood flow to systemic organs
