Terms in this set (25)
1. Transporting between cells (this does not occur in the BBB as there are tight junctions inhibiting this method of transport)
2. Mostly lipid soluble drugs, they diffuse directly through the cell membrane
3. Use of transmembrane protein carriers to move the drug across and through a cell
4. Self explanatory...
There are four mechanisms of drug permeation listed below. Give a brief description of each:
1. Paracellular pathway
2. Transcellular pathway
4. Endocytosis & Exocytosis
The route of administration.
What determines the rate and efficacy of absorption of a drug?
Which route of administration has the drug completely absorbed?
The first-pass effect is when a drug is passed through the liver when administered via some routes (such as oral or rectal), thereby undergoing some metabolism prior to the drug reaching systemic circulation.
What is the first-pass effect and how does it affect the bioavailability of a drug?
Are the following routes of administration subject to the first-pass effect or not?
2. Parenteral (10-15°)
5. Parenteral (90°)
6. Parenteral (45°)
Which of these is an enteral and which of these is a parenteral route of administration of a drug and when applicable name the angle of injection?
Non-ionized as they are usually liposoluble.
pH - pK = log(unprotonated/protonated)
Are ionized or non-ionized drugs able to better diffuse across a cell membrane and why?
Is a weak acid liposoluble when protonated or unprotonated?
Is a weak based liposoluble when protonated or unprotonated?
What is the Henderson-Hasselbach equation?
It will passively diffuse/reabsorb across the renal tubule and reenter the circulation, thereby escaping excretion.
We can prevent its reabsorption in the kidney by manipulating the pH of the urine leading to ion trapping.
Alkaline urine would excrete weak acid drugs faster and acidic urine would excrete weak base drugs faster.
What occurs if a drug is in a liposoluble form during its passage down the renal tubule?
As a result, how can we accelerate the excretion of a drug?
What type of urine would excrete weak acid drugs faster and which type of urine would excrete weak base drugs faster?
Absorptive surface area meaning that the small intestines is the primary site of drug absorption.
It would slow down the absorption time because it would increase the amount of time it takes for the drug to get to the small intestines.
Anything that promotes gastric emptying.
A drug moving quickly through the GI tract such as when a patient has diarrhea.
What is a major determinant of the site of absorption of drugs from the GI tract?
Would taking a drug with food slow down or speed up the absorption time of a drug and why?
What sort of factor would increase the rate of drug absorption?
What would cause poor absorption of a drug in the GI tract?
It is a MDR1 transmembrane protein exposed to the gut lumen the is responsible for transporting several drugs across the cell membrane thereby reducing drug absorption.
What is P-glycoprotein and how does it affect drug absorption?
It is the fraction of the administered dose of a drug that reaches the systemic circulation. To calculate it we find the area under a plasma concentration curve for a route of administration and then use the following calculation:
Bioavailability (F) = (AUC oral)/(AUC IV)x100
What is bioavailability and how is it calculated?
They are when two drug products are considered to be pharmaceutically equivalent.
It requires that they contain the same active ingredients, and are identical in concentration, dosage form, and route of administration.
When their concentration-time plots are nearly superimposable.
What is bioequivalence and what four things are required for drugs to be considered bioequivalent?
When are two pharmaceutically equivalent drug products considered to be bioequivalent?
The liver, kidney, brain, and other well perfused organs.
Muscles, most viscera, skin, and fat is much more slowly perfused.
Which organs initially receive the most amount of a drug?
Which areas receive a drug at a later time?
1. Basic drugs
2. Acidic drugs
1. Sulfonamides are acidic and can displace physiological components such as unconjugated bilirubin from albumin. In newborns this can lead to kernicterus as it would lead to increased levels of unbound, unconjugated bilirubin.
2. Warfarin acts in a very narrow therapeutic index and is normally bound to albumin. If a patient taking warfarin starts taking sulfonamides it causes some of the warfarin to be displaced from the albumin and would lead to increased plasma levels of unbound warfarin which can cause bleeding.
Many drugs are transported in the blood bound to plasma proteins. Which type so drugs bind to the following protein:
1. α1-acid glycoprotein
2. Plasma albumin
Are bound or unbound drugs pharmacologically active?
How can this cause problems? Use the following examples:
1. Sulfonamides in newborns
2. Warfarin and sulfonamide interaction
In fat cells
Liposoluble drugs because of the tight junctions and astrocytes that form the BBB keep drugs from crossing paracellularly.
Drugs can accumulate in tissues and serve as a reservoir for prolonged drug action. Where do liposoluble drugs commonly accumulate?
What type of drugs are the only type that cross the BBB and why?
Inactive metabolites but they are sometimes transformed to metabolites with potent biological activity or toxic properties.
1. Phase 1
2. Phase 1
3. Phase 1
4. Phase 2
5. Phase 1
6. Phase 1
It is the covalent bonding between a drug molecule and glucuronate, acetate, glutathione, amino acids, or sulfate forming a big polar molecule that is more easily and readily excreted.
In general, biotransformation/metabolism of drugs give drugs that have what charge?
Are they commonly metabolized to active or inactive form?
Is the following a phase 1 or phase 2 reaction?
5. Hydrolytic reactions
What is a conjugation?
Phase 1 converts a parent drug to a more polar metabolite which generally results in it becoming inactive.
Phase 2 reactions form a covalent bond which forms a large polar molecule suitable for excretion.
The GI tract
What occurs in a phase 1 reaction of metabolism and what occurs in a phase 2 reaction of metabolism?
What is the primary organ of metabolism?
Besides the liver what other organ system contributes to the first-pass effect?
Where are the majority of the enzymes involved in phase 1 reactions found within the cell?
Where are the majority of the enzymes involved in phase 2 reactions found within the cell?
CYP3A4 - metabolizes about 50% of all drugs
What catalyzes most of the phase 1 reactions?
Which CYP450 enzyme accounts for about 30% of the enzymes in the liver and approximately what percentage of drugs does it metabolize?
Increased transcription of the CYP450 enzymes.
Phenobarbital, rifampin, and carbamazepine.
The drugs enter the hepatocyte and bind to the xenobiotic receptor (intracellular receptor). The drug-receptor complex then enters the nucleus and bind to promoters to induce increased transcription of various CYP450 enzymes.
What causes induction of CYP450 enzymes?
Name three drugs involved in increasing the synthesis of one or more P450 enzymes.
How does this CYP450 enzyme induction occur?
2. PXR & CAR
They can increase the their own metabolism.
They can increase the metabolism of the other co-adminstered drug.
In either case it can lead to a reduction in plasma levels below therapeutic levels.
It could increase the amount of toxic reactive metabolites resulting in tissue damage.
Three xenobiotic receptors that induce cytochrome enzyme transcription are AhR (aryl hydrocarbon receptor), PXR (pregnant X receptor), and CAR (constitutively active receptor). Which are bound by the following drugs?
How do these drugs interactions with these xenobiotic receptors affect their metabolism?
How could they affect the metabolism of other co-adminstered drugs?
How can induction of CYP450 enzymes lead to cellular damage?
1. Inhibition of CYP450
2. Induction of CYP450
3. Inhibition of CYP450 and inhibition of P-glycoprotein transporters (along with other macrolide antibiotics)
4. Inhibition of CYP450
5. Induction of CYP450
6. Inhibition of CYP450
7. Induction of CYP450
P-glycoprotein is also transcriptionally regulated by PXR. As a result, drugs that induce P450 enzymes through the PXR pathway also induce P-glycoprotein.
Does the following drug lead to induction or inhibition of CYP450 enzymes or inhibition of P-glycoprotein transporters?
What is the relationship between P-glycoprotein and P450 enzymes induced via the PXR pathway?
Acetaminophen is metabolized by CYP2E1 to NAPQI (a toxic intermediate) but is quickly converted to a non-toxic metabolite using GSH. As GSH is used up when this drug is taken in high doses the NAPQI builds up and leads to attachment to cell proteins and liver cell death.
We treat acetaminophen toxicity with N-acetylcysteine (acetadote) which both supplies cysteine for glutathione production and reacts directly with NAPQI.
How does ingesting acetaminophen in large doses lead to toxicity?
What can be given to counteract this toxicity and how does it work?
Genetic variation in enzymes that catalyze drug metabolism.
It is a graph of variations in acetylation of isoniazid that is a result of genetic variations in enzyme polymorphisms.
The slow acetylators are homozygous for a lower activity level enzyme whereas fast acetylators have higher activity enzymes that are genetically inherited.
NAT2 (N-acetyltransferase 2)
What is the most common factor responsible for pharmacogenetic variation in drug responses?
What does the following graph show?
What enzyme is involved?
It inhibits both P-glycoprotein and CYP34 leading to increased absorption of some drugs in the SI and decreased metabolism of those drugs, respectively.
How does grapefruit juice affect drug metabolism?
They induce CYP450 enzymes leading to faster metabolism of drugs.
Many of the reactions are slowed in both young children and the elderly.
They can reduce drug metabolism as a result of decreased liver function.
How do aromatic hydrocarbons in cigarette smoke affect drug metabolism?
How does age affect metabolism of many drugs?
How do chronic diseases affecting the liver affect drug metabolism?
The drug needs to be free, not bound, and have a molecular weight less than 20,000.
Where are the majority of drug metabolites excreted?
Name another location they are excreted from.
What affects whether a drug is filtered by the glomerulus?
Does lipid solubility and pH influence the passage of drugs into the glomerular filtrate?
One pumps cations and one pumps anions.
Two active transport systems are responsible for pumping drug metabolites into the renal tubules. What is the function of each?
What type of drug metabolites are reabsorbed from the renal tubules?
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