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VPTox > Topic 2 Part 2 > Flashcards

Topic 2 Part 2 Flashcards

1
Q

What is absorption of the drug absorption process?

A
  • Transfer of a drug from its site of administration into bloodstream
  • For IV route –> full absorption
  • For other routes –> partial absorption
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2
Q

Where is the site of absorption of oral drugs?

A
  • Stomach: Lipid-soluble drugs & weak acids absorbed directly
  • Small intestine: Primary sites of absorption –> large surface area allows efficient drug absorption
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3
Q

What are the mechanisms of drug absorption?

A
  • Passive diffusion
  • Active transport
  • Endocytosis
  • Exocytosis
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4
Q

Passive diffusion (drug absorption)

A
  • Drugs diffuse passively along concentration gradient –> most common
  • Water-soluble drugs penetrate mbn through the aqueous channels (e.g. sodium channels)
  • Lipid-soluble drugs diffuse lipid bilayers
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5
Q

Active transport (drug absorption)

A
  • Large drugs & lipid-insoluble drugs transported across cell mbn by special carrier protein
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6
Q

Endocytosis (drug absorption)

A
  • Very large drugs & impermeant drugs
  • Bound to cell surface receptors
  • Engulfed by a cell mbn
  • Vesicle pinched off from cell mbn
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7
Q

Exocytosis (drug absorption)

A
  • Reverse process of endocytosis
  • Vesicles containing drugs fuse with cell mbn
  • Expulsion of drugs intracellular space
  • E.g. Vit B12 is tpted across gut wall
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8
Q

What are the factors affecting absorption?

A
  1. Drug properties
  2. Routes of administration
  3. Blood flow to administration site
  4. Surface area for absorption
  5. Dosage forms of drugs
  6. Drug-drug interactions
  7. Disease status of patients
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9
Q

How does drug properties affect drug absorption?

A
  • Size: small molecules are more easily absorbed
  • Hydrophilicity & hydrophobicity (lipid solubility): hydrophilic drugs are poorly absorbed because they cannot cross the cell lipid mbn
  • pKₐ of drug: determines the fraction of unionized drug in different pH. Unionized drug crosses membrane more readily
  • Chemical stability of drug (e.g. insulin is unstable in gastric environment –> injection)
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10
Q

`How does the routes of administration affect the drug absorption process?

A
  • IV: into circulation directly –> complete absorption
  • IM, SC, intradermal & topical: into circulation indirectly –> incomplete absorption
  • Oral: first-pass effect by liver –> drug is absorbed in GI tract & transported to the liver where it is metabolized before entering the systemic circulation
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11
Q

How does blood flow to site of administration affect the drug absorption process?

A
  • Highly vascularized, more blood flow –> greater absorption (small intestine > stomach
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12
Q

How does surface area for absorption affect the drug absorption process?

A
  • Bigger surface area = greater absorption (small intestine > stomach)
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13
Q

How does dosage form affect the drug absorption process?

A
  • Type of vehicle used in drug formulations can affect dissolution & absorption
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14
Q

How does drug-drug interaction affect the drug absorption process?

A
  • Drug combinations can increase or inhibit drug absorption

- E.g. charcoal tablets absorb other drugs

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15
Q

How does disease status affect the drug absorption process?

A
  • GI disease alters drug absorption (e.g. malabsorption)

- Cardiac failure –> less blood flow –> less absorption

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16
Q

What is drug distribution and the major compartments in the body?

A
  • Process of drug leaving circulation and entering extracellular space or cells of tissues

Major compartments

  • Plasma
  • Extracellular space (interstitium)
  • Cells/tissues
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17
Q

Plasma compartment (drug distribution process)

A
  • Free drug is active
  • Bound drug is inactive
  • Bound drug: bound to plasma proteins (e.g. albumin) –> bound drugs are too large to cross capillary
18
Q

What is plasma drug concentration and what is it used for?

A
  • Measure of total amt of drug in plasma (bound & unbound)
  • Varies with passage of time post-drug administration
  • Used to predict the efficacy/side effect
  • The area under the plasma drug concentration-time curve (AUC) reflects the actual body exposure to drug after administration
19
Q

What are the factors that affect plasma drug concentrations?

A
  1. Route of drug administration
  2. Mechanism ADME
  3. pH and ionization status of drug
  4. Absorptive surface area
  5. Blood supply to area of drug administration
  6. Solubility of the drug
  7. Dosage form
  8. Time of sampling
  9. Drug-drug interaction
20
Q

What does the movement from plasma to interstitium depend on?

A
  1. Drug properties
  2. Blood flow
  3. Capillary permeability
  4. Binding of drugs to proteins
21
Q

How does drug properties affect the movement of drugs from plasma to interstitium?

A

Hydrophobic

  • with uniform distribution of electrons & no net charge
  • easy to move across the mbn

Hydrophilic

  • non-uniform distribution of electrons/positive/negative charges
  • not able to readily penetrate –> must go through the slit junciton
22
Q

How does capillary permeability affect the movement of drugs from plasma to interstitium?

A

Endothelial cells in body
- slit junctions (space b/w endothelial cells) aids distribution (e.g. in liver, spleen)

Brain capillary
- tight junctions causes blood-brain barrier (highly selective semipermeable barrier)

23
Q

How does binding of drugs to proteins affect the movement of drugs from plasma to interstitium?

A
  • Reversible binding to plasma proteins (e.g. albumin)

- Acts as a drug reservoir, bound drug dissociates from protein when in need

24
Q

What is drug biotransformation?

A

Chemical modification of compound by an organism

metabolism

25
Q

What is the purpose of drug biotransformation and what are the end products of this process?

A

Main purposes

  • Inactivate drug
  • Converting to water-soluble form for elimination by the kidneys
End product (AKA metabolite)
- less active (most often)/more active or even toxic

Two main rxns: phase I and phase II

26
Q

Where is the primary site of drug biotransformation?

A
  • Primary site is in the liver

- Most tissues has ability to metabolize drugs

27
Q

What occurs in phase I of the drug biotransformation process?

A
  • Convert parent drug to a more polar metabolite by introducing/unmasking polar functional group (-OH, -NH₂)
  • Cytochrome P-450 being the major enzymes
    (other exceptions –> e.g. oxidation of catecholamines; alcohol dehydrogenation)
  • Main chemical rxns involved: oxidation, reduction, hydrolysis
28
Q

What is the Cytochrome P450 system (CYP)?

A
  • CYP comprises of many families of enzymes found mainly in the liver & GI tract
  • CYP 450 activity can be enhanced (enzyme inducer)/inhibited (inhibitor) by other drugs or hormones
29
Q

How does CYP 450 affect drug-drug interactions?

A
  • CYP 450 enzyme inducers/inhibitors may result in a drug-drug interaction when administered simultaneously with another drug which is metabolized by CYP 450
  • Altered pharmacologic response to a drug that is caused by 2nd drug
30
Q

Describe an example of phase I of drug biotransformation process

A

Phenobarbitone with Warfarin

  • Phenobarbitone (anti-seizure) induces CYP450 enzymes
  • Warfarin (anticoagulant for stroke) is metabolized by CYP 450 enzymes
  • This increases the metabolism of warfarin
  • This lowers the plasma drug concentration of warfarin
  • This results in a sub-therapeutic effect of warfarin
31
Q

What occurs in phase II of the drug biotransformation process?

A
  • Drugs not eliminated in phase I undergo phase II
  • Reaction of newly incorporated functional group in phase I with endogenous substrates to form highly polar conjugate to be eliminated by kidney
32
Q

What are some endogenous substrates?

A
  • Amino acid
  • Glucuronic acid
  • Sulfuric acid
  • Acetic acid
33
Q

What is the main purposes of phase II of the drug biotransformation process?

A
  • Make drug water-soluble for elimination through kidneys (most common rxn: glucuronidation)
  • Make drug therapeutically inactive
  • Drugs which possess an -OH, -NH₂, or -COOH group may undergo phase II metabolism without phase I metabolism
  • Some drugs undergo phase II then phase I
34
Q

What enzyme plays a part in phase II of drug biotransformation and what does it do?

A

Glucuronyl transferase

- Catalyze conjugation of glucuronic acid

35
Q

What are the factors affecting biotransformation?

A
  1. Genetic differences
  2. Liver diseases
  3. Age
  4. CYP enzyme induction/inhibition
36
Q

How does genetic differences affect biotransformation?

A
  • Each indiv has varying capacity to metabolize drugs
  • Major deficiencies due to inherited recessive traits (e.g. defects in oxidative metabolism of warfarin which leads to bleeding)
37
Q

How does liver diseases affect biotransformation?

A
  • decreased blood flow to liver

- damaged liver cells

38
Q

How does age affect biotransformation?

A
  • neonates have immature liver function

- elderly have decreased liver function and blood flow

39
Q

What is the first pass effect?

A
  • Oral and intra-peritoneal drugs
  • Have to pass through the liver before reaching the circulation
  • The liver metabolizes the drug
  • Therefore, the drug level that reaches the circulation is less than the actual dosage given
40
Q

What is enterohepatic cycling?

A
  • Drug is excreted through the bile
  • It is reabsorbed in the small intestines and recycled back to the liver through the hepatic portal vein
  • It then returns to the systemic circulation, prolonging the drug effect
  • e.g. penicillin, sulfonamides
41
Q

How does liver disease affect first-pass effect & enterohepatic cycling?

A
  • Chronic liver cirrhosis decreases first-pass effect
  • This leads to a decrease in drug metabolism rate and decrease in clearance of parent drug
  • Drug effect is prolonged
  • If drug level not monitored –> may lead to toxicity
42
Q

What can affect the first pass effect?

A
  • Liver disease

- Will affect first pass effect and enterohepatic cycling and therefore drug effect

VPTox (4 decks)

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