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Pharm Exam 1 > Pharm. Disposition > Flashcards

Pharm. Disposition Flashcards

1
Q

Pharmacokinetics - Definition

A

Effect of the body on the drug

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2
Q

Pharmacodynamics - Definition

A

The effect of the drug on the body

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3
Q

4 Principle Processes of Disposition:

A

A. Absorption

B. Distribution

C. Metabolism

D. Excretion

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4
Q

Barriers to absorption

A
  • lipid membrane
  • BBB (in brain - tight junction and need highly lipid drug to pass)
  • Metabolic inactivation (example: binding to albumin makes it too big to pass through capillaries)
  • drug-drug interaction
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5
Q

Diffusion Through Membrane Depends Upon:

A
  • area of membrane
  • thickness of membrane
  • concentration gradient across membrane
  • lipid solubility of membrane (partition coefficient)
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6
Q

4 Rules About Drug Diffusion

A

Rule #1 – The larger the partition coefficient, the more rapid the absorption

Rule #2 – ionized molecules do not cross by simple diffusion

Rule #3 – when the pH on either side of the membrane is the same then the total amounts of drug on each side of the membrane are the same.

Rule #4 – If the pH on each side of the membrane is different, there will be a difference in concentration across the membrane. This difference is known as ion trapping or pH partitioning.

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7
Q

Drug Distribution by Compartment (over time)

A

Blood>Vessel Rich Group (heart, brain, kidneys)>muscle>fat

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8
Q

Major Site of Oral Absorption and Rate

(2 more rules)

A

Rule #1 – major site for absorption is the small intestine. Large surface area, transit time.

Rule #2 – Rate of absorption is dependent upon how fast stomach empties (glass of water increases absorption because it hastens emptying)

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9
Q

Routes of Administration

A
  • IV
  • Inhalation
  • IM
  • Enteral
    • sublingual
    • rectal
    • oral
  • Topical
  • Placental
  • Breast Milk
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10
Q

IV Administration - Pros and Cons

A

Pros

  • rapid onset of action
  • accurate control of blood levels
  • directly to the central compartment (i.e., blood)

Cons

  • non-removable
  • rapid with high concentrations (fast can be toxic)
  • embolism, fever, excessive fluid loads
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11
Q

IM/Sub Q Administration - Pros and Cons

A

Pros

  • IM more rapid than SC
  • IM less sensitive to irritants than SC
  • SC - slow absorpotion with a vasoconstrictor
  • sustained release preparations possible

Cons

  • PAIN - irritation and local necrosis with SC
  • must use small volumes
  • infection
  • sterile abscess
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12
Q

Inhalation Administration - Pros and Cons

A

Pros

  • large surface area
  • high blood flow
  • efficient absorption of gases, aerosoles and atomized particles
  • local and systemic delivery
  • equipment-dependent metered doses

Cons

  • allergic reactions
  • route used for drugs of abuse and for occupational/environmental toxins
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13
Q

Topical Administration - Pros and Cons

A

Pros

  • dermis is freely permeable, so more absorption through abraded or burned skin
  • absorption dependent on surface area
    • enhanced by oily suspension of drug
    • hydrated skin more permeable
  • controlled release patches are popular

Cons

  • allergic reactions, especially to adhesives in patch
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14
Q

Sublingual/Buccal - Administration

A
  • under the tongue or between check and gum
  • drains into superior vena cava, bypass the liver and do not get first pass metabolism
  • onset of action is rapid
  • lipid solubility and ionization are important factors
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15
Q

Rectal - Administration

A
  • wide variety of drugs available
  • useful for unconscious patients, children or drugs that irritate the GI lining
  • 50% of drug absorbed will bypass liver

Cons

  • absorption is incomplete, irregular
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16
Q

Oral - Administration

A
  • most common
  • economical
  • safe
  • sustained release preps. possible

Cons

  • irritates the GI tract
  • destroys drug
  • irregular absorption - slow onset
  • overdose
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17
Q

Placental Exposure

A
  • placental membranes are normal cell membranes
  • if available orally, fetus will be exposed
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18
Q

Breast Milk - Exposure

A
  • pH is slightly acidic (6.8)
  • Basic compounds tend to accumulate in BM relative
  • neutral compounds found in amounts similar to plasma
19
Q

What is the major enzyme family responsible for microsomal reactions?

A

Cytochrome P-450 family

20
Q

Facts you must know about CYP-450 family

A

Located in the ER

Absorption at 450 nm

Broad specificity (lots of drugs fit in its catalytic site)

50 functional in humans

Major Liver include a variety, but CYP3A4 and 3A5 are the isoforms involved

21
Q

CYP3A is responsible for metabolism of what drugs and what percent of drugs?

A

CYP3A – 50%

  • rifampin
  • barbituates
  • anticonvulsants
  • St. John’s wort
22
Q

What happens during the CYP-450 cycle?

A
  • NADPH is oxidized to NADP+
  • P450 reductase reduces flavoprotein
  • Reduced flavoprotein donates its electrons to the P450[Fe3+} drug complex (so it gets reduced)
  • O2 is added to the drug complex, which increases water solubility and electronegativity
  • Water is generated and a single activated Oxygen is transferred to the drug
  • the drug falls off the P450[Fe3+] complex for further processing
23
Q

What are some common CYP-450 reactions

A
  • N-, S-, O-dealkylations
  • hyrdoxylation
  • N-oxidation
  • dehalogenation
  • S-oxidation
  • deamination
  • desulfuryation
24
Q

What happens on first pass CYP-450 metabolism?

A

Depends upon drug, but generally speaking:

  • Pro-drug: activation (must occur for drug to act on the body)
  • typical drug: deactivation
  • some drugs: toxic intermediate formed (along with nontoxic intermediates or in their entirety
25
Q

Other Phase 1 Reactions

A

Reductions: rare, but can occur

Hydrolyses

  • Esters, amides
  • aspirin, acetylcholine, local anesthetics

Non-microsomal oxidations

  • monoamine oxidases
  • alcohol dehydrogenases
26
Q

Type of Phase II Conjugations

A
  • Glucuronidation – UDPGA and PAPS for both, charged species at physiologic pH so that they can be pumped into renal filtrate
  • Sulfation – same as above
  • Glutathione conjugation – leukotrienes, glutathione is the cofactor, detoxification (something transferase)
  • methlyation and acetylation (he did not seem to care if we knew these two)
27
Q

What happens in a Type II Metabolism Reaction?

A

Conjugations – these require activated cofactors to synthesize conjugate

-make it more water soluble or charged. All do one or the other, or both.

28
Q

How does the body eliminate substances that undergo Phase II glucurondiation and sulfation?

A

-glucaronic acid (or sulfuronic acid) has a -COOH group attached and the kidney has specialized active transport systems to pump these into the renal filtrate

29
Q

What are the categories of drug-drug interactions?

A
  • P450 Inhibition
  • P450 Induction
  • Drug Transporter Inhibition
  • Excretion
  • Enterohepatic Recycling
30
Q

Drug-Drug Interactions: P450 Inhibition

A

Generally due to either:

  • Competitive inhibition - Reversible, competition of substrate and inhibitor for site on enzyme
  • Direct inhibition: irreversible, formation of stable complex between drug metabolite and enzyme
  • For Phase 2 enzymes, inhibit by depletion of cofactors (starving, alcoholic)
  • Culprits: cimetidine, omeprazole, grapefruit juice, metrondiazone, ciproflaxin, sulfonamides, erythromycin, omeprazole, EtOH (binge)
31
Q

Consequences of Inhibition

A
  • decreased rate of metabolism
  • decreased oral first pass metabolism
  • increased bioavailablity
  • incread drug plasma concentrations
32
Q

Drug-Drug Interactions: P450 Induction

Why does it occur?

A
  • occurs because drug binds to nuclear receptor and upregulates CYP transcription
  • Requires repeated exposure to or administration of a drug or repeated exposure to other agent (ex. smoke, charbroiled meats, PCBs)
33
Q

P450 Induction: What Happens?

A
  • Increased rate of synthesis of the P450 enzyme

OR

  • Decreased rate of degradation of the enzyme
  • increased rate of metabolism
  • enhanced oral first pass metabolism and reduced bioavailability
  • decreased drug plasma concentrations
  • reduced drug exposure
34
Q

Induction can occur because of what agents other than drugs?

A
  • cigarette smoke, polycyclic aromatics, charbroiled meats, cruciform vegetables, PCB’s
35
Q

Drug-Drug Interactions: Drug Transporter Inhibition

A
  • most of time due to competitive inhibition between substrate and drug

Influx - OATP

Efflux – MDR1/P-gp/ABCB1

36
Q

What are the effects of disease on metabolism?

A
  • hepatic disease generally inhibits
  • cardiac disease can cause a slower metabolism because delivery to liver by blood is rate limiting
  • thryoid status - effects metabolism
37
Q

Excretion

A
  • drugs and metabolites eliminated from the body
  • protein binding limits the filtering of drugs
  • reabsorption based on pH and ionization
38
Q

First Pass Effects

A
  • If the liver metabolizes the drug, it will not all get into the circulation
  • In other words, all of the drug is not bioavailable
39
Q

What is enterohepatic recycling

A

When liver passes drug into bile and the gut allows it to re-enter through the portal system and back through the liver to be passively absorbed or reabsorbed. Provides a reservoir of drug for longer duration action.

40
Q

What happens to the AUC in a drug plasma vs. time curve?

A

Inhibition - increases

Induction - decreases

NB: this is a measure of the bioavailabity of a drug

41
Q

Ionization of Weak Acids

A

HA <–> H+ + A-

42
Q

Ionization of Weak Bases

A

BH+ <–>H+ + B

43
Q

What you need to know about pH and distribution

A

Reminder: pKa is the pH at which there is 50% ionized and 50% un-ionized forms of the drug in solution

Hendersson-Hasselbach

pH = pKa + log([acid]/[base])

So, REMEMBER

When pH is LOW (i.e., acidic), acids will be un-ionized, bases will be ionized

When pH is high, bases will by un-ionized, acids will be ionized

Steady state:

  • Weak acids accumulate on the basic side
  • Weak bases accumulate on the acidic side

Pharm Exam 1 (3 decks)

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