Pharm. Disposition Flashcards
Pharmacokinetics - Definition
Effect of the body on the drug
Pharmacodynamics - Definition
The effect of the drug on the body
4 Principle Processes of Disposition:
A. Absorption
B. Distribution
C. Metabolism
D. Excretion
Barriers to absorption
- 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
Diffusion Through Membrane Depends Upon:
- area of membrane
- thickness of membrane
- concentration gradient across membrane
- lipid solubility of membrane (partition coefficient)
4 Rules About Drug Diffusion
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.
Drug Distribution by Compartment (over time)
Blood>Vessel Rich Group (heart, brain, kidneys)>muscle>fat
Major Site of Oral Absorption and Rate
(2 more rules)
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)
Routes of Administration
- IV
- Inhalation
- IM
- Enteral
- sublingual
- rectal
- oral
- Topical
- Placental
- Breast Milk
IV Administration - Pros and Cons
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
IM/Sub Q Administration - Pros and Cons
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
Inhalation Administration - Pros and Cons
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
Topical Administration - Pros and Cons
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
Sublingual/Buccal - Administration
- 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
Rectal - Administration
- 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
Oral - Administration
- most common
- economical
- safe
- sustained release preps. possible
Cons
- irritates the GI tract
- destroys drug
- irregular absorption - slow onset
- overdose
Placental Exposure
- placental membranes are normal cell membranes
- if available orally, fetus will be exposed
Breast Milk - Exposure
- pH is slightly acidic (6.8)
- Basic compounds tend to accumulate in BM relative
- neutral compounds found in amounts similar to plasma
What is the major enzyme family responsible for microsomal reactions?
Cytochrome P-450 family
Facts you must know about CYP-450 family
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
CYP3A is responsible for metabolism of what drugs and what percent of drugs?
CYP3A – 50%
- rifampin
- barbituates
- anticonvulsants
- St. John’s wort
What happens during the CYP-450 cycle?
- 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
What are some common CYP-450 reactions
- N-, S-, O-dealkylations
- hyrdoxylation
- N-oxidation
- dehalogenation
- S-oxidation
- deamination
- desulfuryation
What happens on first pass CYP-450 metabolism?
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
Other Phase 1 Reactions
Reductions: rare, but can occur
Hydrolyses
- Esters, amides
- aspirin, acetylcholine, local anesthetics
Non-microsomal oxidations
- monoamine oxidases
- alcohol dehydrogenases
Type of Phase II Conjugations
- 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)
What happens in a Type II Metabolism Reaction?
Conjugations – these require activated cofactors to synthesize conjugate
-make it more water soluble or charged. All do one or the other, or both.
How does the body eliminate substances that undergo Phase II glucurondiation and sulfation?
-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
What are the categories of drug-drug interactions?
- P450 Inhibition
- P450 Induction
- Drug Transporter Inhibition
- Excretion
- Enterohepatic Recycling
Drug-Drug Interactions: P450 Inhibition
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)
Consequences of Inhibition
- decreased rate of metabolism
- decreased oral first pass metabolism
- increased bioavailablity
- incread drug plasma concentrations
Drug-Drug Interactions: P450 Induction
Why does it occur?
- 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)
P450 Induction: What Happens?
- 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
Induction can occur because of what agents other than drugs?
- cigarette smoke, polycyclic aromatics, charbroiled meats, cruciform vegetables, PCB’s
Drug-Drug Interactions: Drug Transporter Inhibition
- most of time due to competitive inhibition between substrate and drug
Influx - OATP
Efflux – MDR1/P-gp/ABCB1
What are the effects of disease on metabolism?
- hepatic disease generally inhibits
- cardiac disease can cause a slower metabolism because delivery to liver by blood is rate limiting
- thryoid status - effects metabolism
Excretion
- drugs and metabolites eliminated from the body
- protein binding limits the filtering of drugs
- reabsorption based on pH and ionization
First Pass Effects
- If the liver metabolizes the drug, it will not all get into the circulation
- In other words, all of the drug is not bioavailable
What is enterohepatic recycling
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.
What happens to the AUC in a drug plasma vs. time curve?
Inhibition - increases
Induction - decreases
NB: this is a measure of the bioavailabity of a drug
Ionization of Weak Acids
HA <–> H+ + A-
Ionization of Weak Bases
BH+ <–>H+ + B
What you need to know about pH and distribution
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
