Transcript First-pass metabolism

• Pharmacokinetics:
– How drugs are handled by the body
Lets say you have a headache
and you need to take some
meds –
This illustrates the basic
processes in the branch of
pharmacokinetics
pharmacokinetics.......
1. the route of administration
- how a drug is taken into the body
2. absorption and distribution
- factors affecting its absorption and how it gets
distributed to the brain
3. metabolism (detoxification or breakdown)
how a drug is broken down or made into inactive
forms
4. excretion – (elimination)
– how the drug is eliminated
Knowing about pharmacokinetics tells us
critical information about insight into the
actions of a drug.
Ex. anti-anxiety drugs –
• benzodiazepenes
– ultra short acting, short acting, long acting
• Examples of BZ
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lorazepam – persists for at least 24 hr
triazolam – 6 – 8 hours
midazolam – 1 – 2 hrs
uses?
Drug Absorption
• Absorption – the process by which a drug enters
the bloodstream without being chemically altered or
• The movement of a drug from its site of application
into the blood
What are the routes of drug
administration?
oral administration
• most common, sometimes referred to as po
• safe, self administered, economical BUT blood
levels are often irregular (most complicated
route of adm)
• liquid more readily absorbed than solids
What do orally administered drugs
have to deal with?
– chemicals in stomach must deal with:
– stomach acids
– digestive enzymes
– first pass metabolism through liver
– other items in stomach
• ex. tetracycline
Advantages of oral administration
– Convenient - can be self- administered, pain free,
easy to take
– Absorption - takes place along the whole length of
the GI tract
– Inexpensive - compared to most other parenteral
routes
oral administration
• disadvantages of oral administration:
– vomiting/stomach distress
– variability in dose
– effect too slow for emergencies
– unpleasant taste of some drugs
– unable to use in unconscious patient
– first pass metabolism
First-pass metabolism
• First pass metabolism - term used for the hepatic
metabolism of a drug when it is absorbed from the gut and
delivered to the liver via the portal circulation.
• The greater the first-pass effect, the less the agent will reach
the systemic circulation when the agent is administered
orally
first pass metabolism
oral administration
• disadvantages of oral administration:
– vomiting
– stomach distress
– variability in dose
– first pass metabolism
• ex. buspirone (BuSpar) – antianxiety drug
– 5% reaches central circulation and is distributed to
brain
– metabolism can be blocked by drinking grapefruit
juice (suppresses CYPp450 enzyme)
Grapefruit Juice Increases Felodipine Oral Availability in Humans by
Decreasing Intestinal CYP3A Protein Expression
Hours
J.Clin. Invest. 99:10, p.2545-53, 1997
Some additional interesting points
regarding oral adm
• Drugs that are destroyed by gastric juice or
cause gastric irritation can be administered in
a coating that prevents dissolution in acidic
gastric contents (however may also preclude
dissolution in intestines)
• Controlled – Release Preps -
Factors that affect rate of absorption
following PO route
• GI motility- speed of gastric emptying affects
rate of absorption
– ex. migraine and analgesics vs metoclopramide
• Malabsorptive States – GI diseases, ex. Crohn’s disease can affect
absorption
Factors that affect rate of absorption
following PO route
• Food – iron, milk alters tetracycline
– fats
• first pass metabolism
Parenteral or Injection
• chemicals delivered with a hypodermic
needle;
– most commonly - injected into vein, muscle or
under the upper layers of skin, in rodents also
intraperitoneal cavity
• requirements for parenteral:
• must be soluble in solution (so it can be injected)
B. Parenteral (Injection)
– Intravenous
– Intramuscular
– Subcutaneous
– Intracranial
– Epidural
– Intraperitoneal
Intramuscular
• not typical for drugs of abuse
• absorption more rapid than SC
– less chance of irritation;
• ways to speed up or slow down absorption
• depot injections -
Intravenous
• extremely rapid rate of absorption
• adv: useful when you need rapid response or
for irritating substances
• Disadv: rapid rate of absorption
Absorption for parenteral route
• contingent on blood flow SO
– IV, intraperitoneal, IM, SC
• increasing or decreasing blood flow affects drug
absorption
• Drugs leave bloodstream and are exchanged
between blood capillaries and body tissues
Mucosal membranes
• nasal, oral, buccal
• medications include: nitroglycerine, fentanyl
–(1998) , nicotine gum, lozenges,
buprenorphine
• cocaine –
• snuff, cigars
Advantages and Disadvantages
of Buccal
– Advantages:
• rapid absorption
• avoid first-pass effect
– Disadvantages:
• inconvenient
• small doses
• unpleasant taste of some drugs
transdermal or transcutaneous
• 1990’s – several medications incorporated into
transdermal patches:
– estrogen, nicotine, fentanyl, nitroglycerin,
scopolamine
• controlled slow release for extended periods
of time
Rectal Administration
• usually suppository form
• for unconscious, vomiting or unable to
swallow
• disadv: not very well regulated dose;
irritation (yikes)
Inhalation
• not really used for psychotropics
Route for administration
-Time until effect-
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intravenous 30-60 seconds
inhalation 2-3 minutes
sublingual 3-5 minutes
intramuscular 10-20 minutes
subcutaneous 15-30 minutes
rectal 5-30 minutes
ingestion 30-90 minutes
transdermal (topical) variable (minutes to hours)
Drug Absorption
• The rate at which a drug reaches it site of
action depends on:
– Absorption - involves the passage of the drug
from its site of administration into the blood
– Distribution - involves the delivery of the drug to
the tissues
Drug Absorption
• Factors which influence the rate of
absorption
– routes of administration
– dosage forms
– the physicochemical properties of the drug
– protein binding
– circulation at the site of absorption
– concentration of the drug
Distribution
• drugs are distributed throughout body by blood
• very little at site of action at any one time
• role of passive diffusion, concentration gradient
Absorption
• Mostly a passive process – from higher conc to lower (in blood)
Concentration Gradient
Drug goes from higher concentration to lower concentration
 [DRUG]
receptors
≈ [DRUG]
circulation
Additional issue for drugs to reach the
CNS
• Blood brain barrier– layer of thickly packed epithelial cells and
astrocytes that restrict access of many
toxins/drugs to the brain
3 Factors that affect how well a drug can cross the
blood brain barrier (or placental barrier)
• Lipid solubility – how soluble the drug is in fats
– cell membranes are lipid bilayers
– similar characteristics allow drugs to cross brain as
to cross into cells
3 Factors that affect how well a drug can cross
the blood brain barrier
• Lipid solubility
• Size of molecule
• Ionization – whether the degree has a charge
(+ or -)
• pKa –
the pH at which ½ of the molecules are
ionized
• most drugs are either weakly basic or
weakly acidic
• Basic drugs are highly ionized in acidic
environment
• Acidic drugs are highly ionized in basic
environment
• pKa –
the pH at which ½ of the molecules are ionized
the closer the pKa of the drug is to the local
tissue pH, the more unionized the drug is.
ex. morphine – pKa of 8
stomach ~ pH ~ 3
caffeine – pH .5
Distribution half-life and therapeutic
levels
– Distribution half-life: the amount of time it takes
for half of the drug to be distributed throughout
the body
– Therapeutic level: the minimum amount of the
distributed drug necessary for the main effect.
Until this time, drug movement has
been mostly passive from regions
of higher concentration to lower
concentration.
Elimination of drugs usually requires more of
an active process (except gaseous drugs).
How are drugs eliminated?
1. Biotransformation (metabolism)
chemical transformation of a drug into a different
compound in the body (metabolite)
Most biotransformation takes place in the liver
2. Excretion - removal of drug to outside world
***Drug elimination may be by both or either of
these mechanisms
Biotransformation
• role of liver
– most significant organ in biotransformation
Biotransformation
• role of liver
– most significant organ in biotransformation
– largest organ in body
– serves many functions
• transforms molecules via enzymes
Liver enzymes biotransform drugs (and
other compounds) by
1. deactivating the molecule
2. ionize the molecule
3. make it less lipid soluble
** product of biotransformation is called a metabolite
Cytochrome p450 enzyme family
• located primarily in hepatocytes
• important for metabolism of alcohol, tranquilizers, barbiturates,
antianxiety drugs, estrogens, androgens, PCBs and other agents
• oxidative metabolism – makes drugs more water soluble (so
more easily excreted)
Can metabolism rate be altered?
• CYP enzymes – enzyme induction • liver produces extra enzyme to break down drug with
continued exposure
Can metabolism rate be altered?
• CYP enzymes -
– enzyme induction • liver produces extra enzyme to break down drug with
continued exposure
• Genetics
Can metabolism rate be altered?
• CYP enzymes – enzyme induction • liver produces extra enzyme to break down
drug with continued exposure
• Genetics
• Liver disease
In some cases, biotransformation can be to
another psychoactive compound
ex. benzodiazepenes
diazepam
nordiazepam
oxazepam
Routes of Excretion- fluid
• all drugs not in gaseous state need to use fluid
routes of excretion
– fluid routes include -sweat, tears, saliva, mucous,
urine, bile, human milk
– amount of drug excreted in each of these fluids is
in direct proportion to amount of fluid excreted
SO…….
Kidneys
• numerous functions –
– filters out metabolic products
Kidneys
• numerous functions –
• main function – maintain correct balance
between water and salt in body fluids
– filters out metabolic products
– blood continuously flowing through kidneys
• factors that influence a substance not being
resorbed
– not lipid soluble
– ionized
• dialysis –
absorption distribution and excretion do
not occur independently
2 Summary Slides
first pass metabolism
blood
brain
Other factors that affect drug
pharmacokinetics
1. Body weight - smaller size
•
concentration of drug based on body fluid
2. Sex differences
3. Age
Other factors that affect drug
pharmacokinetics
4. Interspecies differences
rabbits – belladonna (deadly nightshade)
5. Intraspieces differences
6. Disease states
7. Nutrition
8. Biorhythm
Blood level
Resultant
Elimination
Distribution
2
4
6 8 10 12
Time in hours
14
• half-life - time takes for the blood
concentration to fall to half its initial value
after a single dose
• ½ life tells us critical information about how
long the action of a drug will last
How long would it take for a drug
to reach 12.5% remaining in blood
if its ½ life is 2 hours?
How long would it take for a drug
to reach 12.5% remaining in blood
if its ½ life is 100 hours?