Download pharmacokinetics

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Pharmacokinetics:
◦ How drugs are handled by the body
◦ Overview followed by details!!
Lets say you have a headache
or a really really really bad
reaction to poison ivy and you
take some meds –
This illustrates the basic
processes in the branch of
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)
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how the drug is eliminated
Knowing about pharmacokinetics tells us
critical information about insight into the
actions of a drug.
Ex. benzodiazepenes
ultra short acting, short acting, long acting
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lorazepam (Ativan) and triazolam (Halcion) –
pharmacokinetics
lorazepam – persists for at least 24 hr
triazolam – 6 – 8 hours
midazolam – 1 – 2 hrs
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Absorption – the process by which a drug
enters the bloodstream
chemically altered or
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without
being
The movement of a drug from its site of
application into the blood
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oral
injection
◦ iv, im, sc, intrathecal, intraperitoneal
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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
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soluble and stable in stomach (not destroyed
by stomach enzymes more acidic)
enter intestine; penetrate lining of intestine,
pass into bloodstream and reach site of
action
absorption favored if the drug is nonionized
and more lipophilic
◦ chemicals in stomach must deal with:
◦ stomach acids
◦ digestive enzymes
◦ first pass metabolism through liver
◦ other items in stomach
 ex. tetracycline
◦ 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
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disadvantages of oral administration:
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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
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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
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disadvantages of oral administration:
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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)
Hours
J.Clin. Invest. 99:10, p.2545-53, 1997
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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 -
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GI motility- speed of gastric emptying affects
rate of absorption
◦ ex. migraine and analgesics vs metoclopramide
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Malabsorptive States ◦ GI diseases, ex. Crohn’s disease can affect
absorption
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Food ◦ iron, milk alters tetracycline
◦ fats
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first pass metabolism
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chemicals delivered with a hypodermic
needle;
◦ most commonly - injected into vein, muscle or
under the upper layers of skin, in rodents also
intraperitoneal cavity
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requirements for parenteral:
 must be soluble in solution (so it can be injected)
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Intravenous
Intramuscular
Subcutaneous
Intracranial
Epidural
Intraperitoneal
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absorption more rapid than SC
◦ less chance of irritation;
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ways to speed up or slow down absorption
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depot injections -
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extremely rapid rate of absorption
adv: useful when you need rapid response or
for irritating substances
Disadv: rapid rate of absorption
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contingent on blood flow SO
◦ IV, intraperitoneal, IM, SC
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increasing or decreasing blood flow affects
drug absorption
Drugs leave bloodstream and are
exchanged between blood capillaries and
body tissues
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bolus or depot shots
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related - drugs that accumulate in fat
◦ ex. THC
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nasal, oral, buccal
medications include: nitroglycerine, fentanyl
–(1998) , nicotine gum, lozenges,
buprenorphine
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cocaine –
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snuff, cigars
◦ Advantages:
 rapid absorption
 avoid first-pass effect
◦ Disadvantages:
 inconvenient
 small doses
 unpleasant taste of some drugs
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1990’s – several medications incorporated
into transdermal patches:
◦ estrogen, nicotine, fentanyl, nitroglycerin,
scopolamine
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controlled slow release for extended periods
of time
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usually suppository form
for unconscious, vomiting or unable to
swallow
disadv: not very well regulated dose;
irritation (yikes)
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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)
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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
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Factors which influence the rate of
absorption
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routes of administration
dosage forms
the physicochemical properties of the drug
protein binding
circulation at the site of absorption
concentration of the drug
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drugs are distributed throughout body by blood
very little at site of action at any one time
role of passive diffusion, concentration gradient
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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
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Mostly a passive process ◦ from higher conc to lower (in blood)
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Binding to plasma proteins
◦ results in a store of bound drug in plasma
 examples  95-99% - chlorpromazine, diazepam, imipramine
 90 - 95% - valproate, propanolol, phenytoin
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Renal insufficiency
last trimester of pregnancy
drug interactions (other drugs that bind to
proteins)
diseases
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Blood brain barrier◦ layer of thickly packed epithelial cells and
astrocytes that restrict access of many toxins/drugs
to the brain
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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
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Lipid solubility
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Size of molecule
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Ionization – whether the degree has a charge
(+ or -)
pKa –
the pH at which ½ of the molecules are
ionized
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most drugs are either weakly basic or
weakly acidic
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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
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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: 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).
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
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role of liver
◦ most significant organ in biotransformation
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role of liver
◦ most significant organ in biotransformation
◦ largest organ in body
◦ serves many functions
 transforms molecules via enzymes
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
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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)
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CYP enzymes ◦ enzyme induction  liver produces extra enzyme to break down drug
with continued exposure
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CYP enzymes ◦ enzyme induction  liver produces extra enzyme to break down drug
with continued exposure
Genetics
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CYP enzymes -
◦ enzyme induction  liver produces extra enzyme to break
down drug with continued exposure
 Genetics
 Liver
disease
cirrhotic liver
In some cases, biotransformation can be to
another psychoactive compound
ex. benzodiazepenes
diazepam
nordiazepam
oxazepam
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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…….
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numerous functions –
◦ filters out metabolic products
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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
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dialysis –
absorption distribution and excretion do
not occur independently
first pass metabolism
blood
brain
1.
Body weight - smaller size
•
concentration of drug based on body fluid
2.
Sex differences
3.
Age
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
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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?