Download Pharmacokinetics-Pharmacodynamics

Psychopharmacology
Pharmacokinetics and
Pharmacodynamics
Pharmacokinetics
• The time course of a particular drug’s action.
• Along with knowledge of the dosage taken,
allows determination of:
– concentration of a drug at its receptors.
– intensity of drug effect on the receptors over
time.
Pharmacokinetics
Four Processes: ADME
1. Absorption: movement of drug from site of
administration to the blood
2. Distribution: movement of drug from blood to
rest of body
3. Metabolism: breakdown of drug
4. Elimination of drug’s metabolic waste products
from the body
Absorption
Major routes of administration:
1.
2.
3.
4.
5.
6.
Oral administration
Rectal administration
Inhalation
Absorption through mucous membranes
Absorption through the skin
Injection
Oral Administration
• Drug must be soluble and stable in stomach
fluid.
• Absorbed through upper intestine through
passive diffusion.
• Drugs must generally be somewhat lipid soluble.
• Disadvantages:
– Vomiting and stomach distress
– Hard to know how much of drug will be absorbed
due to genetic differences.
– Stomach acid destroys some drugs.
Rectal Administration
• Used if patient is vomiting, unconscious, or
unable to swallow.
• Absorption is often irregular, unpredictable,
and incomplete.
Inhalation
• Popular for recreational drugs (e.g., tobacco,
marijuana, cocaine, heroin).
• Lung tissues’ large surface area allows for rapid
absorption into blood.
• Pulmonary capillaries carry drug directly into
left side of heart and then directly into the aorta
and arteries going to the brain.
• Even faster onset than injection.
Mucus!
• Absorbed through membranes in mouth or
nose.
• Examples: heart patient’s nitroglycerine, cocaine,
nasal decongestants, nicotine gum.
Pharmacokinetics
5. Administration Through the Skin
– Transdermal patches provide continuous,
controlled release.
– Allow for slow, continuous absorption over
hours or days, minimizing side effects.
– Examples: nicotine, fentanyl (for chronic pain),
nitroglycerine (for angina pectoris), estrogen
(hormone replacement therapy).
Injection
• Intravenous Administration
– Drug introduced directly into bloodstream.
– Dosage can be extremely precise.
– Fastest onset of pharmacological action (most
dangerous route).
• Intramuscular Administration
• Drugs injected into skeletal muscle.
• More rapid than absorption from stomach, but slower
than intravenous.
• Type 1: Rapid onset/short duration of action
- Drug dissolved into aqueous solution.
• Type 2: Slow onset/prolonged duration
- Drug suspended in oily solution.
• Subcutaneous Administration
• Injected under the skin.
Distribution
Drug molecules may be found in different
places in the blood.
1. Plasma–more likely with water soluble drugs
2. Platelets–more likely with lipid soluble drugs
3. Attached to proteins (e.g., albumin)–bound vs. free
Taking the First Pass
• Before the blood goes to the rest of the
body from the gastrointestinal (GI) tract,
it passes through the liver.
• The liver is the major organ that breaks
down drugs.
• Therefore, a certain amount of the drug
will be inactivated or metabolized as it goes
through the liver.
• Other routes may not be subject to this
“first pass” effect.
The BBB
• The brain must protect neurons from toxins.
• But the brain has a great need for nutrients
and oxygen (it has a high blood flow), which
increases the risk of toxic danger.
• Solution = the blood-brain barrier (BBB)
• Capillaries in brain do not allow drugs to pass
as easily as capillaries in rest of body.
Metabolism
• Definition: Chemical changes that usually reduce
the effect of drugs and increase their excretion.
• Kidneys filter waste from blood, collect it in
bladder.
• Lipid-soluble drugs are hard for kidneys to hold
onto; after collection, the molecules cross back
into the circulation before they are excreted.
The Liver
• The liver protects the body from toxic
substances.
– Contains enzyme systems that can detoxify
harmful substances.
– Changes from highly lipid-soluble to less lipidsoluble.
– More likely to ionize.
– May produce another lipid-soluble molecule, an
“active metabolite”
Pharmacokinetics
Enzyme Induction
• Past experience with drugs will affect the
enzyme systems.
• Levels of enzymes can be increased by
previous exposure to a specific drug.
• Called enzyme induction.
St. John and Your Liver
Examples and Consequences:
St. John's Wort: (with active ingredient hyperforin)
stimulates a receptor (SXR in humans, PXR in
nonhumans) in the liver to induce CYP3A, which
breaks down many other drugs: Theophylline (asthma),
warfarin (anticlotting), birth control pills, and
immunosuppressant cyclosporin.
Enzyme Inhibition
• Some drugs inhibit CYP enzymes and
increase their own levels, as well as levels
of any other drug metabolized by that
enzyme. Can produce toxicities.
• Example: Inhibition of antipsychotic
medication by SSRIs.
Intact Excretion
• Lithium
• Mushroom amanita muscaria
– In large doses it is toxic and lethal; small amounts
are hallucinogenic.
– Hallucinogenic ingredients are not greatly
metabolized and are passed to the urine. Siberian
tribespeople discovered this and recycled the drug
by drinking their urine.
Excretion
• Primarily accomplished by kidneys.
2 organs (about the size of a fist) located on
either side of the spine in the back.
Keep the right balance of water and salt in
the body
Filter everything out of blood and then
selectively reabsorb what is required.
pH of urine can be manipulated to alter
excretion of drugs.
Can be useful for eliminating certain drugs
in overdose.
Half-Life (T-1/2)
The rate of excretion for most drugs can
be described in terms of a half-life: time
taken for the body to eliminate half of a
given blood level of a drug.
The Therapeutic Window
• For medical treatment, it is important that the right
amount of drug is maintained in the blood.
– If the amount is too high, the therapeutic effect will not be
any better, but there will be more undesirable side effects.
– If the amount is too low, it won’t have any beneficial effect.
• Drugs should be given in such a way that the blood
concentration stays between a level that is too high and
too low. This is called the Therapeutic Window.
Pharmacodynamics
• In contrast to pharmacokinetics (the study of
what the body does to drugs), pharmacodynamics
is the study of what a drug does to the body.
Under Lock and Key
Receptors for Drug Action
1. Receptors are usually membranespanning proteins.
2. Not a simple globule, but a
continuous series of amino acid
loops embedded in the
membrane.
3. Drugs and neurotransmitters
attach inside between coils; held
in place by ionic attractions.
Classic concept of a receptor
Binding
4. Reversible ionic binding activates
the receptor by altering the
structure of
the protein.
5. Intensity of signal partly
determined by percentage
of receptors active.
6. Drugs can affect signal by
binding either to receptor
7. site or to nearby site.
Schematic of 5-HT1A receptor
Pharmacodynamics
Receptors for Drug Action
Binding results in 1 of 3 actions:
1. Binding to site of normal endogenous
neurotransmitter initiates similar cellular response
(agonistic action).
2. Binding to nearby site to facilitate transmitter binding
(allosteric agonistic action).
3. Binding to receptor site, blocking access of
transmitter to binding site (antagonistic action).
Agonism and Antagonism
Receptor Structure
• Ion Channel Receptors: Activation opens channel,
allowing flow of ions to trigger or inhibit neural
firing.
– Benzodiazepines are GABA receptor allosteric agonists.
• Bind to nearby sites and facilitate GABA, flooding neurons with
Cl-, inhibiting neural actions.
• Used as sedative, antianxiety, amnestic, antiepileptic.
– Flumazenil binds to benzodiazepine site but does not
interfere with GABA.
• Technically a benzodiazepine antagonist, used to treat
benzodiazepine overdose.
G Protiens
• G Protein-Coupled Receptors: Induce release of
intracellular protein, trigger second messengers.
– Also called metabotropic receptors.
– Control many cellular processes (e.g., ion channel
function, energy metabolism, cell
division/differentiation, neuron excitability).
Acting Indirectly
• Carrier Proteins: Bind to neurotransmitters to
transport them back to presynaptic neuron.
– Many drugs block carrier proteins for a specific
neurotransmitter (e.g., SSRIs).
• Enzymes: Function to break down neurotransmitters
in synaptic cleft.
– Inhibition by drugs increases transmitter availability.
– Irreversible acetylcholine esterase inhibitors are used as pesticides
and nerve gases.
– Monoamine oxidase inhibitors inhibit breakdown of NE and
DA (used as antidepressants).
Dose Response
Potency
• Potency = how well drug molecules attach to their
sites of action (receptors).
– More potent drugs usually attach better than less potent
drugs (binding); bind more tightly than less potent
drugs.
– Binding = affinity. A more potent drug has
greater affinity for its receptor (binds more tightly).
• A less potent drug has less affinity for its receptor; does not
bind so tightly, can be more easily knocked off the receptor.
– Different drugs may bind to the same receptor, but with
different affinities.
A Slippery Slope
• Refers to the mostly linear central part of the
curve; how sharply the effect changes with
each change in dose.
• If a small change in dose produces a large
change in effect, the slope is steep.
• If even large changes in dose produce
small changes in effect, the slope is
shallow.
Efficacy
• The maximum effect obtainable, with
additional doses producing no effect.
– Some drugs may be potent, but they might never
be able to produce a peak response no matter
how much is given.
– A drug that is more efficacious (effective) can
produce a greater peak, or maximum, effect than a
drug that is less efficacious.
Efficacy, Potency, and
Slope Illustrated
Heroin and morphine have equal efficacies, with heroin more potent.
Aspirin has lower potency, efficacy, and slope than both heroin and morphine.
The Therapeutic Index
• ED50
– The drug dose that produces desired effect in 50
percent of test subjects.
• LD50
– The lethal dose for 50 percent of test subjects.
– Tested using experimental animals.
• Therapeutic Index = ratio of LD50 to ED50
I Shall Please
• Many studies today use double-blind, randomized,
controlled clinical trials.
– However, even these trials can misrepresent the placebo effect.
– Notably, the placebo effect in antidepressant studies has risen
dramatically between 1980 and 2000.
• Double-blind tests with a placebo run-in period may
eliminate much of the placebo effect.
– In these tests, every patient is administered a placebo for a
week. Patients who respond positively are removed from study.