Pharmacology: pharmokinetics Flashcards
Neuro-psychopharmacology
the study of the actions of drugs on the CNS and their effects on human behavior
Drug actions
specific molecular changes resulting from drug binding to the target site receptor
Drug effects
widespread alterations in physiology or psychology resulting from drug action
Therapeutic effects
drug-target interactions producing the desired physiological or behavioral changes
Side effects
any effect that isn’t the therapeutic effect
Adverse effects
undesirable or harmful drug effects
Specific effects
biochemical interaction between the drug and the receptor
Non-specific effects
interactions that go beyond the interaction between the drug and the receptor
Placebo
Measurable therapeutic effect of a treatment without specific activity for the receptive condition
Pharmacokinetics
factors contributing to bioavailability and efficacy of drugs in the human body. Provides performance guidelines for efficacy, efficiency, and drug use in clinical settings
ADME
Absorption, distribution, metabolism, excretion
Absorption
movement of the drug from site of administration to the circulatory system
Distribution
dispersal of the drug through body fluids to the target tissues of the body
Depot binding
when the drug binds to non-target tissues
Metabolism
biotransformation or inactivation of drugs in the body into metabolites
Excretion
removal of substances or metabolites from the body
First pass effect
blood flow from the stomach/intestines goes directly to the liver for detox, drug gets metabolised into a usable form for the body
the more of a drug you take the more
adverse the effects become
Nonspecific effects may occur as a result of
unique characteristics of the individual or an individuals state
Placebo effect is affected by
expectancy and conditioning
Placebo is a
confound in neuropsychopharmacology
PO =
oral administration
IV =
intravenous
IM =
intramuscular
Inhalation
intake of drugs through the nose
Advantages and disadvantages of oral Administration
Advantages: self administered, economical
Disadvantages: slow, variable absorption, subject to first pass metabolism
Advantages and disadvantages of intravenous Administration
advantages: Rapid, accurate blood concentration
Disadvantage: overdose danger, cannot be readily reversed, sterility
Advantages and disadvantages of intramuscular Administration
Advantages: slow and even absorption
Disadvantages: irritation at injection site, sterility
Advantages and disadvantages of subcutaneous Administration
Advantages: slow and prolonged absorption
Disadvantages: variable absorption depending on blood flow
Advantages and disadvantages of inhilation Administration
Advantages: most rapid, large absorption surface
Disadvantages: irritation of nasal passages, could damage lungs
Advantages and disadvantages of topical Administration
Advantages: localized action and effects, easy to self-administer
Disadvantages: may be absorbed into general circulation
Advantages and disadvantages of transdermal Administration
Advantages: controlled and prolonged absorption
Disadvantages: local irritation, useful only for lipid soluble drugs
Advantages and disadvantages of epidural Administration
Advantages: bypass blood brain barrier, very rapid effects of the CNS
Disadvantages: not reversible, need a trained anesthesiologist, possible nerve damage
Oral rout has the greatest
breakdown of a drug
Absorption is affected by
drug concentration, breakdown by metabolic or digestive processes, solubility and ionizing of the drug
Absorption is dependent on
passive diffusion
Drug concentration is affected by
age, sex, body size, body fat content
Polar molecules
Water soluble
Hydrophilic - water loving
Lipophobic - fat hating
Non-polar molecules
Lipid-soluble Hydrophobic - fear water
Lipophilic - fat loving
polar molecules are transported through
aqueous compartments
Non-polar molecules freely diffuse across
semi-permeable membranes
aqueous compartments
blood, CSF, ECF
semi-permeable membranes
intestinal wall, BBB, cell membranes
Non-polar molecules tend to be
less soluble in water
Polar or charged (ionized) drugs are prevented from
diffusing through membranes
Many orally administered drugs are weak acids or bases
gaining or losing charges based on the pH of the external environment
How aspirin moved through the system
stomach - around the same acidity to freely moves across the cell membrane - becomes ionized in the blood and is readily soluble - in the intestines’ it alternates between ionized and non-ionized forms and diffuseness more slowly across the membranes
Surface area of body compartments
surface area affects drug absorption
Stomach has a relatively small surface area
slow absorption
Intestines have relatively large surface area
(fast absorption) and are the site of most (oral) drug absorption
Once in the bloodstream drugs circulate to the entire body within
minutes
Drug concentration is highest in tissues with
greatest blood flow
Drug concentration is highest in tissues with greatest blood flow
Heart, brain, kidneys, liver
Peripheral capillaries are highly
porous allowing ready distribution of drugs (lipophilic or hydrophilic) into tissues
Blood-brain barrier
permits passive diffusion of only lipophilic drugs
Three main compartments affect drug concentration in the brain
Blood plasma, Cerebral spinal fluid, extracellular fluid
Blood plasma
Permeates entire brain
Carries soluble drugs and nutrients (glucose, oxygen, amino acids)
Removes waste products and gases
Cerebral spinal fluid (CSF)
Fills subarachnoid space, ventricles, cisternae
Highly regulated concentration of solutes, glucose, very low protein
Isolated from systemic circulation
Extracellular fluid (ECF)
Interstitial space between cells in the brain
Similar composition to CSF but more varied between brain regions
Isolated from systemic circulation by the blood-brain barrier (BBB)
Astrocytes are to blame for
hydrophilic substances being unable to pass through the blood brain barrier
typical capillary
capillaries are porous, allowing hydrophilic drugs to freely enter tissues
Brain capillaries are
are coupled by tight junctions and lined by astrocyte endfeet creating a highly impermeable barrier
The BBB limits access to
98% of small molecule pharmaceuticals (and 100% of large molecule pharmaceuticals
Passage of solutes through the BBB often occurs at
specific transporters (e.g. glucose and amino acid transporters)
Some drugs are actively removed from the ECF by
efflux transporters (i.e. p-glycoprotein, a.k.a. multidrug resistance protein-1)
BBB is not a complete barrier
certain sites have direct access to the circulatory system
Chemoreceptor trigger zone
allows direct detection of toxins in the blood
where is the Chemoreceptor trigger zone located
the medulla (vomit center)`
Hypothalamus
allows direct access to capillaries for secretion of neurohormones and hormone-releasing factors
some drugs get into the brain Via the
passage way the hypothalamus uses
Drugs (licit and illicit), alcohol, gaseous anaesthetics, and gases (e.g. carbon monoxide) readily cross the placental barrier and can cause
acute toxicity or teratogenic effects to the fetus
the placenta is
Slightly more permeable than the BBB
drug depot sites
Adipose tissue (lipid-soluble drugs)
Muscle tissue
Albumin (plasma protein)
drug depot sites and circulation
Decreases circulating drug concentration
drug depot sites and Prolongs drug action
Can function as reservoirs for drug release
Protects stored drug from metabolism
depot binding and drug efficacy
Can explain individual differences in drug efficacy
rapid binding to depot before reaching target tissue = what therapeutic effect
slower onset and reduced effects
individual differences in the amount of binding = what therapeutic effect?
less free drug, so some need higher doses, low binding means more free drug so some individuals are more sensitive
competition among drugs for depot binding sites = what therapeutic effect
higher than expected blood levels of the displaced drug, possibly causing greater side effects even toxicity
bound drug is not metabolized = what therapeutic effect?
drug remains in the body for prolonged action
binding to depots follows the rapid action at targets (redistribution) = what therapeutic effect?
rapid termination of drug action
Metabolism occurs primarily in the
the liver under control of microsomal enzymes
cytochrome P450 family (CYP ~ 57 in total)
oxidize the majority of psychoactive drugs (incl. opioids, antidepressants, amphetamines, nicotine)
CYP1A2
metabolizes many antidepressants and antipsychotics – induced by smoking
CYP3A4
metabolizes many opioids, antidepressants, statins, anxiolytics – inhibited by grapefruit juice
Metabolism is a non-specific
detoxification process that occurs in two distinct types or phases
Metabolism is a non-specific detoxification process that occurs in two distinct types or phases (type 1)
non-synthetic modifications, oxidation, reduction, and hydrolysis
Metabolism is a non-specific detoxification process that occurs in two distinct types or phases (type 2)
synthetic modifications. conjugation with glucuronide, sulfate, or methyl groups
Type I metabolism during first pass can produce
active metabolites of the pharmaceutical preparation of drugs
Metabolic products (active and inactive) are returned to circulation from
the liver and can reach target sites of action or sites for excretion (kidneys, biliary, or fecal excretion)
4 factors that influence metabolism
Enzyme induction
Enzyme inhibition
Drug competition
Individual differences (age, sex, genetics)
Enzyme induction
repeated use results in increase in liver enzymes (contributes to tolerance and cross tolerance)
Enzyme inhibition
drugs targeting enzymes (e.g. monoamine oxidase inhibitors - MAOI) decrease their own clearance and other drugs
Drug competition
competition for enzymes may prevent some drugs being metabolized in a safe fashion
Individual differences
genetic polymorphisms have been identified in metabolic enzymes
different individuals have different rates of clearance for drugs
Routes of excretion include
breath, sweat, saliva, feces, breast milk, and urine
Primary means of excretion is
filtration by kidney and excretion through urine
Most drugs are excreted by
first-order kinetics
Exponential elimination
constant fraction removed in a given time
Half-life (t½)
describes the interval required to eliminate half of the drug from circulation
Very few drugs removed by
zero-order kinetics (constant rate)
- alcohol is
