Pharmacokinetics Flashcards
What is neuropsychopharmacology?
The study of the actions of drugs on the central nervous system and their subsequent effects on human behaviour
What are drug actions?
Specific molecular changes resulting from drug binding to a target site or receptor
What are drug effects?
Widespread alterations
in physiology or psychology resulting from drug actions
What are therapeutic effects?
drug-target interactions producing the desired physiological or behavioural changes
What are side effects?
all other drug effects
What are adverse effects?
undesirable or harmful drug effects
What is Diphenhydramine’s trade name?
Benadryl
What is Benadryl’s abbreviated chemical name?
Diphenhydramine
What does Benadryl do?
Antihistamine and decongestant
What are benadryl’s therapeutic effects?
drying
mucous membranes
What are benadryl’s side effects?
drowsiness
What is another use for benadryl?
mild sedative for insomnia
As a treatment for insomnia, what is Benadryl’s therapeutic effect?
Drowsiness
As a treatment for insomnia, what is Benadryl’s side effect?
Drying of mucous membranes
What are specific effects?
Occur as a result of biochemical interactions between drug and target receptor
What are nonspecific effects?
Occur as a result of interactions beyond the receptor (e.g. lipid membranes, fluid compartments)
- May occur as a result of unique characteristics of an individual or an individual’s state
Describe the placebo effect
- Measurable therapeutic effect of a treatment without specific activity for the respective condition
- Affected by expectancy and conditioning
- Particular confound in neuropsychopharmacology
Describe the confound in neuropsychopharmacology
- Antidepressants have efficacy of ~ 50-70% in major depression
- Placebo is effective in 20-30% of cases
- During development fluoxetine (Prozac) had to endure 5 clinical trials to achieve 2 showing significantly better response than
placebo
Describe the Levine experiment
- Classic experiment (Levine 1973) on ulcer patients given placebo
- Group A given placebo by physician who assured the medication would give relief (efficacy of 70%)
- Group B given placebo by nurse who described it as experimental in nature (efficacy of 25%)
What is pharmacokinetics?
The dynamic factors contributing to the bioavailability and efficacy of drugs in the human body.
Provides performance guidelines for efficacy and efficiency of drug use in clinical settings.
What is absorption?
Administration and absorption of the drug into body fluids
What is distribution?
- Dispersal of drug through body fluids to the target tissues of the body
- Depot binding in bodily fluids and non-target tissues
What is metabolism?
- Biotransformation or inactivation of drugs in the body into metabolites
What is excretion?
Removal of substances or metabolites from the body
Name all the routes of administration
- Oral administration (PO)
- Intravenous (IV)
- Intramuscular (IM)
- Subcutaneous (SC)
- Inhalation
- Topical (mucous membranes of nasopharynx, conjunctiva, colon, vagina, urethra)
- Sublingual (below the tongue)
- Transdermal (e.g. nicotine patch) * Epidural
- Intraperitoneal (IP)*
- Intracranial*
- Intracerebroventricular*
- Intracisternal*
What are the advantages and disadvantages of oral administration?
A: Safe, self-administered, economical, no needle related comps.
D: Slow and highly variable absorption, subject to first pass metabolism, less predictable blood levels
What are the advantages and disadvantages of IV administration?
A: Most rapid, most accurate blood concentration
D: Overdose danger, can’t readily be reversed, requires sterile needles and medical technique
What are the advantages and disadvantages of IM administration?
A: Slow and even absorption
D: Localized irritation at site of injection; needs sterile equipment
What are the advantages and disadvantages of subcutaneous administration?
A: Slow and prolonged absorption
D: Variable absorption depending on blood flow
What are the advantages and disadvantages of inhalation administration?
A: Large absorption surface, very rapid onset, no injection equipment needed
D: Irritation of nasal passages, small particles inhaled may damage lungs
What are the advantages and disadvantages of topical administration?
A: Localized action and effects, easy to self-administer
D: May be absorbed into general circulation
What are the advantages and disadvantages of transdermal administration?
A: Controlled and prolonged absorption
D: Local irritation, useful only for lipid soluble drugs
What are the advantages and disadvantages of epidural administration?
A: Bypasses BBB, very rapid effect on CNS
D: Not reversible, needs trained anesthesiologist, possible nerve damage
Describe first pass metabolism
Drug from intestines is taken by bloodstream to the liver via portal vein and its broken down
Describe oral administration
- Most convenient
- Safe self administration
- First-pass effect
- Blood flow from stomach/intestines goes directly to the liver for detox
- Oral route has greatest breakdown of drug
- Blood-brain barrier (BBB) affects usefulness for neuropharmacology
Describe delivery to CSF
- Epidural, intracranial, intracerebroventricular, or intracisternal most direct way to access the CNS
- Bypasses liver and BBB
- Highly invasive
- Effectively for experimental use only
- Slow steady release possible with implantable shunts or osmotic minipump
Describe absorption
- Movement of drug from the site of administration to the circulatory
system - Affected by:
- Drug concentration
- affected by age, sex, body size, body fat content*
- Breakdown by metabolic or digestive processes * Solubility and ionization of drug
- Largely dependent on passive diffusion through biological membranes
What does polar mean?
- Water soluble
- Hydrophilic (loves water)
- Lipophobic (fears fat)
- Polar molecules are freely transported through aqueous compartments (e.g. blood, CSF, ECF)
What does non-polar mean?
- Lipid soluble
- Hydrophobic (fears water)
- Lipophilic (loves fat)
- Non-polar molecules freely diffuse across semi-permeable membranes (e.g. intestinal wall, BBB, cell membranes)
Describe how absorption is dependent on drug polarity
- Non-polar, lipid soluble drugs can freely diffuse across cell membranes
- Passive diffusion down concentration gradients
- 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
Describe how aspirin is an example of this
Aspirin (acetylsalicylic acid) has a pKa* of ~3.5
In the stomach (pH 2) aspirin is uncharged and can readily diffuse across cell membranes, but is less soluble
In the blood aspirin becomes ionized and is readily soluble
In the intestines (pH 5.5) alternates between ionized and non-ionized forms and diffuses more slowly across membranes
What other factors affect absorption?
- Intrinsic properties of the drug
- Polarity
- Solubility
- pKa
- pH of body compartments
- Surface area of body compartments
- 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
Describe drug distribution
- Once in the bloodstream drugs circulate to the entire body within
minutes - 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
Describe peripheral capillaries
Peripheral capillaries are porous, allowing hydrophilic drugs to freely enter tissues
Describe brain capillaries
Brain capillaries are coupled by tight junctions and lined by astrocyte endfeet creating a highly impermeable barrier
Describe crossing the BBB
- 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)
Describe permeable sites
- BBB is not a complete barrier – certain sites have direct access to the circulatory system
- Chemoreceptor trigger zone (CTZ)
of the medulla (area postrema - vomit centre) - allows direct detection of toxins in the blood
- Hypothalamus
- allows direct access to capillaries for secretion of neurohormones and hormone-releasing factors
Describe the placental barrier
- The placenta creates a similar selective barrier (unique to pregnant mammals)
- 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
Describe depot binding
- Drug depots are inactive drug binding sites with no measurable biological effect
- Adipose tissue (lipid-soluble drugs)
- Muscle tissue
- Albumin (plasma protein)
- Decreases circulating drug concentration
- Prolongs drug action
- Can function as reservoirs for drug release
- Protects stored drug from metabolism
- Can explain individual differences in drug efficacy
Describe drug metabolism
- Biotransformation and elimination affects bioavailability
- Metabolism occurs primarily in 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
- Type I – non-synthetic modifications
- oxidation, reduction, and hydrolysis
- Type II – synthetic modifications
- conjugation with glucuronide, sulfate, or methyl groups
Describe biotransformation
- 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)
Describe how zocor is an example of this
SIMVASTATIN (ZOCOR)
- prepared in lactone form
- - hydrophobic
Simvastatin is hydrolyzed in the liver to the bioactive acid form
What factors influence metabolism?
Enzyme induction
repeated use results in increase in liver enzymes
accelerates rate of biotransformation of all drugs metabolised by a given enzyme (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 (age, sex, genetics)
genetic polymorphisms have been identified in metabolic enzymes different individuals have different rates of clearance for drugs
Describe excretion
- Routes of excretion include breath, sweat, saliva, feces, breast milk, and
urine - Primary means 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 (t1⁄2) describes the interval required to eliminate half of the drug from circulation
- Very few drugs removed by zero-order kinetics (constant rate)
- Alcohol excreted at ~ 10-15 ml/hr
What is first order elimination kinetics?
Exponential elimination
