Chapter 1, The Science of Drug Action Flashcards
Pharmacology
The scientific study of the actions of dugs and their effects in a living organism.
Neuropharmacology
Concerned with drug-induced changes in the functioning of cells in the nervous system.
Psychopharmacology
Emphasizes drug-induced changes in mood, thinking, and behaviour.
Neuropsychopharmacology
Has a goal to identify chemical substances that act on the nervous system to alter behaviour that is disturbed because of injury, disease, or environmental factors.
Drug action
The specific molecular changes produced by a drug when it binds to a particular target site or receptor. These molecular changes lead to more widespread alterations in physiological or psychological functions.
Therapeutic effects
The drug-receptor interaction produces desired physical or behavioural changes.
Side effects
All other effects that are produced along side the therapeutic effects. (These can very from mildly annoying to dangerous.)
Specific drug effects
Effects that are based on the physical and biochemical interactions of a drug with a target site in living tissue.
Non-specific drug effects
Effects that are based not on the chemical activity of a drug-receptor interaction, but on certain unique characteristics of the individual.
Psychoactive drug
A chemical substance that acts primarily on the central nervous system where it alters brain function, resulting in temporary changes in perception, mood, consciousness and behaviour.
Principles of psychoactive drugs:
- Drugs are not good or bad.
- Every drug has multiple effects.
- Both the size and quality of a drug’s effects depend on the amount an
individual has taken. - The effect of any psychoactive drug depends on the individual’s history
and expectations.
Pharmacokinetics
Study of drug molecules into, through,
and out of the body.
Pharmacodynamics
Study of interactions of a drug with the structure with which it interacts to produce its effects.
Placebo
Nocebo effect
inert substance causes perceived harm.
Bioavailability
(The amount of drug
in the blood that is free to bind at target sites)
Pharmacokinetic factors will depend on…
- The frequency and/or history of prior drug use.
- Nonspecific factors characteristic of individuals (e.g., genetic differences, size and sex of the individual) and their environment (e.g., at an office party vs. a bar).
Pharmacokinetic Factors
- Drug administration.
- Absorption and distribution.
- Binding (Target site: neuron receptor, and Inactive storage depots: bone and fat.)
- Inactivation.
- Excretion.
Drug Administration
How and where a drug is administered determines how quickly and how completely the drug is absorbed into the blood.
Absorption and Distribution
Because a drug rarely acts where it initially contacts the body, it must pass through a variety of cell membranes and enter the blood plasma, which transports the drug to virtually all of the cells in the body.
Binding
Once in the blood plasma, some drug molecules move to tissues to bind to active target sites (receptors). While in the blood, a drug may also bind (depot binding) to plasma proteins or may be stored temporarily in bone or fat, where it is inactive.
Drug Inactivation (biotransformation)
It occurs primarily as a result of metabolic processes in the liver as well as other organs and tissues. The amount of drug in the body at any one time is dependent on the dynamic balance between absorption and inactivation. Therefore, inactivation influences both the intensity and the duration of drug effects.
Excretion
The drug metabolites are eliminated from the body with the urine or feces. Some drugs are excreted in an unaltered form by the kidneys.
Routes of Administration
Fastest –> Slowest
* Inhalation
* IV injection
* Mucous membrane
* SC injection
* IM injection
* Transdermal
* Oral (liquid)
* Oral (tablet)
Systematic Routes of Administration
- Enteral methods
- Parenteral methods
Enteral methods
- Administration involving the gastrointestinal (GI) tract
- Typically slow
- Subject to first-pass metabolism
- Oral (PO), rectal administration
Parenteral methods
- Administration that does not involve the GI tract
- Injection, inhalation, insufflation, sublingual, topical / transdermal administration
First Pass Metabolism
- Before blood goes to the rest of the body from the GI tract, it passes through the liver
- The liver is the major organ that breaks down drugs
- Certain amount of the drug will be inactivated or metabolized as it goes through the liver
- Evolutionary beneficial because it chemically alters harmful chemicals and toxins in the liver before it passes through the heart
- Therapeutic drugs that are administered orally are reduced in bioavailability due to undergoing extensive metabolism
- Variability in first-pass metabolism due to personal characteristics, such as genetics
Rectal Administration
ADVANTAGES
* May be used if the patient is
vomiting, unconscious, or
unable to swallow
DISADVANTAGES
* Irregular, unpredictable, and
incomplete absorption
* Can irritate the membranes
that line the rectum
Oral Administration
- Taken by mouth
- Drugs must be:
- Soluble
- Stable in stomach fluid ( A prodrug is a precursor of a drug that must undergo chemical conversion by metabolic processes before becoming an active
pharmacological agent)
-Lipid soluble ( Cytochrome P-450 enzymes (CYPs), especially CYP3A4 are important in the biosynthesis and degradation of drugs; Grapefruit juice is contraindicated in patients receiving drugs that are extensively metabolized by CYP3A, especially if the drug has a small therapeutic window)
ADVANTAGES
- Clean and easy
- No discomfort
DISADVANTAGES - Vomiting and stomach distress
- Genetic variability in amt of drug absorption
- Less precise dosing
- Complete destruction of some
drugs (e.g., insulin)
Intravenous (IV) Administration
- Drugs are injected into a vein ADVANTAGES
- Fast absorption
- More accurate dosing (can be done slowly and stopped immediately)
DISADVANTAGES - Overdose danger; cannot be readily reversed
- Requires sterile techniques; expert administration
- Not suitable for insoluble substances
Intramuscular (IM) Administration
- Drug injected into skeletal muscle, usually the arm, thigh or buttock* Generally absorbed fairly
rapidly but… - Rate of absorption depends on
- Blood flow to muscle
- Solubility of drug
- Volume of injection
- Solution drug is dissolved in
ADVANTAGES - Slow and even absorption DISADVANTAGES
- Needs sterile equipment
- Localized irritation of the site
Subcutaneous (SC) Administration
- Injection of medications beneath the skin
ADVANTAGES - Slow and prolonged absorption
DISADVANTAGES - Variable absorption
- Possible irritation of the site
Inhalation Administration
- Drugs are absorbed into the blood by
passing through the lungs
ADVANTAGES - Very rapid onset of action
(within seconds) - Large absorption surface
DISADVANTAGES - Irritation of lungs and nasal passages (e.g., small particles may damage lungs)
Membranous Administration
- Drugs are absorbed through the mucous membranes of the nose or
mouth - Insufflation or intranasal administration (e.g., cocaine powder)
- Transmucosal (e.g., chewing tobacco)
- Sublingual (e.g., LSD)
ADVANTAGES - Ease of use
DISADVANTAGES - Possible irritation of the mucosa
Transdermal Administration
- Absorption through the skin
Examples: - Nicotine: to deter smoking
- Fentanyl: to treat chronic pain
- Estrogen: used for contraception
ADVANTAGES - Slow and controlled absorption over hours/days; minimizes drugs side effects
DISADVANTAGES - Local irritation
- Only for lipid-soluble drugs
Drug Absorption & Distribution
- Once drugs are absorbed into the blood, they are quickly
distributed through the bloodstream - It is quickly delivered to areas with high blood flow
- In an average-sized adult, the entire blood volume circulates in the body
once every minute - Drug redistribution can terminate drug action
Different membrane types affect the distribution of drugs
1. Cell membranes
2. Capillary walls
3. Blood-brain barrier
4. Placental barrier
Bioavailability and Diffusion
- Bioavailability: how much of
the drug that is administered will
actually, reach the target in the
brain - A drug that can pass through
membranes easily will diffuse
faster than one that cannot - Small vs. large
- Nonionized vs. ionized
- Lipophilic vs. hydrophilic
Passage through Cell Membranes
- The most important factor in determining plasma drug levels is
the rate of passage through cell membranes - Recall: the cell membrane is a phospholipid bilayer, with a negatively
charged region (hydrophilic), and two uncharged tails (hydrophobic) - Lipid-soluble drugs can pass through cell membranes through
passive diffusion - Movement from high concentration à low concentration
Passage Through Capillaries
- Capillaries are small, cylindrical blood vessels formed by a single-cell layer
- Contain small pores (clefts or fenestra) that allow passage of small molecules
- Drugs move down their
concentration gradient
Passage Through the BBB
- The brain is protected from toxins by the blood-brain barrier
- The brain is protected from toxins by the blood-brain barrier
- Brain capillaries have distinct morphology, minimizing movement of water-soluble molecules (but not impeding lipid-soluble molecules)
Passage Through the Placenta
- Special consideration must be given to pregnant women
- The fetus is exposed to essentially all drugs taken by the mother
- The slow, under-developed metabolism of the fetus makes drug exposure more dangerous
- Special consideration must be given to pregnant women
- Example: Fetal Alcohol Syndrome (FAS). Exposure to alcohol during the first trimester (when facial
features are still developing) is
the most dangerous (though use
at any point increases the risk of
FAS) - Example 2: Opiates such as heroin easily enter fetal circulation; newborns of heroin- or methadone-addicted mothers experience opiate withdrawal upon birth and must have special treatment
Drug Distribution: Depot Binding (Silent receptors)
- Binding at inactive sites where no biological effect is initiated; affects the magnitude and duration of drug action
- Depot binding is nonselective; similar drugs can compete for binding sites
- This can result in higher-than-expected blood levels of a
displaced drug and overdose
Drug Inactivation
- Drugs are eliminated via biotransformation (metabolism) and metabolites are excreted
- Two phases of biotransformation:
- Phase I: oxidation, reduction, or hydrolysis
- Phase II: synthetic reactions- products are ionized, water-soluble, and biologically inactive
- Most drug metabolism happens in the liver
- Biotransformation ultimately produces water-soluble, inactive
metabolites that are excreted via kidneys or bile* Drug clearance from the blood is usually exponential (first-order kinetics) - When blood levels are high, clearance is faster. As blood levels drop, the rate of clearance is reduced
- Half-life: the amount of time required for the removal of 50% of the drug (t½)
- When psychoactive drugs are used therapeutically, the goal is to maintain the concentration of a drug in the blood plasma at a constant level
- Steady-state plasma level (target therapeutic concentration) is only achieved after multiple doses
- The bottom curve illustrates elimination if only a single dose is given
- Some drugs are eliminated according to zero-order kinetics: molecules are cleared at a constant rate regardless of concentration
Metabolites
Drugs that are converted to active metabolites have a
prolonged duration of action
Factors influencing drug metabolism:
- Drug-taking history (i.e., changes to enzyme availability due to repeated drug use)
- Drug competition
- Individual differences in age, gender, and genetics
- Some drugs are inactive until they are metabolized
- Example: codeine is metabolized in the body to the active drug morphine,
making codeine a prodrug
Drug Excretion
- Major route of drug elimination à Renal (urinary) excretion of drug metabolites produced by biodegradation of drugs in liver
Therapeutic Drug Monitoring
- Take repeated blood samples and run a statistical correlation between drug plasma concentration and the degree of therapeutic effect to determine a therapeutic window
Goals of Therapeutic Drug Monitoring
- Assess whether the patient is taking medication as prescribed
- Avoid toxicity
- Enhance therapeutic effectiveness by focusing on the amount of drug measured in plasma (as opposed to the amount of drug
administered) - To reduce unnecessary costs of drug therapy
- Especially important for drugs that have a narrow therapeutic
index
“Fentanyl is 100x more potent than heroin”
“The difference in strength
between heroin and fentanyl
arises from differences in
their chemical structures. The
chemicals in both bind to the
mu opioid receptor in the
brain. But fentanyl gets there
faster than morphine …”
Spinal Injections
- Drug injected into the CSF, bypassing the blood brain barrier
- Epidural Injections: Drugs are injected into the space between the bony vertebrae and the outermost meninge layer, the dura mater. Used in childbirth
- Intrathecal Injections: Drugs are injected into the subarachnoid space between the two innermost meninge layers, the arachnoid mater and the pia mater.
