Chapter 1, The Science of Drug Action

Question 1

Pharmacology

Answer 1

The scientific study of the actions of dugs and their effects in a living organism.

Question 2

Neuropharmacology

Answer 2

Concerned with drug-induced changes in the functioning of cells in the nervous system.

Question 3

Psychopharmacology

Answer 3

Emphasizes drug-induced changes in mood, thinking, and behaviour.

Question 4

Neuropsychopharmacology

Answer 4

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.

Question 5

Drug action

Answer 5

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.

Question 6

Therapeutic effects

Answer 6

The drug-receptor interaction produces desired physical or behavioural changes.

Question 7

Side effects

Answer 7

All other effects that are produced along side the therapeutic effects. (These can very from mildly annoying to dangerous.)

Question 8

Specific drug effects

Answer 8

Effects that are based on the physical and biochemical interactions of a drug with a target site in living tissue.

Question 9

Non-specific drug effects

Answer 9

Effects that are based not on the chemical activity of a drug-receptor interaction, but on certain unique characteristics of the individual.

Question 10

Psychoactive drug

Answer 10

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.

Question 11

Principles of psychoactive drugs:

Answer 11

1. Drugs are not good or bad.
2. Every drug has multiple effects.
3. Both the size and quality of a drug’s effects depend on the amount an
   individual has taken.
4. The effect of any psychoactive drug depends on the individual’s history
   and expectations.

Question 12

Pharmacokinetics

Answer 12

Study of drug molecules into, through,
and out of the body.

Question 13

Pharmacodynamics

Answer 13

Study of interactions of a drug with the structure with which it interacts to produce its effects.

Question 14

Placebo

Question 15

Nocebo effect

Answer 15

inert substance causes perceived harm.

Question 16

Bioavailability

Answer 16

(The amount of drug
in the blood that is free to bind at target sites)

Question 17

Pharmacokinetic factors will depend on…

Answer 17

• 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).

Question 18

Pharmacokinetic Factors

Answer 18

1. Drug administration.
2. Absorption and distribution.
3. Binding (Target site: neuron receptor, and Inactive storage depots: bone and fat.)
4. Inactivation.
5. Excretion.

Question 19

Drug Administration

Answer 19

How and where a drug is administered determines how quickly and how completely the drug is absorbed into the blood.

Question 20

Absorption and Distribution

Answer 20

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.

Question 21

Binding

Answer 21

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.

Question 22

Drug Inactivation (biotransformation)

Answer 22

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.

Question 23

Excretion

Answer 23

The drug metabolites are eliminated from the body with the urine or feces. Some drugs are excreted in an unaltered form by the kidneys.

Question 24

Routes of Administration

Answer 24

Fastest –> Slowest
* Inhalation
* IV injection
* Mucous membrane
* SC injection
* IM injection
* Transdermal
* Oral (liquid)
* Oral (tablet)

Question 25

Systematic Routes of Administration

Answer 25

- Enteral methods - Parenteral methods

Question 26

Enteral methods

Answer 26

* Administration involving the gastrointestinal (GI) tract * Typically slow * Subject to first-pass metabolism * Oral (PO), rectal administration

Question 27

Parenteral methods

Answer 27

* Administration that does not involve the GI tract * Injection, inhalation, insufflation, sublingual, topical / transdermal administration

Question 28

First Pass Metabolism

Answer 28

* 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

Question 29

Rectal Administration

Answer 29

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

Question 30

Oral Administration

Answer 30

* 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)

Question 31

Intravenous (IV) Administration

Answer 31

* 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

Question 32

Intramuscular (IM) Administration

Answer 32

* 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

Question 33

Subcutaneous (SC) Administration

Answer 33

* Injection of medications beneath the skin ADVANTAGES * Slow and prolonged absorption DISADVANTAGES * Variable absorption * Possible irritation of the site

Question 34

Inhalation Administration

Answer 34

* 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)

Question 35

Membranous Administration

Answer 35

* 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

Question 36

Transdermal Administration

Answer 36

* 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

Question 37

Drug Absorption & Distribution

Answer 37

* 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

Question 38

Bioavailability and Diffusion

Answer 38

* 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

Question 39

Passage through Cell Membranes

Answer 39

* 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

Question 40

Passage Through Capillaries

Answer 40

* 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

Question 41

Passage Through the BBB

Answer 41

* 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)

Question 42

Passage Through the Placenta

Answer 42

* 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

Question 43

Drug Distribution: Depot Binding (Silent receptors)

Answer 43

* 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

Question 44

Drug Inactivation

Answer 44

* 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

Question 45

Metabolites

Answer 45

Drugs that are converted to active metabolites have a prolonged duration of action

Question 46

Factors influencing drug metabolism:

Answer 46

* 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

Question 47

Drug Excretion

Answer 47

* Major route of drug elimination à Renal (urinary) excretion of drug metabolites produced by biodegradation of drugs in liver

Question 48

Therapeutic Drug Monitoring

Answer 48

* Take repeated blood samples and run a statistical correlation between drug plasma concentration and the degree of therapeutic effect to determine a therapeutic window

Question 49

Goals of Therapeutic Drug Monitoring

Answer 49

1. Assess whether the patient is taking medication as prescribed 2. Avoid toxicity 3. Enhance therapeutic effectiveness by focusing on the amount of drug measured in plasma (as opposed to the amount of drug administered) 4. To reduce unnecessary costs of drug therapy * Especially important for drugs that have a narrow therapeutic index

Question 50

“Fentanyl is 100x more potent than heroin”

Answer 50

“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 …”

Question 51

Spinal Injections

Answer 51

- 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.