Module 1 - Principles of Pharmacology

Question 1

What are Drugs?

Answer 1

Any substance received by a biological system that is not received for nutritive purposes, and which influences the biological function of the organism.

Chemicals, biological agents, and herbal products are all considered drugs.

Question 2

What is Pharmacology?

Answer 2

The science of drugs, including their uses, effects, and mechanisms of action.

Question 3

3 Historical Influences on Pharmacology.

Answer 3

1. the many discoveries made by ancient civilizations
2. the role of poisons in history
3. the influence of religion

Question 4

Ancient Greek Influence.

Answer 4

Textbook on therapeutics that included opium

opium is contained in the opium poppy which contains:
* morphine
* codeine

Question 5

Ancient Egypt Influence

Answer 5

Documents called papyri which contained true observations on the use of drugs
* especially drugs called purgatives (used for bowel movements)
*one of the drugs suggested was senna, which products today still contain this

Question 6

Influence of Ancient China.

Answer 6

The earliest recorded drug experiments are those emanating from China in the year 2700 BCE.

Ma Huang - used for for influenza in Chinese medicine, now it treats asthma

Question 7

Influence of Poisons: Curare

Answer 7

Curare:
* use as a poison = acted upon the voluntary muscles of the animal, causing paralysis and eventually death by respiratory paralysis
* use as a drug = used by Indigenous peoples inspired allopathic medicine, and eventually, curare was used by anesthetists during surgery

Question 8

Influence of Poisons: Ergot

Answer 8

The poisonous fungus that grows on the heads of rye during wet seasons

The effects of ergot poisoning impact various systems in the body
*nervous system: mental frenzy, hallucinations and convulsions
*cardiovascular: constriction of blood vessels leading to fingers, toes, and limbs, becoming starved of their blood supply, and a resulting burning sensation - over time the limbs become black and gradually die, and, in extreme cases, they may fall off
*reproductive system: violent contractions of the uterus

Question 9

Ergot use as a drug

Answer 9

2 compounds derived from ergot

ergotamine: useful in the treatment of migraines

ergonovine: it can be used to arrest uterine bleeding after childbirth

Question 10

Influence of religion

Answer 10

Peyote
*cactus was used for spiritual use
*contains a potent substance which causes hallucinations, feelings of well-being, and distortion of perception

Question 11

Drug discovery

Answer 11

Drugs that act on the brain:
*alter the normal chemical signalling in the brain - LSD synthesized by Albert Hofmann

Drugs that act against infectious disease
*an infectious disease is any disease caused by an organism, such as bacteria, viruses, fungi, parasites
*1900s organoarsenicals - Paul Enrich
*1930s sulfa drugs - Gerhrd Domagk
*1940s penicillin - Alexander Fleming
*1950s streptomycin - Selman Waksman

Question 12

Drug development step 1

Answer 12

Basic Research and drug discovery
*Identification of the target - a target for a new potential drug could be a receptor that, when activated, causes relief of pain, once a compound that binds well to the target is identified, it will be studied to determine its pharmacological effects at the molecular, cellular organ, and whole animal level

*Studying the target - if a compound shows promise in the initial studies, it is identified as a lead compound and enters more detailed studies on safety and efficacy

Question 13

Efficacy

Answer 13

the maximum pharmacological response that can be produced by a specific drug in that biological system

Question 14

Drug development Step 2

Answer 14

Pre-clinical trials - asks if the drug is safe and effective

2 main categories:
*Pharmacology studies - determine the detailed mechanism of action of the new drug
*toxicology studies - determine the potential risks or harmful effects of the drug

Clinical Trials - studies new tests and treatments and evaluates their effects on human health outcomes

Three main steps are required before they can proceed:

*proof of safety - pharmaceutical manufacturer must submit proof of the safety and efficacy of the drug in several animal species to the government regulatory agency in the particular country concerned
*methodology - the method of the proposed clinical trial in humans is required
*investigation - the submission is evaluated by qualified scientists in the regulatory agency

Types of trials: Phase 1,2,3

Question 15

Phase 1 clinical trials

Answer 15

Carefully evaluate the absorption, distribution, elimination, and adverse effects of the new drug

The tolerability is determined, the efficacy of this drug is NOT assessed during this phase

Limited number of health volunteers (20-80)

Question 16

Phase 2 clinical trials

Answer 16

Determine whether the drug is effective in treating the condition for which it is recommended, in a limited number of people (100-500)

Pay careful attention to the safety of the drug

Conducted in patients with the disease for which the drug is designed to treat

Question 17

Phase 3 clinical trials

Answer 17

Called randomized controlled trials (RCT)
*main studies used for marketing and licensing

Include:
* number of participants - 1000+
*goal - goal of these studies is to determine how safe and effective the drug is compared to no treatment (placebo) or the currently recommended therapy
*duration - months to years
*location - conducted at centres in many cities (multi-centred)
*cost - most expensive part of drug development

3 stages:
* determining enrolment prior to the study - target population, study population, consent, inclusion/exclusion criteria,
*allocating participants to treatment groups and conducting the trial - double-blind design, randomization, control (placebo, gold standard)
*monitoring and analyzing the results - compliance, quality of life, statistics

Question 18

Drug development Step 3

Answer 18

Health Canada Review and manufacturing - manufacturer will submit to the regulatory body a new drug application containing the detailed results of the clinical trial

generic vs name brand - manufacturers come up with a new drug name (generic) and brand name for the drug

bioequivalence - two drug products, generic and brand name, which contain the same active ingredients and give similar blood levels are said to be bioequivalent

Question 19

Drug development step 4

Answer 19

Post-market surveillance/phase 5 clinical trials

risks that are delayed or less frequent than 1 in 1000 administration may be missed in phase 3 clinical trials
*thus, surveillance of the effects of drugs is required after the drug is released for general use
*this phase is commonly referred to as post-market surveillance or phase 4 clinical trials

Question 20

Drug action

Answer 20

Includes:
*drug targets - receptors, other drug targets, drugs and receptors,
*drug response - the intensity of the pharmacological effects produced by a drug increases in proportion to the dose
*efficacy and potency - maximum pharmacological response that can be produced by a specific drug in that biological system (efficacy), potency refers only to the amount of drug that must be given to obtaining a particular response (potency)
*therapeutic range - give a dose that keeps the blood concentration of a drug above the minimum concentration that produces the desirable response, but below the concentration that produces a toxic response

Question 21

Receptors

Answer 21

molecule or a complex of molecules located on the outside of a cell that has regulatory or functional role in the organism

receptors in the body are normally bound to an activated by endogenous ligands, which are substances ordinarily found in the body such as hormones and neurotransmitters

many different receptors exist, and they are distributed throughout the body
*the location of these receptors determines where a drug will act and whether the response that results from the drug receptor interaction is beneficial or detrimental

Question 22

Other drug targets

Answer 22

some drugs interact non-specifically with the biological system and not via receptors
*chemical reactions
*physical-chemical forces

Question 23

Drugs and receptors

Answer 23

most drugs mimic the action or block the effect of, the endogenous ligand (a molecule that bins the receptor) at the receptor

drugs that bind to and stimulate a receptor are called agonists and drugs that bind to but block the responses at a receptor are called antagonists

Question 24

Lock and key analogy

Answer 24

receptor is the lock

the drug is the key that turns the lock and sets the events in motion

Question 25

Drug Response

Answer 25

the intensity of the pharmacological effects produced by a drug increases in proportion to the dose

for a drug to achieve its desired response, many receptors need to be activated at once:
*low doses - a low dose of drug, very little response is observed, as not many receptors are being activated
*threshold - a threshold exists where a certain number of receptors need to be activated before an effect will be seen
*therapeutic dose - once the threshold is reached, a small increase in dose results in a large increase in response
*maximal effect - once the maximal effect is reached, continuing to increase the amount of drug will have no further increase in the therapeutic response (dose-response curve)

Question 26

Pharmacokinetics

Answer 26

a term that refers to the movement of a drug into, through, and out of the body

Question 27

Process involved in pharmacokinestics

Answer 27

ADME
* absorption
* distribution
* metabolism
* excretion

Question 28

Routes of administration

Answer 28

topical - refer to drugs that are applied directly to a particular place on or in the body
* on the skin
* through the skin
* inhalation

enteral - refer to administration via the gastrointestinal (GI) tract, either directly via the mouth or an artificial opening
* mouth
* rectum
* sublingual and buccal

parenteral - refers to administration bypassing the GI tract
* intravenous - injected directly into the blood
*intramuscular - injected into the muscle
*subcutaneous - injected into the deepest layer of skin

Question 29

Administration and bioavailability

Answer 29

because, during absorption, not all of the drug ends up in the blood — bioavailability differs between drugs

bioavailability = the fraction of administered dose that reaches the systemic circulation (blood) in an active form

Question 30

ADME: Absorption

Answer 30

for a drug to be absorbed and distributed to the sites of action, storage, and excretion, it must be able to cross biological membranes

first method: diffusion through aqueous pores

second method: diffusion through lipids

third method: active or carrier-mediated transport

Question 31

Diffussion through aqueous pores

Answer 31

drugs with small molecular weights that are water-soluble can move across membranes by first dissolving in the aqueous fluids surrounding cells then passing through the small openings between cells

Question 32

Diffusion through lipids

Answer 32

cellular membranes are composed of a lipid bilayer structure

the majority of drugs have molecular weights greater than 150 Daltons, and therefore do not pass through the membrane by dissolving in the lipid portion of the membrane

these drugs still flow down a concentration gradient to the other side of the cell membrane

the ability of a drug to cross a membrane via this method depends on its lipid solubility

Question 33

active or carrier-mediated transport

Answer 33

a number of drugs bind to proteins, termed carrier proteins or transporters, which carry molecules across a membrane

once bound, the carrier protein drug complex moves across the membrane and releases the drug on the other side of the membrane

transporter-mediated drug transfers can move down a concentration gradient but can also be an active process requiring energy to move a drug against a concentration gradient

Question 34

ADME: distribution

Answer 34

the rate at which drugs distribute in and out of a particular organ depends on the blood flow to an organ

the concentrations of the drug at the sites of distribution are in equilibrium, with its concentration in the blood
*if the concentration in the blood drops below the concentration at any of the distribution sites, the drug will move from that site to the blood to maintain equilibrium

that is the greater the blood flow to an organ, the more rapidly drugs reach that organ and vice versa

distribution can result in the termination of the therapeutic effect or some drugs

Question 35

Thiopental

Answer 35

Ultra short-acting sedative which functions to rapidly induce anesthesia

Question 36

ADME: metabolism

Answer 36

drug metabolism also referred to as biotransformation is the conversion of a drug to a different chemical compound in order to eliminate it

the products of metabolism are called metabolites and they are usually, but not always, devoid of pharmacological action

to be eliminated from the body by the kidneys, a drug must be water soluble
*most drugs can be converted to more water-soluble compounds

the liver is the organ where most biotransformation reactions occur

Question 37

P450 - Biotransformation reaction

Answer 37

enzymes capable of biotransforming drugs — they are found in most tissues but present in high concentrations in the liver

responsible for biotransforming about 50% of all drugs

taking multiple drugs simultaneously, the drugs might compete for this enzyme, resulting in reduced biotransformation of one or both drugs which could lead to toxic effects

Question 38

Phase 1 - Biotransformation reaction

Answer 38

the purpose is to add or unmask functional groups on the drug to prepare it for the addition of a larger water-soluble molecule in the phase 2 reaction
* function groups = a substituent of a molecule that is responsible for the molecule’s characteristic effects

phase 1 reaction as adding a handle to which you can later attach a water-soluble molecule

Question 39

Phase 2 - Biotransformation equation

Answer 39

add large water-soluble moiety, usually glucuronic acid to sulphate, to the product resulting in phase 1 biotransformation, making the metabolite water-soluble for excretion by the kidney
* moiety = a part or functional group of a molecule

Question 40

Excretion - Biotransformation equation

Answer 40

the water-soluble drug can now be excreted by the kidneys this is the last step in pharmacokinetics

Question 41

ADME: excretion

Answer 41

drug excretion includes moving the drug and its metabolites out of the body

*Kidney
*GI tract
*lungs
*breast milk
*salvia and sweat

Question 42

Variation in drug response

Answer 42

the recommended dose of a drug is the amount of drug that will cause the desired effect in most people but will not cause the desired effect in all people

a wide difference in response to a drug exists within a population, which is why drug doses sometimes need to be adjusted based on the individual’s response

Question 43

Factors for drug response variation:

Answer 43

• genetic factors
• environmental factors
• disease states
• altered physiological states
• presence of other drugs

Question 44

Toxic effects of drugs

Answer 44

adverse effects

drug-drug and drug-food interactions

Question 45

Adverse effects

Answer 45

• extension of therapeutic effect - OD
• unrelated to the main drug action - Not expected
• allergic reaction - mediated by an immune response
• withdrawal and addiction - unwanted physiological and psychological effects of the drug
  *teratogenesis - drug produces defects in the fetus
• adverse biotransformation reaction - can cause tissue or organ damage

Question 46

Drug-drug interactions

Answer 46

occurs when one drug changes the pharmacological effect of a second drug

This can occur at many points:
* absorption - decreasing contact with the second intestinal wall, thereby decreasing absorption
* metabolism - a drug can block the inactivation of a second drug in the liver
* excretion - a drug can facilitate the excretion of a second drug by the kidney

Question 47

Drug-food interactions

Answer 47

involve the interference of food with drugs taken concurrently

Tyramine:
* it is capable of raising blood pressure and is broken down in the liver by an enzyme known as monoamine oxidase (MAO)
* it a patient is being treated with MAO inhibitor and consumes a food containing tyramine, it will not be broken down to inactive products and the blood pressure

Grapefruit:
* known to alter the absorption of some drugs

Question 48

Prediction of adverse drug reactions

Answer 48

the rarity of the occurrence:
* The toxic reaction may be rare, making it difficult to predict the adverse drug reaction

length of usage:
* The toxic reaction may only appear after prolonged use

detectability in animals:
* the toxic effect may not be detectable in animals

time period specificity:
* the toxic effect may be unique to a particular period in time

Question 49

CNS

Answer 49

cerebral cortex (cerebrum)
* overall function is: sensory and motor coordination, mental processes, intelligence, memory, vision, judgement, thought, speech, emotions, and consciousness
* neurons in the cerebral cortex can be stimulated (excited) or depressed (inhibited) by drugs

limbic system:
* region of the brain that integrates memory, emotion, reward
* contains the dopaminergic reward centres, which are targets for commonly misused drugs and are associated with addiction

Question 50

The neuron

Answer 50

the functional unit of the brain is the neuron which is a nerve cell capable of generating and transmitting electrical signals

new neurons are generated continuously through a process called neurogenesis

the connection between neurons is constantly being reshaped through what it’s known as neuroplasticity

Question 51

Structure of the neuron

Answer 51

dentrites:
* they function as the receiving antennae for incoming information and accept information through receptors located on the dendritic membranes

the cell body (soma):
* the largest part of the neuron and contains a nucleus and surrounding cytoplasm
* the cytoplasm contains abundant pre-packaged neurotransmitters which can be secreted

axon:
* a single fibre that extends from the cell body and ends at a synapse
* continues to carry incoming information away from the dendrites and cell body by way of an electrical pulse

Question 52

The synapse

Answer 52

an electrical impulse has to be somehow communicated across the junction of one neuron to another if it is to produce a further effect

the junction between two neurons is called a synapse and is the area where one neuron axon ends and another neuron dendrite or cell body gains

Question 53

Synaptic transmission (neurotransmission)

Answer 53

the passage of a signal from one neuron to another neuron

the endogenous chemicals that transmit a signal between two neurons are called neurotransmitters

Question 54

Synaptic transmission and termination response

Answer 54

1. a neurotransmitter can be taken back up to the presynaptic neuron through transporters
2. Neurotransmitters can be broken down by enzymes in the synaptic cleft
3. a neurotransmitter can be taken up into adjacent glial cells which are cells that support neurons

Question 55

Neurotransmitters and receptors

Answer 55

1. glutamate
2. catecholamines
3. GABA
4. Serotonin
5. acetylcholine
6. opioid peptides

Question 56

Glutamate

Answer 56

the primary excitatory neurotransmitter in the CNS and found in almost every neuron

Acts on a family of receptors called the glutamatergic receptors

Question 57

Catecholamines

Answer 57

Dopamine: dopaminergic pathways are involved in the control of some hormonal systems, motor conditions, and motivation and reward

Norepinephrine: can bind to a large number of receptor types, but two main classes are alpha (a) and beta (b) - usually leads to excitation of the cell

Question 58

GABA

Answer 58

gamma-amino butyric acid is the primary inhibitory transmitter in the CNS

neurons that release GABA are found in high concentrations in the cerebral cortex, among other areas

Question 59

Serotonin

Answer 59

hyperactivity of the serotonergic system is involved in anxiety, and hypoactivity in depression

Question 60

Acetylcholine

Answer 60

produces an excitatory response in the CNS

two types of receptors bind:
1. nicotinic receptors
2. muscarinic receptors

Question 61

Opioid peptides

Answer 61

3 main classes:
1. enkephalins
2. endorphins
3. dynorphins

they have varying degrees of selectivity for three opioid receptors: mu, delta and kappa