Module 1 - Principles of Pharmacology Flashcards
What are Drugs?
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.
What is Pharmacology?
The science of drugs, including their uses, effects, and mechanisms of action.
3 Historical Influences on Pharmacology.
- the many discoveries made by ancient civilizations
- the role of poisons in history
- the influence of religion
Ancient Greek Influence.
Textbook on therapeutics that included opium
opium is contained in the opium poppy which contains:
* morphine
* codeine
Ancient Egypt Influence
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
Influence of Ancient China.
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
Influence of Poisons: Curare
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
Influence of Poisons: Ergot
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
Ergot use as a drug
2 compounds derived from ergot
ergotamine: useful in the treatment of migraines
ergonovine: it can be used to arrest uterine bleeding after childbirth
Influence of religion
Peyote
*cactus was used for spiritual use
*contains a potent substance which causes hallucinations, feelings of well-being, and distortion of perception
Drug discovery
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
Drug development step 1
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
Efficacy
the maximum pharmacological response that can be produced by a specific drug in that biological system
Drug development Step 2
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
Phase 1 clinical trials
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)
Phase 2 clinical trials
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
Phase 3 clinical trials
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
Drug development Step 3
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
Drug development step 4
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
Drug action
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
Receptors
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
Other drug targets
some drugs interact non-specifically with the biological system and not via receptors
*chemical reactions
*physical-chemical forces
Drugs and receptors
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
Lock and key analogy
receptor is the lock
the drug is the key that turns the lock and sets the events in motion
Drug Response
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)
Pharmacokinetics
a term that refers to the movement of a drug into, through, and out of the body
Process involved in pharmacokinestics
ADME
* absorption
* distribution
* metabolism
* excretion
Routes of administration
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
Administration and bioavailability
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
ADME: Absorption
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
Diffussion through aqueous pores
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
Diffusion through lipids
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
active or carrier-mediated transport
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
ADME: distribution
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
Thiopental
Ultra short-acting sedative which functions to rapidly induce anesthesia
ADME: metabolism
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
P450 - Biotransformation reaction
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
Phase 1 - Biotransformation reaction
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
Phase 2 - Biotransformation equation
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
Excretion - Biotransformation equation
the water-soluble drug can now be excreted by the kidneys this is the last step in pharmacokinetics
ADME: excretion
drug excretion includes moving the drug and its metabolites out of the body
*Kidney
*GI tract
*lungs
*breast milk
*salvia and sweat
Variation in drug response
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
Factors for drug response variation:
- genetic factors
- environmental factors
- disease states
- altered physiological states
- presence of other drugs
Toxic effects of drugs
adverse effects
drug-drug and drug-food interactions
Adverse effects
- 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
Drug-drug interactions
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
Drug-food interactions
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
Prediction of adverse drug reactions
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
CNS
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
The neuron
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
Structure of the neuron
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
The synapse
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
Synaptic transmission (neurotransmission)
the passage of a signal from one neuron to another neuron
the endogenous chemicals that transmit a signal between two neurons are called neurotransmitters
Synaptic transmission and termination response
- a neurotransmitter can be taken back up to the presynaptic neuron through transporters
- Neurotransmitters can be broken down by enzymes in the synaptic cleft
- a neurotransmitter can be taken up into adjacent glial cells which are cells that support neurons
Neurotransmitters and receptors
- glutamate
- catecholamines
- GABA
- Serotonin
- acetylcholine
- opioid peptides
Glutamate
the primary excitatory neurotransmitter in the CNS and found in almost every neuron
Acts on a family of receptors called the glutamatergic receptors
Catecholamines
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
GABA
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
Serotonin
hyperactivity of the serotonergic system is involved in anxiety, and hypoactivity in depression
Acetylcholine
produces an excitatory response in the CNS
two types of receptors bind:
1. nicotinic receptors
2. muscarinic receptors
Opioid peptides
3 main classes:
1. enkephalins
2. endorphins
3. dynorphins
they have varying degrees of selectivity for three opioid receptors: mu, delta and kappa
