Module 1- Introduction to pharmacology Flashcards
What is pharmacology
Study of substances that affect or alter living systems through chemical processes
Drug
Any substance received by a biological system that is not received for nutritive purposed (i.e. chemicals, biologicals, and herbals)
Pharmacodynamics
Effects of a drug on the body (mechanism of action that causes these effects)
Pharmacokinetics
How the body handles the drug (absorption, distribution, metabolism, and excretion)
what are the 2 reasons drugs are administered
- to achieve a beneficial effect on an individual
- to exert a selectively toxic effect on the individual
What are the two areas of pharmacology?
- Pharmacodynamics
- Pharmacokinetics
Most drugs influence biological systems by…
interacting with and binding to receptors
What are endogenous ligands
Substances ordinarily found in the body (i.e., hormones and neurotransmitters)
Where do receptors bind
Bound to and activated by endogenous ligands
What are 4 types of receptors
- Regulatory proteins
- Transporters
- Enzymes
- Structural proteins
Regulatory Proteins
Proteins that mediate the actions of endogenous chemical signals
What is meant by signalling mechanisms
Once an endogenous ligand or drug binds to and activates its receptor, the activated receptor triggers a series of biochemical events that results in the pharmacological effect
What are the 4 common signalling mechanisms
- ligand gated ion channels
- G-protein coupled receptors
- regulated transmembrane enzymes
- intracellular receptors
Ligand gated ion channels
Regulatory proteins used to transport sodium, chloride, and other ions across the cell membrane when an endogenous ligand or drug binds to the receptor
G-protein coupled receptor
Receptors that undergo a conformational change when an endogenous ligand or drug binds, activating a second messenger system
Regulated Transmembrane Enzymes
Receptors that activate an enzyme inside the cell when an endogenous ligand or drug binds
Intracellular Receptor
Receptors that move into the nucleus when bound to an endogenous ligand or drug increasing gene expression
Transporters
Proteins that transport endogenous substances across cell membranes
Note: Drugs targeting transporters often inhibit the function of the transporter
Enzymes
Proteins that catalyze biological reactions
Note: drugs targeting enzymes often inhibit the catalytic function of the enzymes
Structural Proteins
Proteins that contribute to the cell structure
Note: Drugs can bind to structural proteins in a cell and disrupt their normal function
Antacids
Commonly used to neutralize stomach acids through a simple acid-base neutralization
Chemotherapy Drugs
a # of chemo drugs do not bind to specific receptors, but kill cancer cells by chemically disrupting normal cell function
5 drug classifications
- Agonists
- Partial agonists
- Allosteric activator
- Competitive antagonist
- Non-competitive antagonist
Agonist
Binds to and activates the receptor, producing a full response
Partial Agonist
Binds to the receptor and activates it, but produces a weak response
Allosteric Activator
Binds to a different area of the receptor than the agonist, but makes the receptor easier to activate
Competitive antagonist
Reversibly binds to the same receptor site as an agonist, but does not activate it
Non-competitive antagonist
irreversibly binds to an blocks the receptor
Dose-response relationship
Intensity of the pharmacological effects produced by a drug increases in proportion to the dose
What does ED50 mean?
Dose that results in 50% of the maximal effect
What is threshold effect?
You need a certain amount of drug binding to an activator, to activate a certain amount of receptors before you see a response in the body
Efficacy vs potency
Efficacy: max pharmalogical response that can be produced by a specific drug
Potency: amount of drug required to obtain a particular response
Clinically, which is more important, efficacy or potency?
Efficacy is more important than potency; because the max effectiveness of a drug is generally what determined which drug is chosen to treat a specific conditions.
Note: potency does not matter as much, as the dose can be adjusted to achieve a desired response
The dose response curve of a drug w low potency is shifted ______ compared to the dose response curve of a drug with high potency
right
The dose response curve of a drug w low efficacy is __________ compared to the dose response curve of a drug w high efficacy
condensed
Drug disposition
process involved in the journey of a drug through the body
what does ADME stand for?
Absorption
Distribution
Metabolism
Excretion
What physical-chemical properties can a drug have?
Solids
Liquids
Gas at room temp
Bioavailability
actual measure of what is detected in systemic blood stream after consumption of the ingredient
Note: can only be properly determined in pharmacokinetic trials
Absorption
- release of drug from dosage form
- drug must dissolve in GI fluids before it can be absorbed into the blood
- Must cross biological membranes to be absorbed into blood and distributed to the sites of action, storage, and excretion
Diffusion through lipid
Lipid soluble drugs pass through the membranes by dissolving in the lipid portion of the membrane and flowing down a concentration gradient to the other side of the cell membrane
Membrane permeability
ability of a drug to cross a membrane and be absorbed depending on its lipid solubility
Un-ionized form
Lipid soluble; can readily cross lipid membranes
Ionized form
water-soluble; does not readily cross the lipid membrane
What does the degree of ionization depend on?
the pH of the environment and the pka
what it the pKa of a drug?
the pH where a drug is 50% unionized and 50% ionized
Weak acids
drug that is a neutral molecule and can dissociate into a negatively charged molecule and a proton
Example: aspirin
Weak bases
drug that is a neutral molecule and can combine w protons to form a positively charged molecule
example: norepinephrine
Acidic environment
an excess of protons are available, so the unionized form of a weak acid, and ionized form of a weak base will predominate
basic environment
few protons are available, so the ionized form of a weak acid, and the unionized form of a weak base will predominate
Under acidic conditions, which drug is lipid soluble?
Weak acid
under basic conditions, which drug is lipid soluble?
weak base
Distribution
for a drug to act, it must move from its site of absorption to other areas of the body, including sites of action
Recall: if the concentration in the blood drops below the concentration at any of the distribution sites, the drug will move from that site into the blood to maintain equilibrium
At all sites of distribution, drugs exist in what 2 forms
- free drug
- drug bound to protein
Note: when a drug is bound to protein in the blood, it is not able to cross membranes and is therefore unable to produce its pharmacological effects or be readily excreted by the kidney
3 organ-specific distribution sites
- blood brain barrier- limits the access of many drugs to the brain/ spinal cord
- placenta- very permeable to drugs + most drugs reach the fetal tissue
- fat soluble drugs will accumulate in Fat cells, and since blood flow to fatty tissue is limited drugs will leave fat tissue slowly
Metabolism
The conversion of a drug to a different chemical compound
A drug will undergo biotransformation if it needs to be converted into another compound so it can exert its effects or be eliminated from the body
Biotransformation in the liver
These reactions involve the conversion of drugs into more water-soluble compounds
- once water soluble, the drug can be eliminated from the body by the kidneys
What happens without biotransformation?
Some chemicals that are very lipid soluble would never be excreted from the body
Where can biotransformation occur?
Liver, kidneys, intestines, lungs, skin, and most other organs
Phase 1 of biotransformation reactions
purpose add or unmask a functional group so that the phase 2 reaction can add a large water-soluble component to allow excretion by the kidney
What are 3 phase 1 reactions
- oxidative reactions via Cytochrome P450
- Other oxidative reactions
- hydrolysis of esters and amides
Oxidative reactions via Cytochrome P450
are a family of enzymes located primarily on the smooth endoplasmic reticulum in the liver
CYPs- bind the substrate and activte oxygen
Other oxidative reactions
Not mediated by CYPs are oxidation of amines and dehydrogenation of alcohol –>mediated by the enzyme monoamine
Hydrolysis of Esters and Amides
these drugs are converted to the acid and the corresponding alcohol or amine by carboxyl esterase’s found in the liver, blood, GI tract and other tissues
phase 2 biotransformation reactions
add a large water-soluble moiity to the phase 1 biotransformation product, making the metabolite water-soluble for excretion via kidney
Four main phase 2 conjugation enzymes are
- UDP- glucuronosyltransferase (UGT): forms a glucuronide
- Sulfotransferase (SULT): forms a glucuronide
- Glutathione transferase (GST): forms a glutathione conjugate
- N-acetyl transferase (NAT): forms an N-acetylated metabolite
First pass effect
the biotransformation and inactivation of a drug during absorption from the intestine
Factors affecting biotransformation
Drug interactions can occur when two drugs are competing for the same enzyme, or when one drug inhibits the biotransformation of another drug
- age
- genetic factors
- disease states
Excretion
Moving a drug and its metabolites out of the body
Drug excretion via kidney
Kidney’s receive about 20% of the blood from the heart (cardiac output), and are very efficient in excreting water-soluble drugs and metabolites
Process of renal excretion
- glomerular filtration: most drugs pass from glomerulus into Bowman’s capsule and then into the proximal tubule of the kidney
- passive tubular reabsorption: concentration is higher in renal tubules than in the blood, so some lipid soluble drugs can be reabsorbed back into the blood as they are moving down the concentration gradient
- active tubular secretion: active transporters in renal tubule move drugs from the blood into the urine to be excreted
Other routes of Drug Excretion
- gastrointestinal tract
- other bodily fluids (milk, saliva, sweat)
- through the lungs
Apparent Volume of Distribution (Vd)
The volume of which a drug appears to be distributed
Vd= dose of drug / concentration of drug in plasma
V= apparent; does not represent an actual volume somewhere in the body
Clearance of a drug
process of removing a drug from the body
Clearance = rate of elimination / drug concentration in blood
First order elimination
Constant fraction of drug eliminated over a set period of time
If concentration is high, more drug is excreted, as the liver and kidney have higher amounts of drug available to eliminate
If concentration is low, the opposite it true
Zero order kinetics
a constant amount of drug is eliminated in a set period of time (instead of a constant proportion), as the enzymes responsible for elimination are saturated and there is more drug than can be transformed
Elimination half-life
time needed for the liver and kidney to remove 50% of the drug from the blood
The plateau principle
When a drug is administered repeatedly, the plasma concentration of the drug will increase until the rate of administration is equal to the rate of elimination
drug input = drug output
How long does it typically take for drug input = drug ouput?
5 elimination half lives
Compliance with therapy
a drug is not effective if the patient does not take the drug correctly
What is compliance when medication is self-administered
between 20%-90%
Calculating drug doses
administered by weight or volume
other drug measurements
- household measures (i.e. teaspoon)
- units (based on biological activity of drug)
- surface area (body weight)
Therapeutic index
TI = TD50 / ED50
Note: the higher the therapeutic index, the safer the drug
When a drug has a low TI, its more likely toxicities will occur
What is TD50?
The dose that is toxic to 50% of a population
What is ED50?
the dose that is effective in 50% of a population
Adverse Drug Reactions
- extension of therapeutic effect
- effects in non-target tissues or organs
- unrelated to main drug action
- drug idiosyncrasy
- allergic reactions
- adverse biotransformation reactions
- tolerance, withdrawal, addiction
- teratogenesis (birth defects)
Extension of therapeutic effect
occurs when too much of drug is in the blood (common w drug overdose)
i.e. benzodiazepines- taken for sedative effects; an overdose will produce over-sedation
Effects in non-target tissues or organs
when receptors for the drug exists in more areas than the target tissues, you can observe effects in these non-target tissues/organs
i.e. morphine - produces analgesic effects by acting on opioid receptors but acts on GI receptors also
Unrelated to main drug action
effects that are unexpected and unrelated to the intended pharmacological action of the drug
i.e. digitalis- treat heart failure; causes nausea, vomiting, and abnormal vision (unrelated to heart)
Drug idiosyncrasy
Genetic- refers to an unusual response to a drug that is only observed in a small number of people
i.e. succinylcholine- produces muscle relaxation but approx 1 in 3000 patients lack the enzyme that normally inactivates the drug
allergic reactions
mediated by immune system
i.e. penicillin
adverse biotransformation reactions
occurs when a drug is converted into a chemically reactive metabolite that can bind to tissue components and cause tissue or organ damage
i.e. acetaminophen- at recommended doses is converted but overdose leads to production of chemically reaction metabolites
tolerane, withdrawal, and addiction
tolerance/withdrawal =. unwanted physiological effects
addiction= psychological effect
teratogenesis (birth defect)
multifactorial and depends on the drug, usually refers to drug-induced defects in the developing fetus
Why is drug toxicity hard to predict?
- adverse effect is rare
- toxic reaction only appears after prolonged use
- toxic effect is not detectable in animals
- adverse effect is unique to a particular period or circumstance
who is at risk for an adverse reaction?
Age:
- newborns and individuals >60
- immature or damaged organs
Genetics:
- enzymes that bio transform and inactivate drugs can exist in different forms based on genes that code for enzymes
Multiple diseases in the same patient:
- the presence of more than one disease can increase chances
drug-drug interactions
Modifications of the pharmacological effect of one drug by the presence of another drug in the body
the potential increases as the number of drugs taken by the patient increases
Types of drug-drug interactions
Addictive: combined pharmacological effect of the 2 is the sum of the individual effects
Synergistic: pharmacological effect of 2 drugs is greater than the sum of individual
Potentiation: pharmacological effect of one drug is increased by a second drug, even tho the second drug is devoid of the intended therapeutic effect
antagonism: one drug reuced pharmacological effect of another drug by binding to and competing for the same receptor
altered physiology: one drug my alter the physiology of the body so the response to another drug is altered
Drug to food interactions
Grapefruit:
- contains compounds that inhibit CYP 3A4, one of the p450s found in GI cells which contributes to first pass effect
- when inhibited it increases pharmacological effect normally observed with that dose
Tyramine:
- antidepressants of the monoamine oxidase inhibitor class and any food containing tyramine, such as ages cheddar cheese
- monoamine oxidase inhibitors prevent the inactivation of tyramine, and tyramine can cause a large increase in blood pressure leading to a hypersensitive crisis
Drug discovery and development
- identify biological target
- identify pharmacological effects
- conduct more studies
drug development: can take ~2-8 years and up to 25 000 different chemical compounds
Stages of Drug development: 25,000 compounds (3-6 years)
Preclinical studies:
1. pharmacological studies
2. toxicology studies
a. acute toxicity study
b. sub-chronic study
c. chronic toxicity study
stages of drug development: 30 compounds (6-7 years)
Clinical trials
1. Phase 1: determining safe dosages
2. phase 2: determining the initial efficacy
3. phase 3: conducting randomized control trials
Stages of drug development: 1 FDA approved drug (0.5-2 years)
- health canada review
- manufacturing: genetic vs brand name
a. bioavailability studies
phase 4: post market surveillance
