Week 1-3

pharmacy

the art, practice, or profession of preparing, preserving, compounding, and dispensing medical drugs

therapeutics

the treatment of disease or injury

pharmacology

the science that deals with the fate of drugs in the body and their actions on the body

drug

any substance that when applied to or introduced into a living organism into a living orgarnism, has the effect of altering biological functions

earliest record of pharmacology and toxicology

• ebers papyrus

• dioscorides

• chakraka samhita

• sushruta samhita

• etc.

paracelsus

German physician, introduced experimentation into the study of poisons and established importance of dose as a determinant of therapeutic versus toxic

mathieu orfila

first academic consideration of toxicology, wrote treatise in 1815 on toxicology

toxicology

the study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem including the prevention and amelioration of such adverse effects

purpose of toxicology

• identify harm: Determine if a chemical can harm people or the environment.

• Compare doses: Find the difference between a safe/therapeutic dose and a toxic dose of a drug.

• Understand harmful effects: Learn how chemicals cause damage and contribute to disease.

• Set safety regulations: Provide scientific evidence to control chemical exposure and pollution in workplaces and the environment.

poison

a substance that in relatively small doses produce serious illness or death

toxin

poisonous substance secreted or created by plants or animals

venom

a poisonous substance secreted by animals

toxicant

any substance the produced toxicity following exposure

xenobiotic

any substance that is “foreign to the body”

focal efforts in toxicology

• ecological - study how chemicals impact non-human organisms

• veterinary - concerned with effects of toxic substances on farm animals and pets

• medical - focuses on chemicals used to treat disease

• occupational - focus on toxic substances of concern in workplace

• forensic - determines whether poison was involved in death

basis of selective toxicity

• difference in translocation factors - how drugs get into cells and site of action

• difference in biotransformation - drugs get removed or inactivated in body depending on amount and type

• difference in presence or absence or nature of receptors

host factors for selective toxicity

• genetic traits

• age

• gender

• pre-existing conditions or diseases

• behavioural/life-style traits

• medications/vitamins

types of exposure

• acute

• subacute

• subchronic

• chronic

persistent organic pollutants (POP), polychlorinated binephyls (PCB) and dioxins

• ubiquitous environmental contaminants

• route of exposure - oral

• endocrine disrupters

• lipid soluble

• adverse effects include - cancer, development defects of the urogenital tract in offspring, fertility problems, chloracne

lead

• major sources - car batteries, lead based paint

• route of exposure - oral

• blood, kidney, and neurological disorders

• children are more susceptible

• treatment - chelation (DMSA , EDTA)

natural preparations (galenicals)

crude extracts or preparations of plant or animal material

pure compounds

active ingredients found in natural compounds

semi-synthetic compounds

results from chemical modification of pure compounds to increase bioavailability or affinity for a receptor

• hydroxylation of morphine, fluorination of hydrocortisone

purely synthetic compounds

substances that were created based on predicted chemical properties, or synthetic compunds that were the result of industrial processes that were found to have therapeutic properties

• disulfiram

biological drugs

molecules synthesized in living cells and organisms

• hormones, monoclonal antibodies, clotting factors

prescription

controlled, only be purchased with permission of physician

over the counter (OTC)

can be bought in stores

supplements

vitamins and herbal extracts

personal/non-medical

illicit drugs

industrial

food colouring, artificial flavouring

agriculture

pesticides, feed for livestock

bioavailability

the proportion of drug that reaches the systemic circulation

factors of bioavailability

• nature or physical properties of the drug

• route of administration

• sex

• age

• health status

ADME

a - absorption

d - distribution

m - metabolism

e - elimination

pharmacodynamics

mechanism of drug action

• interactions between drugs and its drug targets

pharmacometrics

the study of relationship between drug dose or concentration and the magnitude of effect

structure activity relationship

concerns the ability of a drug to bind its receptor and the molecular properties of a drug that dictate its affinity for its receptor

agonist

initiate biochemical or biophysical changes (mimics)

antagonist

block the natural fuction of a receptor, usually by preventing an endogenour compound from binding to the receptor

inverse agonist

elicit the opposite effect of an agonist when binding a receptor

specific binding

binding of drug to receptor, saturable

non-specific binding

drug taken up by structures other than receptors

specificity

a characteristic of a drug to selectively target receptor binding sites

affinity

tendency for a drug to bind to the receptor

efficacy

tendency for a bound drug to activate the receptor (insintric activity)

b-max

binding capacity

• concentration at which all receptors in the tissue/cell are saturated, density of receptors

K

concentration of radioligand at which binding reaches half of Bmax

Emax

maximal response a drug can produce

EC50

concentration needed to produce a 50% maximal response

pharmacokinetics

study of drug disposition

competitive antagonism

• aganost occupancy at a given agonist concentration will be reduced

• can be overcome by increasing concentration of agonist

• maximal response and slope binding curve are unchanged

• binds at same site as agonist

degree of shift/dose ratio

increase in agnoist concentration required to overcome antagonism

Kb

dissociation constant of antagonist

irreversible competitive antagonism

• binds to same site on receptor as agonist

• cannot be overcome by increasing concentrations

partial agonist

• cannot indice same maximal response as full agonist

• reduced efficacy even when 100% of receptors are bound

• used when wanting to elicit a response but only a reduced response

constitutive activation

when agonist is absent, receptor adopts a confirmation that makes it active

biased agonism

in some cases, one agonist will favour one response over another

law of mass action

drug (a) + free receptor (r) → AR complex

Two ways drugs move throughout the body

• bulk flow

• diffusion

Bulk flow

• movement over larger distances

• movement of fluid and constituents within major fluid compartments

  • bloodstream, lymphatics, cerevrospinal fluid, GI tract

• chemical nature of drug does not impact bulk flow

diffusion

• movement over shorter distances; microscopic scale

• physical characteristics of drug have impact on its diffusional characteristics

  • lipid solubility

  • size

absorption

the passage of a drug from its site of administration into the plasma

for a drug to act, it must reach its ___

site of action

types of route of administration

• topical

• percutaneous

• G.I. tract

• pulmonary epithelium

• injection

topical

manual, direct local applications to epithelial surfaces

• accessible body surface

  • eyes, nose, skin, mouth, throat, urethra, vagina, and rectum

preparation of topical

creams, ointments, powders, and sprays

advantage of topical

• drug reaches only site of action, avoids systemic effects

• can control magnitude of effect

• safe and easy

• mostly non-invasive

disadvantages of topical

• drug must be used in small concentrations and volumes to ensire only at that action site

• can cause reactions

percutaneous

A topical application that is meant to reach the systemic circulation or a site just under the skin.

examples of percutaneous

nitroglycerin, nicotine, scopolamine, contraceptives

advantages of percutaneous

slow, safe delivery; prolonged duration of action.

disadvantages of percutaneous

• drug limitations (size, hydrophobicity)

• variable and unpredictable absorption

• skin reactions

• inconvenient

GI tract - Oromucosal

Drug enters systemic circulation by absorption through the oral mucosa

• under tongue

• between gum and inside of cheek

examples of oromucosal

Nitroglycerine, Buprenorphine, Lorazepam

advantages of oromucosal

rapid, does not enter enterohepatic circulation (no “first-pass” metabolism in the liver)

disadvantages of oromucosal

compliance, not well controlled, mouth irritation

GI tract - oral

By mouth - site of absorption is the stomach and/or small intestine

Oral advantages

• easiest method of delivery

• large surface area of the G.I. tract allows for greater absorption

• generally longer duration of action

disadvantages of oral

• rate of absorption varies wildly

  • based on gastric emptying rate, pH, G.I. motility, solubility of drug, binding of drugs to other substances in stomach

GI tract - rectal

Suppositories and enemas

• drug is administered through the rectum and absorbed through the rectal mucosa (used for treatment of ulcerative colitis, status epilepticus, etc).

• Drugs absorbed through the rectal mucosa are protected from first pass metabolism (biotransformation)

advantages of rectal

drug can be administered when patient is unconscious or vomiting

• Useful if the drug has a bad taste or if it is destroyed by acid or digestive enzymes

disadvantages of rectal

Absorption is often irregular or incomplete, irritation of the rectal mucosa, risk of toxicity

pulmonary epithelium

Drugs are absorbed through bronchial mucosa or alveolar surfaces for local action or for rapid access to circulation

• gas, vapours, or aerosols

examples of pulmonary epithelium

albuterol, general anaesthetics, cannabinoids

advantages of pulmonary epithelium

A noninvasive delivery system, low enzymatic environment, reproducible absorption kinetics

disadvantages of pulmonary epithelium

Airway geometry, humidity, clearance mechanisms and presence of lung disease influence the deposition of aerosols

• can be partly absorbed into circulation

injection - intravenous (IV)

1. rapid injection - drug administered rapidly as a bolus (a ball)

2. slow fusion - drug administered over ~ 20 mins

advantages of rapid injection

• achieve rapid, precise drug plasma concentration

• Good for drugs whose duration of action is intended to be short- lived.

disadvantages of rapid injection

higher risk of toxicity, infection, vascular injury

advantages of slow fusion

allow drug levels to be “titrated”

disadvantages of slow fusion

embolism is the most serious

other types of injection

• subcutaneous

• intramuscular

• intraperitoneal

• intrathecal

subcutaneous

• only non-irritating drugs

• Allows for slow and even absorption of drug (preparation can be mixed with vasoconstrictors or hyaluronidase to control absorption rates)

intramuscular

• slow and even absorption possible if mixed with an oil

• Complications include muscle irritations and abscesses.

intraperitoneal

• Rare in clinical settings due to high risk of infections and intestinal or vascular injury

• More commonly used in laboratory procedures.

intrathecal

• administration directly into the space surrounding the spinal cord

• substance is injected into the subarachnoid space

• Rare circumstances directly into through skull

choice of route is dictated by

• Therapeutic objective (eg, inhalation or IV for rapid, short-lived effect or oral for long lasting effects with moderate and even intensity)

• Properties of the drug (eg, thiopental, penicillin G)

three common routes of exposure to toxicant

• oral

• topical

• inhalational