BM213 - Megaset

Pharmacology (definition)

Deals with the mechanisms of action, uses and unwanted effects of drugs on living tissues.

Drug (Definition)

an exogenous substance that modifies the activity of living tissue

Physiology (defintion)

The science of how living tissues function

Therapeutics (definition)

The study of the use of pharmacological agents in disease states

Pathology (definition)

The study of how the body goes wrong in disease states.

Agonist (definition)

Drugs, or naturally occurring body substances, that directly cause a measurable excitatory or inhibitory response.

Affinity (definition)

Binding of agonist (or any drug) to it’s receptor

Efficacy (definition)

Ability of agonist (or any drug) to activate the receptor

Antagonist (definition)

When drugs counteract another by acting on the same receptor type creating opposing effects. Does not create a measurable response (is still quanitifiable)

Competitive antagonism (definition)

Can be outcompeted by increasing agonist concentration (i.e. surmountable)

(types of) drug targets

ion channels, enzymes, transporters/carriers, receptors

Receptors (definition)

chemical structures composed of regulatory proteins. Receive and transduce signals to biological systems

William Blair-Bell

Treated breast cancer with a poisonous substance (lead colloidal mixtures) - poisonous to patients, but more so to cancer cells

(examples of) factors affecting toxicity in patients

age, genetics, pathological conditions, drug-drug interactions, dose

Botulism

caused by contaminated food, associated with canned food that have not been correctly sterilised. Causes muscle paralysis, respiratory failure, and death. One of the most deadly poisons in the world

Structure Activity Relationship (SAR)

Predicts how a chemicals structure will interact with a biological system

Toxicology (definition)

The qualitative and quantitative study of the adverse or toxic effect of substances on organisms

Hazard (definition)

The potential for harm under specific conditions of use or exposure. Hazard considers both toxicity and likelihood of exposure

Risk (definition)

The likelihood of being harmed, taking into consideration the degree or nature of exposure to the hazard and how serious the consequences might be. (Risk is context-dependent and often expressed as a combination of severity and likelihood.)

Xenobiotic (definition)

a foreign substance taken into the body, may produce beneficial effects (such as pharmaceuticals) or they may be toxic (such as lead)

Toxic agents (definition)

is a general term for any material that can cause a harmful effect in a biological system. May be chemical, physical, or biological in nature.

Toxicants (definition)

substances producing adverse biological effects, generally main product or a by-product of human activity.

Toxins (definition)

peptides or proteins produced by living organisms. (e.g. venoms)

Potential toxic agents (examples)

Therapeutic agents (overdose), industrial chemicals, household chemicals (e.g. cleaning agents), environmental contaminants

What effects toxicity?

Substance (inherent chemical composition), amount, situation (exposure), timeframe (duration of exposure)

Paracelsus (poisons quote)

All things are poisons, for there is nothing without poisonous qualities. It is only the dose which makes a thing a poison

Exposure (definition)

The amount of toxin in the area

Dose (definition)

The amount of chemical in the body

Dose/exposure (difference)

Exposure is contact with a substance or change in the physical environment, exposure does not always result in dose. (e.g. polluted air is the exposure, amount inhaled is dose)

Acute exposure (timeframe, example)

Within 24 hours, e.g. drug overdose

Subacute exposure (timeframe, example)

Repeated exposure up to one month, e.g. toxic responses to new medicines that occur in the early stages of therapy

Subchronic exposure (timeframe, example)

Repeated exposures 1-3 months, e.g. contaminated drinking water

Chronic exposure (timeframe, example)

3 months or greater, e.g. occupational exposure to chemicals

Local toxicity (definition)

Can be induced upon initial contact with body such as chemically reactive or irritant toxicants reacting with skin

Systemic toxicant (definition)

Affects the entire body or many organs

Dosage (definition)

Expresses the dose in terms of recipient characteristics (body weight/body surface area e.g. mg/kg)

Dose-response relationship

Correlates exposure with changes in body function or health. Generally the higher the dose the more severe the response.

The threshold effect

The lowest dose where an induced effect occurs

The slope for the dose response

The rate at which adverse effects accumulate, indicative of potency

Lethal dose (LD50)

Common dose estimate for acute toxicity in experimental studies. Statistically derived maximum dose at which 50% of the group of organisms would be expected to die

Effective doses (EDs)

Indicate effectiveness of a substance. can refer to beneficial effect or harmful effect. The specific endpoint must be indicated

Toxic dose (TDs)

Doses that cause adverse toxic effects

NOAEL (No observable adverse effect limit)

Highest dose at which there was not an observed toxic or adverse effect

LOAEL (lowest observable adverse effect limit)

Lowest dose at which there was an observed toxic or adverse effect

Potency (definition)

intensity of effect expressed as the dose of the drug/toxicant required to produce a specific effect of given intensity

Efficacy (definition)

Maximum effect that a drug can produce regardless of dose

Therapeutic Index (definition)

Effective dose and toxic dose determines the relative safety of pharmaceuticals. TI=TD50/ED50

Therapeutic index (drawback)

May be misleading depending on the slope of dose-response curves. Low doses may be effective without toxicity however patients may benefit from higher dose despite consequences.

Margin of Safety (MOS)

Calculated as the ratio of the toxic dose to 1% of the population (TD01) that is 99% effective to the population (ED99)

Toxicokinetics (definition)

Deals with absorption, distribution, biotransformation, and excretion of chemicals.

Absorption (definition)

The process by which a chemical enters the body

Distribution throughout the body

Ultimately decides where toxicity occurs, blood serves as the main avenue for distribution. So - toxicity high in tissue, liver, kidney, efficacy low in teeth, eyes

Metabolism (biotransformation)

Conversion of a chemical from one form to another by a biological organism. Majority of substances are metabolised in liver

Metabolism - Phase 1

Oxidation (via cytochrome P450), reduction, and hydrolysis reactions convert parent drug to more polar (water soluble) active metabolites by unmasking or inserting a polar functional group (-OH, -SH, -NH2)

Metabolism - Phase 2

Conjugation - A drug or it’s metabolite is conjugated with an endogenous substance (e.g. glucuronide conjugate) parent drug is made more polar and inactivated by conjugation to functional group.

Metabolism - End point

Water soluble metabolites are excreted through kidneys lungs or skin

Half life (t1/2)

Time required to reduce blood concentration of the chemical to half

Metabolite toxicity

Substances undergo chemical changes within the body that cause toxicity, causes damage to body and biological systems.

Co-exposures (overview)

Potentially toxic chemicals encountered in day to day life that may cause challenges for risk evaluation and basic toxicological research

Toxicogenomics (definition)

Aims to identify and protect subsets of people vulnerable towards toxicity from chemicals or drugs

Polymorphisms

These versions of enzymes cannot properly metabolise toxicants to facilitate their bodily elimination

Polymorphic (example)

ALDH2 enzyme within mitochondria is responsible rfor converting acetaldehyde that forms during alcohol metabolism, allelic variants cause polymorphisms with reduced effectiveness

Allele

variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule

Botulinum toxin (spores)

Heat-resistant and exist widely in the environment. In the absence of oxygen spores germinate, grow, and excrete toxins

Botulism symptoms

Incubation period of 12-36 hours, but can be up to 8 days. Onset time is dose dependent

Botulism (mechanism)

Inhibits acetylcholine released from nerve terminals, SNARE complex does not form. Communication of the nerve cell’s blocked causing paralysis and death

Botulinum Toxin (medical uses)

Can treat eye conditions (blepharospasm, and strabismus), cervical dystonia (neck and shoulder muscle contractions), persistent migraines, cosmetic uses

Paracetamol (pharmacology)

Cmax (peak plasma conc.) occurs ~1 hour post administration. Half life (at therapeutic dose) 2-4 hours.

Paracetamol (metabolism)

10% oxidised by phase 1 Cytochrome P450 reactions, further neutralised by glutathione. 90% inactivated in liver. Non-toxic products excreted in urine.

Paracetamol (toxicology)

Oxidised by CYP P450 resulting in large quantities of NAPQI being formed resulting in toxic reactions with proteins and nucleic acids.

Examples of agonists found naturally in the body

Histamine, oestrogen, testosterone, and adrenaline

Salbutamol (medical use)

Agonist used to treat asthma attacks where the bronchial tube is inflamed and the smooth muscle on the bronchial tube is tightened and restricted

Salbutamol (mechanism)

Acts on the beta-2 receptor which leads to relaxation of the smooth muscle in the bronchial tube

Mepyramine (medical use)

Antihistamine used to treat allergies

Mepyramine (mechanism)

H1 blocker, binds to the receptor better than histamine (Acting as an antagonist)

Beta Blockers

Beta-1 antagonist for heart arrhythmia

Stomach ulcer treatment

Antagonist of Histamine H2 receptors

High blood pressure treatment

Antagonist of angiotensin II receptor

Heart attack treatment

Antagonist of purinergic (P2Y12) receptor on platelets. Inhibits platelet aggregation

Ozempic (semaglutide)

Binds to and activates the GLP-1 receptor

Analogues (definition)

Compounds that have a structure similar but differ

Analogues (examples)

The pill is an analogue of oestrogen and progesterone that get broken down by the body less

Enzyme inhibitor (example)

Aspirin - acetyl salycilic acid. Affects the COX enzyme preventing it from turning into PGH2 which then becomes TXA2 and PGE

PGE2 (overview)

Prostaglandin involved in inflammation, mediated by COX-2

TXA2

Prostaglandin li,e product involved in platelet aggregation during clotting

ACE (Abbreviation)

Angiotensin converting enzyme inhibitor

REN

Renin angiotensin system regulates your blood pressure

ACE enzyme (function)

In your lungs converts the precursor Ang I to Ang II

Angiotensin (function)

Causes vasoconstriction of blood vessels and increase in blood pressure, increased sympathetic activity, and aldosterone secretion (manages sodium and water concentration)

ACE Inhibitor (function)

Inhibits ACE enzyme in order to reduce high blood pressure

ACE Inhibitor (discovery)

Brazilian pit viper has a venomous peptide that severely lowers blood pressure in order to kill it's victim

Enzyme inhibitor (examples)

Statins, sildenafil (viagra), nevirapine, penicillin

Statins (overview)

Lowers cholesterol and prevents heart attacks

Sildenafil (overview)

Viagra, inhibits the enzyme which breaks down cGMP. Designed as heart medication however found to have effects on ED

Nevirapine (overview)

non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Used to treat HIV and AIDS

Penicillin (overview)

Created by Alexander Fleming. Kills bacteria through binding of the beta-lactam ring to DD-transpeptidase inhibiting it’s cross-linking activity and preventing new cell wall formation (making the bacteria vulnerable)

Transporter

Protein that helps move molecules across a membrane in or out of the cell. Well defined (NOT a pore), actively takes the protein and shuttles it across.

Transporter (examples)

Glucose transporters function in liver and skeletal muscle, amino acid transporters in the intestine take amino acids into the body.

Ion channels (overview)

Pore in the membrane (like a door) that allows molecules to move across.

3 primary neurotransmitters that affect mood

Dopamine, norepinephrine/noradrenaline, serotonin/5-hydroxytriptamine