PHAR 100

Ancient Greece Influence

Opium (pain relief) obtained from the Opium poppy

contains morphine (10%) and codeine (0.5%)

Egypt Influence

Purgatives which aid bowel movement 

Chine Influence

Ephedrine to treat asthma isolated from Ma Huang

Curare

Plant derived drug used by Indigenous people dipped in arrow for hunting to cause paralysis

eventually as anesthetics since its causes muscle relaxation

Ergot

Poisonous fungus that grows on heads of rye

Peyote

causes hallucinations, a feeling of well-being and distortion of perception

Ancient Roman Medicine

Zinc oxide

what is a drug?

any substance received by a biological system that is not received for nutritious purposes and which influences the biological function of the organism

Drugs acting on the brain

Alter the normal chemical signalling in the brain (e.g LSD)

Drugs Acting Against Infectious Disease

Any disease caused by an organism such as bacteria, viruses, fungi, or parasites

E.g cure for syphilis

Drug Development Process

basic research and drug discovery

preclinical trials & clinical trials

Health Canada review and manufacturing

post-market surveillance

phase IV clinical trials

Basic Research and Discovery of the Target

Identification of the target

Studying the target

Efficacy

the max. pharmacological response produced by a specific drug in that biological system

Preclinical studies

Conducted prior to testing the new drug, range from molecular and cellular studies to tissue and whole animal studies

Two main categories: pharmacology studies and toxicology studies

Clinical trials

3 steps: proof of safety, methodology, investigation

Phase 1 CT

one or two doses of the new drug is tested to determine its tolerability

Limited number of healthy volunteers (20-80)

Efficacy of the drug is not yet assessed

Evaluate the drug’s absorption, distribution, elimination + adverse effects

Phase 2 CT

looks to determine whether the drug is effective in treating the condition it's recommended for – looking at efficacy

A limited number of people (100-500), in patients with the diseases for which the drug is intended to treat

Safety of the drug is held important

Phase 3 CT

aka “randomized controlled trials” (RCT)

larger number (usually 1000+) for a more diverse population

determine how safe and effective the drug is compared to placebo/no treatment/the current recommended therapy

months to years, longer than phase 2 studies

multi-centred (centres in many cities) to ensure diversity of patients and a good sample size

Cost – 1 million to upwards of 50 million dollars, the most expensive part of drug development

Stages of Phase 3 trials

Enrollment, inclusion/exclusion criteria, consent, treatment allocation (double blind, randomized), control drug (placebo/gold standard), results

Factors influencing phase 3 clinical trial interpretation:

compliance

quality of life

statistics

Bioequivalence

two drug products with the same active ingredients are essentially interchangeable

Health Canada review and manufacturing

manufacturer will submit detailed results of clinical trials

reviewed by scientists

generic name for drug selected

Post-market surveillance and phase IV clinical trials

Accounts for risks that may be missed in phase 3 trials if they occur in rare instances (less than 1 in 1000)

Receptors

molecule/complex of molecules outside or inside a cell with a regulatory/functional role in the organism

Normally bound to + activated by endogenous ligands (substances found in the body, i.e. hormones and neurotransmitters)

Agonists

drugs that bind to and stimulate a receptor

Antagonists

drugs that bind to but block the response at a receptor

Ligand

signalling molecule that binds to the receptor

most drugs mimic/block the effect of the endogenous ligand at the receptor

Lock and key analogy

receptor = lock, drug = key

Antagonist does not have the same compatibility of fit, so it binds to the receptor but doesn’t activate it (key can fit but can’t open the lock)

Dose-response relationship

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

Low dose

not many receptors being activated → very little response

Threshold (as dosage increases)

more and more receptors are activated until→ desired response is seen

At the threshold

small dosage increase → large increase in response

Once the maximal effect is reached

increasing the dosage will have no further increase in the therapeutic response

Dose-response curve

x-axis = log dose, y-axis = percent response

Percent response is at a max of 100%

As you increase the dose of a drug, you will get a proportional increase in that response

Threshold effect

you need a certain amount of drug binding to/activating a certain number of receptors in order to start seeing a response in the body

ED50

effective dose 50, or the 50% mark in a human body (the does giving you 50% of a response in an individual, or the dose that is effective in 50% of the population)

Potency

drug dosage required to be given in order to obtain a specific response.

Therapeutic range

Drugs are administered to achieve a therapeutic effect

Aim of therapy: give a dose that keeps the [blood] of a drug above the [minimum]that produces the desirable response but below the concentration that produces a toxic response

(duration of action).= therapeutic range

The wider the therapeutic range, the safer the drug.

Pharmacokinetics

The drug must reach the cellular site of action at the right concentration exert its effect be removed from the body

Parts of pharmacokinetics

Absorption

Distribution

Metabolism

Excretion

Topical

drugs applied directly to a particular place on/in the body through the skin

Enteral

administration via the GI tract via the mouth/artificial opening

e.g mouth, rectum

Parenteral

administration bypassing the GI tract (Intravenous)

Intramuscular

Drug injected deep into a muscle

Subcutaneous

Drug injected into the deepest skin layer

Bioavailability

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

Absorption

The movement of a drug from the site of administration into the blood

Must be able to cross biological membranes (from the lumen to interstitium

Steps of Absorption

diffusion through aqueous pores

diffusion through lipid bilayer

active/carrier-mediated transport

Distribution

The movement of a drug from the blood to the site of action and other tissues

How can distribution terminate the therapeutic effect of some drugs?

To compensate for a high concentration of a drug in the blood, the concentration of the drug in muscle and fat will increase – causing the concentration in blood to decrease.

As a result, the drug leaves the target area and moves into the blood.

Metabolism – (aka biotransformation)

The conversion of a drug to a different chemical compound in order to eliminate it

Metabolites

products of metabolism that are usually devoid of pharmacological action

P450

enzymes able to biotransform drugs

Present in high concentrations in the liver

Excretion - kidneys

how the majority of drugs are eliminated

Drugs of sufficient water solubility will be excreted in the urine

Lipid-soluble drugs can be reabsorbed from the kidney back into the blood

Excretion - GI tract

can excrete some drugs after they undergo biotransformation in the liver(i.e. in feces)

Excretion - lungs

can excrete drugs that are volatile/in a gaseous form (alcohol, gaseous/anesthetics, etc.)

Half-life

the time needed for the liver and kidney to remove half the drug from the body

Adverse effects on drugs

Extension of therapeutic effect

Unrelated to the main drug action

Allergic reaction

Withdrawal and addiction

Teratogenesis

Adverse biotransformation reaction

Predicting adverse drug reactions

Rarity of occurrence

Length of usage

Detectability in animals

Time period specificity

therapeutic index

TI = TD50/ED50

Drug-drug interactions

Occurs when one drug changes the pharmacological effects of a second drug

Drug-food interactions

Involve the interference of food with drugs taken concurrently

e.g. Tyramine and grapefruit

Cerebral cortex (cerebrum)

sensory and motor coordination, mental processes, intelligence, memory, vision, judgement, thought, speech, emotions and consciousness

Limbic system

Region of brain that integrates memory, emotion and reward

With hypothalamus, controls emotion and behaviour

Contains dopaminergic reward centers; targets for commonly misused drugs and are associated with addiction

neurons

Functional unit of brain

Nerve cell capable of generating and transmitting electrical signals

Neurogenesis

process of continuously generating neurons

Neuroplasticity

connection between neurons is constantly being reshaped

Dendrites

Short, highly complex branching patterns

Receiving antennae for incoming info and accept info through receptors in membranes

After receiving info, electric current is generated and directed down the neuron

Cell body

Large, contains nucleus and cytoplasm

Cytoplasm contains abundant pre-packages neurotransmitters which can be secreted

Axon

Single fiber extending from the cell body and ending at the synapse

Continues to carry info away from dendrites and cell body by way of electrical pulses

Info is then passed on to subsequent neurons

Synapse

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

Synapse ; junction between two neurons

Area where on neurons axon ends and another neurons dendrite or cell body begins

Synaptic transmission

passage of signal from one neuron to another neuron

Aka neurotransmission

Neurotransmitters

endogenous chemicals that transmit a signal between two neurons

Drugs effect on synaptic transmissions

Synapse can be a target site for drugs, with some drugs interrupting synaptic transmission, whereas others enhance or facilitate it, thereby modifying the activity of the brain

Glutamate

Primary excitatory neurotransmitter in CNS, found in almost all neurons-

Acts on a family of receptors called the glutamatergic receptors

Catecholamines

Dopamine ; control of hormonal systems, motor coordination, and motivation and reward, thought to be involved in addiction

Norepinephrine ; can bind to large number of receptor types (mostly alpha and beta classes), activation of these receptors usually leads to excitation of the cell

GABA

Primary inhibitory neurotransmitter in the CNS

Many CNS depressants enhance GABA receptor function

Opioid peptides

Three main classes;

enkephalins, endorphins, and dynorphins

Opioid receptors

mu, delta, kappa

All opioids interact with these receptors

What is SUD?

must meet 2 criteria: Social Impairments, Risky use, Impaired control, withdrawal, tolerance

The Dopamine Hypothesis

suggests that commonly misused drugs increase dopamine in the reward systems of the brain

Characteristics of Addictive Drugs

Increase dopamine, produce novelty, reduce anxiety

Drug Withdrawal

abnormal physiological state produced by repeated administration of a drug

How would the dose-response curve shown in the figure change after drug tolerance has developed?

The biological system accommodates to the presence of the drug, as indicated by the rightward shift of the dose response curve

Cross Tolerance

resistance or tolerance to one drug because of the resistance or tolerance to a pharmacologically similar drug

Factors Influencing SUD

Genetic Factors

Pre-existing Disorders

Environmental Factors

Developmental Factors

Potential for Misuse of a Drug Factors

Nature of the drug, route of administration, amount/freq of use, availability, inherent harmfulness

Methylphenidate (Ritalin)

Used to treat attention deficit hyperactivity disorder (ADHD)

MDMA (ecstasy)

A derivative of methamphetamine

fosters the feeling of intimacy and empathy, while improving intellectual capacities

is neurotoxic, causing neuronal damage and death

Amphetamines: CNS Effects

it is a CNS stimulant

1. A decreased threshold for transmitting sensory input to the cerebral cortex, leading to C N S excitation.

2. A feeling of euphoria and reward.

3. Temperature-regulation and feeding centre modifications leading to appetite suppression.

4. An increase in aggressive behaviour and mood swings

What effects do you anticipate will be associated with increased C N S excitation?

Increased C N S excitation will lead to increased alertness, a feeling of power, reduced fatigue, and increased responsiveness. It will also result in increased heart rate and blood pressure

Amphetamines Effects of Short-Term Use

Chest pain (i.e., angina) or heart attack

Cardiovascular collapse

Increased respiratory rate

Overdose may result in a seizure, high fever, or stroke.

Amphetamines Effects of Long-Term Use

Chronic sleeping problems

Poor appetite

Anxiety, repetitive behaviour, psychoses, aggressive behaviour

Elevated blood pressure and abnormal cardiac rhythm

Therapeutic Use of Amphetamines

Narcolepsy, ADHD, Methylphenidate (Ritalin)

Amphetamines: Potential for Misuse

extremely high, injectable, resulting in a rapid and intense response

Amphetamines Potential for SUD - TOLERANCE

develops to the euphoria and mood elevating effects, the anorectic effects, the cardiovascular and respiratory stimulatory effects, and the lethal effects of the drugs

Amphetamines Potential for SUD - WITHDRAWAL

results in mood depression that may be profound, prolonged sleep, huge appetite, lack of energy, and fatigue

Amphetamines Potential for SUD - ADDICTION

usually self-administered to produce euphoria and an abrupt awakening sensation (“rush”)

Pharmacology of Cocaine

local anesthetic and as a CNS stimulant

Cocaine Duration of Action

short, usually less than an hour, compared to up to 12 hours with amphetamines