APC1 - intro to Pharmacology :how drugs work

Pharmacology vs pharmacy vs toxicology

Pharmacology: The science

- how drugs affect living systems ,mechanisms interactions,

Pharmacy : The profession

- apply drug knowledge ,dispensing ,how to help science to practice

Toxicology: Understandong harm

-adverse affects and poisoning ,dosage harm, essential for safe practice

What is the brief history of drugs overtime?

1.Traditional medicine era

-empirical use- works don't know why

-natural products ( narrow therapeutic wndow)

-trial and error

2. Revolution of isolation

- active ingredients identified

- to help with doses ,understanding

3. Age of synthesis

- modifying natural products by adding groups

-aspirin

creating new molecules

-start of pharmaceutical industries

What is the modern pharmacology approach ?

empiricism to rational design :

-understanding mechanisms eg.receptor theory ,enzyme inhibition ,link between structure and function

NOTE - GO FROM WHAT WORKS TO Designed to work (personalised medicine lukemia )

What is Pharmacology?

The study of drug effects on living systems

•Encompasses beneficial AND harmful effects

•Studies mechanisms at all levels (molecular to whole body)

•Bridges chemistry and biology

What are the two main Branches ?

·Pharmacokinetics:

What the body does to the drug

-Absorption, Distribution, Metabolism, Excretion

-Determines drug concentration at site of action

·Pharmacodynamics: What the drug does to the body

-Mechanism of action

-Drug-receptor interactions

-Dose-response relationships

( concentration effect)

Why is Pharmacology important ?

●Balance between therapeutic and toxic

plays a key part in :

A-how enters body

D-where and how it goes around the body

M-how it is broken down

E- how it leaves body

What is a drug?

Any substance that, when administered to a living organism, produces a biological effect

What are key characteristics of a drug ?

·External origin (not normally made by body)

·Specific interaction with biological system

·Measurable effect on function

·Given with intent (therapeutic, diagnostic, preventive)

What helps to distinguish drugs from other products?

·Foods: Primary purpose nutrition vs therapeutic effect

·Cosmetics: Surface action vs systemic effects

·Devices: Chemical vs physical/mechanical action

·Poisons: Intent and dose considerations

What makes a good medicine ?

1.Selectivity

Acts on intended targets more than others

Reduces unwanted effects

Challenge: Similar proteins throughout body

2.Appropriate pharmacokinetics

Reaches target site

Suitable duration of action

Predictable elimination

3.Safety margin

Therapeutic dose well below toxic dose

Allows for individual variation

Room for dosing errors

4.Stability

Chemical stability for storage

Metabolic stability for duration

Formulation compatibility

What are other characteristics that make a good medicine and why?

●Medicine vs drugs -has selectivity but drugs have specific purpose

●Last for an appropriate time - no point if destroyed by body

●Narrow safety margin -careful monitoring as it is potent ,therapeutic input

●No accumulation = side effects

How do drugs produce their effects?

-most bind to proteins : receptors, enzymes ,ion channels ,transporters

-non-protein targets - dna/ rna(anti cancer drugs),replacement therapy, gene therapies

Why is binding usually reversible ?

·Allows control of effect duration

·Enables dose adjustment

·Exceptions exist (e.g., aspirin contrast with ibuprofen both target same enzyme (ib =irreversible)

What does drug effects depend on ?

1) Drug concentration at target site

2) Affinity for target 3)Intrinsic activity (if receptor)

how and why are drugs selctive?

1.Molecular recognition

-3d shape ,induced fit, small changes have big effects

2.Chemical complementarity

- charge distribution, hydrophobic/hydrophilic regions ,hydrogen bonding patterns

3.Binding forces

-sum of weak interactions= specificity ,usually reversible

4. Selectivity vs specificity

-no drug completely specific - can bing =d to similar proteins =side effects

How do drug receptor interactions work?

Induced fit

·Both drug and target can adjust shape as a response to each other

·More dynamic than rigid lock/key

Allows fine- tuning of selectivity

What are some types of drug action at receptors?

·Agonists: Activate the receptor

·Antagonists: Block the receptor

·Partial agonists: Partial activation

·Inhibitor: Blocks Enzymes

What factors Affect drug reponse ?

Pharmacokinetic factors-ADME

Pharmacodynamic factors -receptors density ..

Pharmocogenomic factors- genetic variation ,fast/slow metabolism

external - diet other meds

environment

Patient factors- age

,gender,genetics ,body composition

Why do mechanisms matter?

-Same biological effects but different clinical uses

-rational prescribing

-understanding interactions

-managing side effects

What are the basic principles of dose-response realationship?

●Dose -response mathematical relationship

●Graph -sigmoid curve ,horizontal =dose vertical - response(cells)

●Plateau maximum effect of drug because saturated targets

●Max effect -limited by receptors

●

●Some drugs can have a ceiling effect -paracetamol large safety margin but wont really relive pain if dose is increased - low efficacy

●More potent - low dosage best effects

●Why? due to biological pathways it takes

What are the key term definitions for potency ?

Measures of Potency (half-way up the curve):

•EC50 (Effective Concentration 50): The drug concentration that produces 50% of the maximum response (lab based)

•ED50 (Effective Dose 50): The dose that produces a therapeutic effect in 50% of the population (Patient)

What are the key term definitions for efficacy ,e max definitions ?

Efficacy & Emax Definition (Top of the curve):

•Efficacy: The maximum response a drug can produce, regardless of dose

•Emax: The maximum effect on the dose-response curve (same as efficacy)

What are the key term definitions for toxixity and td50 ?

Toxicity & TD50 Definition:

•Toxicity: Harmful effects produced by a drug, usually at higher doses than therapeutic doses

•TD50 (Toxic Dose 50): The dose that produces toxicity in 50% of the population

How do you calculate therapeutic index?

Therapeutic index = ED50 / TD50