Pharmacology

What is pharmacology?

Science of drugs and how the body interacts with biological systems including cells, organs, humans and animals

Why is pharmacology important?

- The discovery of new medicines
- Improving the effectiveness of medicines
- Reducing unwanted side effects of medicines
- Understanding why individuals differ in the way they respond to certain drugs, and why some others cause addiction

Why is pharmacology important for paramedics?

- Administering drug therapy in high pressure situations
- Administering medicines from cradle to grave
- Numerous physiological changes occur throughout the age range
- This can affect how the body handles a medicine
- Autonomous decision making

What is pharmacokinetics?

Study of the effects of the drug on the body and how the body absorbs, distributes, metabolises and eliminates drugs; and the calculation of the rates of these processes to assess drug action.

What is pharmacodynamics?

Study of the effects of drugs on the body and their mechanisms of action and the relationship between drug concentration and effect

What is a drug?

Any man-made, natural, or endogenous (within the body) molecule which exerts a biochemical and/or physiological effect on the cell, tissue, organ, or organism

What is a medicine?

A drug or other preparation used in the treatment, cure, prevention, or diagnosis of disease or used to otherwise enhance physical or mental well-being.

Methods of drug administration

- Parental
- Enteral
- Topical

What is the pathway of drugs through the body?

ADME
- Absorption
- Distribution
- Metabolism
- Excretion

Why is absorption essential in the body?

For delivery of drugs into the body

Where does the drug go once it has been absorbed?

- Travels through portal vein into the liver
- This occurs before the drug enters the circulation and undergoes first pass metabolism

What is first pass metabolism?

Metabolism of drugs by the liver and gut wall that are absorbed orally and this accounts for their bioavailability

What is bioavailability?

The fraction of orally administered drug that enters the circulation intact and available to have its desired effect

What type of administration has 100% bioavailability?

IV

What is the process of first pass metabolism?

- After a drug is ingested, it is absorbed by the digestive system and enters the portal circulation
- The absorbed drug is carried by the portal vein into the liver
- The liver is responsible for metabolising many drugs
- Some drugs are so extensively metabolised by the liver that only a small amount of unchanged drug may enter the systemic circulation

Why does IV administration have 100% bioavailability?

As it is administered directly into circulation system and bypasses liver

When would you use IV route in preference to the oral route?

- Drugs that do not cause local tissue damage
- For drugs that are infused in small volumes
- When a rapid effect is required
- Drugs that require continuous infusion

How do drugs get to the intended target?

- Once absorbed a drug must move to its site of action which is usually in the tissue
- It will target a body compartment

How does a drug move from plasma to tissue?

- Must be 'free' to move
- Must be 'free' to act
- Unbound

What are the limits of a drug moving from plasma to tissue?

- Physical properties of a drug
- Protein binding
- How Lipid (fat) soluble a drug is
- Blood supply to the tissue

Where does metabolism occur?

Liver

What is the aim of metabolism?

Increase water solubility of a drug

What are the 2 phases of metabolism?

- Phase I: Cytocrome P450 Enzymes
- Phase II: Conjugation

What factors affect the rate of metabolism?

- Nutritional status
- Liver disease
- Genetic variation
- Age
- Inhibitors/inducers of CYP450 enzymes

What do cytochrome P450 enzymes do?

- Catalyse the chemical reactions in phase I
- Activity can be increased by inducers or reduced by inhibitors
- Drugs can act as inducers or inhibitors

Give an example of an adverse drug reaction

- Clarithromycin is an inhibitor of cytochrome P450 (CYP3A4)
- Simvastatin is metabolised by CYP3A4
- Clinical consequence of concomitant administration - rhabdomyolysis, kidney damage and death
- Avoid combination

Where does the majority of excretion occur?

- The kidney is responsible for the majority of the excretion of drugs and their metabolites
- Water solubility is a key factor for renal excretion
- Lipid soluble drugs are often reabsorbed in the renal tubules

Where can drugs be excreted from?

- Bile
- Sweat
- Saliva
- Breast Milk
- Lungs

What factors should be considered with renal administration?

- Declines with age so renal excretion of drugs will be reduced
Dose reductions are often required especially for those drugs that are renally excreted such as opioids and benzodiazepines

What is TBW?

Total body water

What percentage of TBW is intracellular and extracellular?

- ICF: 2/3 of TBW
- ECF: 1/3 of TBW

How is ECF divided up?

- 1/4 of ECF is intravascular
- 3/4 of ECF is interstitial

How does water move between body compartments?

Freely by osmosis

What drives the movement of fluids between body compartments?

Concentration of particles in the compartment

How do particles move across cell membranes?

By dissolving in salt or a body protein

How is an IV bolus of water distributed?

Freely to various body compartments in proportion to their percentage of TBW

How long does it take for an IV bolus of water to distribute?

30 minutes

How is in IV bolus of fluids distributed?

Throughout several body compartments so has a large volume of distribution, improving intravascular and extravascular volume

What are drug targets?

Most drug targets are protein molecules and there are approximately 20,000 in the human body

What exceptions are there to drug targets that interact directly with DNA?

- Carcinogens
- Antibacterials
- Antitumour drugs

What are the 4 main drug targets?

- Receptors
- Ion channels
- Carrier molecules
- Enzymes

Why are protein molecules good targets?

- Physiological and biochemical processes rely on co-ordinated communication in the right place and at the right time
- Chemical messengers (chemical transmitters) provide the mechanism for this communication by allowing regulation and internal adjustments
- Chemical messengers include hormones and neurotransmitters
- Sensing proteins such as receptors receive these messages and then elicit a response

What is meant by specificity is reciprocal?

For a drug to be used therapeutically it must act selectively on specific cells and tissues and must show a high degree of binding site specificity

Give an example of a drug that only binds to certain drug targets

- Short acting bronchodilators such as Beta agonists (salbutamol, terbutaline) bind to beta receptors in the lungs
- They do not bind to alpha receptors

What do individual targets recognise?

Only certain classes of drugs and they ignore molecules closely related

What is a receptor?

- A specific protein located on a cell surface or intracellularly
- Senses elements in the body's system of chemical communication

How does a drug bind to a receptor?

- Lock and key mechanism
- Intermolecular forces

In the lock and key analogy, what is the lock and what is the key?

- Lock: receptor
- Key: chemical transmitter

What affects the ability of a drug to bind to a receptor?

- Shape of receptor
- Charge of receptor

What does the effect of the drug after binding depend on?

- How tight it binds (affinity)
- Ability to produce a response (efficacy)

What effects can drugs have on cells?

- Interaction with a receptor
- Block the action of specific enzymes
- Inhibit cell transport mechanisms
- Modifying the cell’s physical or chemical environment
- Act on invading organisms

How are receptors normally stimulated?

By naturally occurring chemical messengers

What can drugs mimic?

Chemical messengers if they fit the same receptor

How do agonists work?

- Bind to tightly to receptors resulting in high affinity
- Produce equivalent response to that of natural messenger resulting in high efficacy

Give an example of an agonist

Salbutamol – beta-2 receptor agonist

How do antagonists work?

- Block the receptor from being activated
- Bind to tightly to receptors resulting in high affinity
- Produce no response and therefore no efficacy

Give an example of an antagonist

Bisoprolol – beta-adrenoceptor antagonist (Beta-blocker)

How do enzymes work?

- The same principle as other drug targets
- Enzymes are responsible for speeding up chemical reactions
- The enzyme binds to a substrate and then breaks this substrate into new molecules
- Inhibiting enzymes can have a profound affect on biochemical pathways

What are examples of enzymes?

- NSAIDs – Ibuprofen – reduce inflammation and pain
- ACE-Inhibitors – Ramipril – reduce blood pressure

Explain reaction of an enzyme

A substrate is broken down into new molecules

Explain inhibition of an enzyme

An inhibitor prevents the enzyme from binding with the substrate and completing the process

Where are neurotransmitters released from?

- Neurones into the synaptic cleft

How do neurotransmitters work?

They will bind to receptors on the postsynaptic neurone and elicit a response of activation or inhibition

What happened to a neurotransmitter after a response is elicited?

It is transported back into the presynaptic neurone by a transporter

What happens when you inhibit the transporter?

Increased neurotransmitter in synaptic cleft which increases binding of receptors on neurone

What is the function of a healthy pancreas, without diabetes?

Insulin secretion results in glucose uptake by cells

What is type 1 diabetes?

No insulin produced by the pancreas

What is type 2 diabetes?

Poor response to insulin

How does insulin work?

- Insulin targets the insulin receptor where it activates it (agonist)
- Glucose channel opens and allows glucose to move into the cell
- Reduces circulatory glucose, possibly leading to hypoglycaemia

What are the other actions of insulin?

- Storage of glucose in the liver
- Inhibiting action of glucagon

What happens to people with type 1 diabetes?

- No insulin is produced by the pancreas so blood sugar rises 
- Cells have no mechanism to take in glucose so no inhibition of glucagon
- Secondary mechanisms for glucose production begin such as fat breakdown, ketone production and DKA

What is the physiological response when the insulin receptors are activated?

Glucose channels open

What is the physiological response when the insulin receptors are bound to by an agonist?

Glucose moves into the cell and blood glucose levels decrease