Pharmacology

What is pharmacology

The study of drug action on animals, organs, tissues or cells

How do drugs work

By mimicking or blocking endogenous signalling molecules

What are examples of signals used in pharmacology

• Hormones

• Cytokines

• Growth factors

• Neurotransmitters

• Pheromones

What causes specific effects of drugs

The drugs chemical structure as a result of binding to specific targets

What causes non-specific effects of drugs

The drugs physiochemical characteristics

What are the typical targets of drugs

• Enzymes

• Ion channels

• mRNA, DNA or epigenetics

• Receptors

What chemical bonds are involved in drug action

• Covalent bond

• Ion - ion

• Ion - dipole

• Dipole - dipole

• Hydrogen bond

• Van der Waals

What is affinity

How tightly a ligand binds to receptor

What is specificity

The geometry of a drug

What is LD50

The dose of a drug which kills 50% of recipients when given to them

What is EC50

The concentration of a drug which is 50% effective on its recipients

How is the therapeutic index calculated

LD50 / EC50

What are the principles of mADME

The mechanism of action of

• Absorption

• Distribution

• Metabolism

• Elimination

How do receptors work as drug targets

What are most drug receptors actually receptors of

Endogenous hormones or neurotransmitters

How are receptors specific

Each receptor only recognised a small number of molecules which all have some structural similarity

Is cannabinoids an agonist or antagonist

• Agonist

• Central and peripheral effects depending on orientation

Is histamine an agonist or antagonist

• Antagonist in the gut

• H1 causes smooth muscle cell contraction

• H2 causes parietal cell acid secretion

What are the types of opiod receptors

• δ receptors - hallucinations, agitation

• μ receptors - pain relief, euphoria, respiratory depression, physical dependance

• κ receptors - spinal analgesia, sedation

What is a ligand

A molecule that binds to a specific receptor

What is an agonsit

A molecule that binds to a receptor causing a conformational change that activates a response in the target cell

What is an antagonist

A molecule that binds to a receptors but initiates no response so is inhibitory to agonists

What is efficacy

The ability of a bound drug to activate the receptor and produce a response

How much concentration of a high affinity drug is required

Low concentration of ligand is required before all the receptor binding sites are occupied

What type of processes do agonists typically evoke

• Reception

• Transduction

• Response

What is the reception of an agonsist

• The binding between a signal molecule and receptor is highly
  specific

• A shape change in a receptor is often the initial transduction of the
  signal

• Most signal receptors are plasma membrane proteins

What is signal transduction

• Usually involved multiple steps

• Relay molecules amplify a signal and proves more opportunities for coordination and multiple cellular responses

What are some examples of the end point target of drugs

• Calcium

• An enzyme

• A structural protein

• A transcription factor

What are metabotropic receptors

• G-Protein Couples Receptors

• Single polypeptide

• 7 transmembrane domains

• Ligand binds to either extracellular domain or within transmembrane domain

What are the common G-protein activated enzymes

How do G protein couple receptors work

1. A ligand binds to the GPCR on extracellular side of cell membrane

2. Causes conformational change in GPCR

3. Activates G protein on the inside of the membrane

4. Made of three subunits, alpha, beta and gamma

5. GPCR causes alpha subunit to exchange GDP for GTP activating G protein

6. Gamma and Beta can now interact with target protein in the cell

How many genes code for GPCRs

800 genes which is about 4% of entire mammalian protein coding geonome

How does phosphorylation switch proteins on

1. Signal in on inactive protein

2. Phosphorylation by a kinase enzyme

3. Protein is now active and signal exits

4. Dephosphorylation by a phosphate enzyme

How does noradrenaline cause bronchodilation

1. Noradrenaline binds to beta 2 receptors

2. This activated G proteins which activated adenylyl cyclase

3. Activates cAMP

4. Activates protein kinase A which inhibits MLCK

5. Causes bronchodilation

What are the types of adrenoreceptors and what do they do

• Alpha increase blood pressure and cause bronchoconstriction in the lungs

• Beta 1 increase heart rate

• Beta 2 causes bronchodilation in the lungs

What is the effect of adding an -OH group to noradrenaline

Greater activity of alpha and beta adrenoreceptors

What is a kinase-linked receptor

• An enzyme linked receptor

• Alpha subunit at the binding domain

• Beta subunit at the kinase domain

• Includes insulin-receptor

How do receptor tyrosine kinases work

1. Lignads bind to extracellular ligand binding domains of RTKs

2. Causes receptor monomers to pair up

3. Activated intracellular tyrosine kinase domains

4. Kinase domains phosphorylate each other on specific tyrosine residues

5. Intracellular signalling proteins bind to phosphorylated tyrosines

6. Activate signalling cascade

What are ionotropic receptors

Receptors linked to ion channels which are nicotinic

What are examples of nicotinic receptors

• Cigarettes

• Toxins

• Poisons

What are examples of GABA

• Alcahol

• Sedatives

Are agonists and antagonists reversible

• Agonists are always reversible

• Antagonists can be irreversible or reversible

  • a-bungarotoxin is irreveriable

  • d-tubocurarine is reversible

What are the action of toxins on nicotinic ACh receptors

Block the receptors stopping muscle contractions

How does snake toxin poisoning cause death

1. Blocks nAChR of the mammalian end plate

2. Causes diaphragm paralysis

3. Leads to death

What is the structure of nAChR

5 subunits joined together

How are nAChRs involved in the central nervous system

1. Nicotine rich blood passes from the lungs to the brain within seven seconds

2. Stimulates immediate release of neurotransmitters

3. Responsible for nicotine’s effects

WHat is a GABAa receptor

1. GABA is an agonist

2. An inverse agonist binds to the agonist site and has the opposite effect to the agonist

3. Instead of enhancing GABAs inhibitory effect it reduces the activity of the GABA receptor

What is an allosteric modulator

Binds to a receptor on an allosteric site and changes the activity of the agonist

What are intracellular receptors

• Typically steroid hormones

• Hormones cross plasma membrane to bind to cycoplasmic receptors

• This alters receptor conformation so it no longer binds inhibitor

• Translocates to nucleus

• Binds to DNA turning on transcription

• Causes change in gene expression

What do transporters move across membranes and how

They move ions and chemicals against their electrochemical gradient using energy from ATP or ion gradients

Give an example of a drug that blocks a transporter

Digoxin blocks the Na+/K+ ATPase

How do tricyclic antidepressants and SSRIs affect monoamine transporters

• Tricyclics block reuptake of noradrenaline and serotonin

• SSRIs selectively block serotonin reuptake

Which neurotransmitter system is most linked with aggression according to transporter pharmacology

The serotonin system and low serotonin turnover is associated with increased aggression

What role to MAO inhibitors play in neurotransmitter regulation

They prevent the breakdown of monoamines like serotonin and dopamine, increasing their availability

What is an example of a calcium channel blocker and its clinical use

Verapamil used for hypertension, angina and arrhythmias

What ion channels do local anaesthetics like lidocaine block

Voltage gated sodium channels

What is the use of sulphonylureas and what channels do they block

Used as an anti-diabetic drug which block potassium channels in pancreatic beta cells

Why are local anaesthetics sometimes combined with vasoconstrictors

To prolong their effect by reducing systemic absorption

What are the characteristics of some local anaesthetics

• Procaine - sort duration, poor tissue penetration

• Lidocaine - moderate toxicity, fast onset

• Mepivacaine - longer duration

• Bupivacaine - high toxicity, very long duration

What type of inhibition does aspirin perform and on which enzyme

Irreversible, non-competitive inhibition of cyclooxygenase

Name two modern COX-2 selective NSAIDs used in veterinary practice

Firocoxib and Robenacoxib

What enzyme is targeted in the treatment of myasthenia gravis

Acetylcholinesterase, inhibited by neostigmine and edrophonium

What is the mechanism of neostigmine in myasthenia gravis

It inhibits acetylcholinesterase, increasing ACh levels at neuromuscular junctions

What is Michaelis-Menten

The binding of a drug to a receptor follows the same kinetics as an enzyme reaction

What does the Michaelis-Menten curve look like

How do high and low affinity drugs differ on the Michaelis-Menten curve

How do drugs with high and low efficacy appear on the Michaelis-Menten curve

Calculate EC50 by taking the log and reading at 50% response

How do competitive antagonists effect the Michaelis-Menten curve

Causes parallel shifts

How do non-competitive antagonists effect the Michaelis-Menten curve

What factors effect drug absorption from the site of administration

• Physical and chemical properties

• Dosage form

• Route of administration

What are the main routes of drug administration

• Oral

• Intravenous

• Intramuscular

• Subcutaneous

• Inhalation

• Topical

Which route of drug administration bypasses the absorption phase

Intravenous administration

What is bioavailability

The fraction of an administered dose of a drug that reaches systemic circulation in an active form

What is the first-pass effect

The metabolism of a drug in the liver after oral administration and before it reaches systemic circulation

What is the main barrier to drug absorption in the GI tract

The lipid bilayer of epithelial cells

What properties of a drug favour passive diffusion across cell membranes

• Lipid solubility

• Non-ionized state

• Small molecular size

What determines the ionization state of a drug

The drugs pKa and the pH of the surrounding environment

What is the Henderson-Hasselbalch equation used for in pharmacology

To determine the degree of ionization of a drug at a given pH

What is drug distribution

The reversible transfer of a drug from the bloodstream to tissues and organs

What factors influence drug distribution

• Blood flow to tissues

• Drug binding to plasma proteins

• Capillary permeability

• Lipophilicity of the drug

What is the volume of distribution

A theoretical volume that relates the amount of drug in the body to the concentration of drug in the plasma

What does a high volume of distribution indicate

Extensive distribution of the drug into tissues

What does a low volume of distribution indicate

The blood in mainly confined to the plasma

How does plasma protein binding affect distribution

Only free unbound drug is active and can cross membranes, binding slows distribution and elimination

Which proteins commonly bind drugs in plasma

Albumin (acidic drugs) and α1-acid glycoprotein (basic drugs)

What is redistribution of a drug

The movement of a drug from one tissue to another affecting drug action duration

Why is the blood-brain barrier significant for drug distribution

It restricts drug entry to the CNS due to tight junctions and efflux transporters

What is meant by perfusion limited distribution

When a drug distribution is determined by blood flow

What is permeability limited distribution

When a membrane permeability limits drug entry into tissue

What is a prodrug

An inactive drug that requires metabolism to become active

What are the two phases of drug metabolism

• Functionalisation reactions

• Conjugation reactions

What is the main purpose of functionalisation reactions in drug metabolism

To introduce or expose a functional group to make the molecule more polar

Name some examples of functionalisation metabolic reactions

• Oxidation

• Reduction

• Hydrolysis

Which enzyme family is most involved in functionalisation oxidation reactions

Cytochrome P450 enzymes

What is the main purpose of conjugation reactions in drug metabolism

To conjugate the drug with a polar molecule, increasing water solubility for excretion

Give examples of conjugation reactions in phase II metabolism

• Glucuronidation

• Sulphation

• Acetylation

• Methylation

• Conjugation with amino acids

• Conjugation with glutathione

Where do most drug metabolism reactions occur

In the liver

What is an example of a drug that undergoes significant first-pass metabolism

Morphine

What is enzyme induction drug metabolism

When a drug increases the activity or amount of metabolising enzymes, accelerating metabolism

What is enzyme inhibition in drug metabolism

When a drug reduces the activity of metabolising enzymes, slowing down metabolism