PBL 7: Gavin Lee -Drug Overdose

Question 1

Enzymes

Answer 1

Drugs that bind to the active site and cause a conformational change

Question 2

Steroid Drugs

Answer 2

Lipid Soluble and pass easily through the membrane to effect DNA

Question 3

Ligand-Gated Ion Channels

Outline

Time Scale

Examples

Answer 3

Outline: Ligand binds to receptor on cell membrane causing hyperpolarisation or depolarisation which then exert a cellular effect.

Time Scale: milliseconds

Examples: Nicotinic Receptors, ACh Receptors

Question 4

G-Protein Coupled Receptors

Outline

Timescale

Examples

Answer 4

Outline: molecule binds to receptor on extracellular side of transmembrane protein, causing dissociation between subunits that activated second-messenger cascade. May cause, Ca²⁺ release, Protein phosphorylation or other cellualr effects.

Time Scale: Seconds

Examples: Muscarinic Ach receptor

Question 5

Kinase-linked receptors

Outline

Timescale

Examples

Answer 5

Outline: molecule binds to receptor causing protein phosphorylation that leads to gene transcription, protein synthesis thus exerting cellular effects.

Timescale: Hours

Example: Cytokine receptors

Question 6

Nuclear Receptors

Outline

Timescale

Examples

Answer 6

Outline: Receptors within the nucleus which promote gene transcription. This leads to protein synthesis and exerted cellular effects.

Timescale: Hours

Example: Oestrogen Receptor

Question 7

What receptors are required for Peptide drugs and Hormones?

Answer 7

Surface protein remember on the cell membrane

Question 8

What are competitive antagonists?

Answer 8

Molecules that compete with the agonist for the binding site on the receptor

Question 9

What effect does the competitive antagonist have on V_MAX (efficacy)

Answer 9

Does not change the Vmax of the drug

Increasing [agonist] can overcome effects of the antagonist

Question 10

How strong is competitive antagonist receptor binding?

Answer 10

Weak

Question 11

How do competitive antagonists effect the dose/response curve?

Answer 11

Shift to the RIGHT

Question 12

What is an example of a competitive antagonist?

Answer 12

Naloxone

Question 13

How do Irreversible Antagonists bind to receptors and what is the strength of the bond

Answer 13

Covalent bonding (very strong)

Question 14

How do Irreversible Antagonists effect the dose/response curve?

Answer 14

Reduces efficacy and potency (curse shift DOWN and RIGHT)

Question 15

What is an example of an Irreversible Antagonist

Answer 15

Aspirin

Question 16

What is an example of a Partial Agonist

Answer 16

Methadone on opiate receptors.

Question 17

Define ED₅₀

Answer 17

The potency of therapeutic effect

Question 18

Define TD₅₀

Answer 18

The potency of toxic effect

Question 19

Define LD₅₀

Answer 19

Potency of lethal effect

Question 20

What is the therapeutic index?

Answer 20

Therapeutic Index = TD₅₀ / ED₅₀

The ratio between the toxic and the therapeutic dose for half the population

A high TI means you can give more drug without being too concerned about toxicity.

Question 21

Recognize that drugs may behave as reversible or irreversible competitive antagonists of receptors for endogenous ligans

Answer 21

Recognize

Question 22

Define Bioavailability

Answer 22

The fraction of dose which reaches the systemic circulation as an intact drug

Question 23

How do we calculate bioavailability?

Answer 23

F = F_g x F_H

F_g = absorbed in GI tract

F_H = fraction escaping liver (1-E_H)

E_H = fraction metabolized by liver (CL_H/Q_H)

Question 24

Hepatic First Pass Clearance

Answer 24

The extrent to which a drug is removed by the liver on first passage in the portal blood through the liver to the systemic circulation

Question 25

Intravenous Bioavailability

Answer 25

IV has a bioavailability of 1 as the drug enters the systeming circulation immediately without being subject to hepatic first pass clearance

Question 26

Factors affecting Oral Administration bioavailability

Answer 26

1. Absorption into GI 2. Size, shape and charge alteration 3. Subject to hepatic first pass clearance 4. Renal Clearance

Question 27

V_D

Answer 27

V_D = Total drug in the body / blood plasma concentration The concentration of drug in the blood compared to total amount of drug in the body.

Question 28

Clearance (CL)

Answer 28

The rate at which a drug is irreversibly metabolize/removed from the body (volume per unit time). CL_sytemic = CL_renal + CL_hepatic

Question 29

Half-Life

Answer 29

The time taken for the concentration of a drug to fall by half of its current concentration 1. Duration of action after a single dose 2. Time required to reach staeady state with chronic dosing 3. Dosing frequency required to maintain steady state concentrations in plasma

Question 30

Elimination half-life

Answer 30

t^1/2 = 0.693 x V _{_____________ CL}

Question 31

Steady State

Answer 31

A balance of drug input with drug clearance, achieved after 3-5 half-lives

Question 32

Q_H

Answer 32

Hepatic Blood Flow Assume (healthy) Q_H = 90L/h

Question 33

E_H

Answer 33

Hepatic extraction ratio Concentration of blood entering - Concentration of blood leaving / concentration of blood entering E_H = CL_H (Hepatic Clearance) / Q_H

Question 34

High Hepatic Drug Clearance

Answer 34

\>0.67 Major determinant is Blood Flow

Question 35

Low Hepatic Drug Clearance

Answer 35

\<0.2 1. Intrinsic clearance (enzyme activity) 2. Fraction of unbound drug in the blood - F_U

Question 36

Drug Elimination for single dose oral administration

Answer 36

1. Dose is given 2. The administered dose x F_g = dose entering portal blood 3. Hepatic first pass dose in portal blood x (1-E_H) = dose entering arterial blood 4. Each half-life circulating dose decreases by half: (circulating dose = CL_S)

Question 37

Drug Elimination time course for single dose IV administration

Answer 37

1. Dose administered 2. Dose administered enters arterial circulation 3. Each half-0life circulating dose decreases by half (circulating dose - CL_S)

Question 38

Which receptors do Opiods bind to that primarily effect respiration?

Answer 38

1. μ₂ receptors

Question 39

What affect does μ₂ receptor binding by opiates have on the Central Respiratory Center of the Medulla?

Answer 39

1. Decreases sensitivity to PCO₂ resulting in reduced firing from the repiratory centre for a given PCO₂ LOWERS pO₂ and RAISES pCO₂ which gives HYPOXIA 1. Lowers firing of respiratory neurons and Recruitment of respiratory muscles Therefore lowers **VENTILATION** LOWERS pO2 and RAISES pCO2 which gives HYPOXIA

Question 40

What affect does μ₂ receptor binding have on the Pre-Botzinger Complex Activity?

Answer 40

Decreases Activity leading to 1. Decreased firing of respiratory neurons 2. Decreased recruitment of respiratory muscles Therefore reduced **VENTILATION** LOWERS pO2 and RAISES pCO2 which gives HYPOXIA

Question 41

What does Hypoxia stimulate?

Answer 41

The Hypoxia ventilatory response

Question 42

How does opiod receptor binding affect peripheral sensitivity to PO₂

Answer 42

Lowers

Question 43

Why can't the Hypoxia ventilatory response compensate for hypoxia?

Answer 43

Reduced peripheral sensitivity to PO₂ inhibits the response Unable to normalise PO₂ and PCO₂ due to reduced sensitivity of central and peripheral chemoreceptors.

Question 44

What are the 3 major effects of Opiod μ2 receptor binding on control of respiration?

Answer 44

1. Decreased sensitvity to PCO₂ in the Central Respiratory Center 2. Decreased activity of the Pre-Botzinger Complex 3. Decreased Peripheral sensitivity to PO₂