Pharmokinetics Suliman Ali - PowerPoint Presentation

Slide1

Pharmokinetics

Suliman Ali

Lectures

Drug Mechanisms

Receptor Interactions

Pharmacokinetics

Pharm definitions and drug selectivity

Drug= A chemical substance that interacts with a biological substance to produce a physiological effect

Agonist (Ach, nicotine)= promotes/stimulates the receptor

Antagonist (atropine, hexamethonium)= Inhibits the receptor

Potency= Depends on affinity (likeliness of drug to seek and bind to receptor) and efficacy (drug does something like a conformational change to the receptor to cause action).

A full agonist has maximal potency while partial agonist has some antagonist activity.

Drugs are selective to bind on certain receptors. There is a structure-activity relationship as once the ‘lock and key’ fit (affinity) the key turns (efficiency) the drug may go from an agonist to antagonist.

Drug Target Sites

Receptors- They are normally proteins within the cell membrane activated by NT or hormones (can be agonist or antagonist) and there are four types of receptors.

Ion channels- Are selective pores allowing the transfer of ions down an electrochemical gradient. There are 2 types voltage sensitive (VSCC) and receptor linked (

nAChR

)

e.g

CCB

Transport Systems- Transport glucose, ions

etc

against concentration gradients. Very specific e.g. Na uptake during NA+/

K+ATPase

(cardiac glycosides and TCA)

Enzymes- Catalytic proteins, increase rate of reaction. Drugs are enzyme inhibitors (

neostigamine

against

AchE

), false substrates (methyldopa) and prodrugs that convert in your body (chloral hydrate to

trichloroethanol

)

Antacids and osmotic purgatives that

asorb

water into gut, soften stool and release water are physiochemical properties that help non-specific drug action

4 types of receptors

Antagonism

Antagonists have affinity but no efficacy. 2 Types:

Competitive- same site as agonist so as it increases more antagonism. The DR curve shifts right and it is surmountable (atropine and propranolol).

Non-competitive/irreversible- binds tightly to enzyme so can’t detach or at different site, insurmountable e.g.

hexamethonium

.

Physiological antagonism-Different receptors mean opposite effects on the same tissue e.g. NA and histamine on

cardiomyocytes

.

Chemical antagonism-Interaction in solution e.g.

dimercaprol

.

Pharmacokinetic antagonism- Antagonist decreases concentration of active drug site by decrease absorption, more excretion and metabolism e.g. barbiturates.

Dose Response Curves

Drug Tolerance

Drug tolerance is the gradual decrease in responsiveness to drugs with repeated admin e.g. benzodiapenes because of:

Pharmacokinetic factors- increase rate of metabolism the more you have it e.g. barbiturates or alcohol.

Loss of receptors- When cells are always stimulated there is receptor down regulation e.g. Beta

adrenoreceptors

Change in receptors: After lots of binding there is conformational change and receptor desensitisation, also maybe fit but no efficacy e.g.

nAchR

at NMJ.

Exhaustion of mediator stores e.g. amphetamine release NA so less storage.

Physiological adaption- Homeostatic responses (RAS system when diuretics decrease BP

Pharmacokinetics: Administration

Entreal

routes (oral, buccal, sub-lingual). It permits self medication, no sterile preparations, incidence of anaphylactic shock lower than intravenous but not complete absorption if you vomit, degraded in acid pH of stomach, undergoes first pass metabolism and requires patient compliance.

Parenteral route- Good for small particles, gas, volatile liquids, enormous S.A. presented by alveolar membrane, simple diffusion but can have a localised effect in lungs only.

IV- Rapid onset, avoids absorption and destruction in G.I tract but slow injection to avoid anaphylactic shock and toxic build up, trained personal requires and complication include embolism, phlebitis and pain.

IM- relatively high blood flow, and increase exercise means depot therapy (prolong absorption from pellet, microcrystalline suspension or solution in oily vehicle) but can have infection and nerve damage (especially in gluteal region)

SC- enables depot therapy, local administration, dissemination minimised for local effect but pain, abscess and tissue necrosis.

Percutaneous- lipid soluble action diffuses rapidly but local irritation and skin reactions, alteration of skin structure.

Pharmacokinetics: Distrubution

Drugs have to transverse both lipid and aqueous environment and they move around the body in bulk flow transfer, i.e. blood stream or diffusional transfer over short distances. Drugs mainly cross barriers via diffusion through lipids or carrier molecules.

Most drugs are weak acid or bases so either polar or non-polar depending on

pH.

Non-polar penetrates more easily.

Pharmacokinetics: Distribution

Factors influencing drug distribution…

Regional blood flow- highly metabolically active tissues mean denser capillary networks (also happens with exercise)

Extracellular binding- Some drugs bind to plasma proteins in blood flow e.g. acidic drugs 50-80%

Capillary permeability (tissue alterations – renal (fenestrated), hepatic (discontinuous), brain/CNS, placental)

Localisation in tissues- fat 2% blood supply and 15% body weight so 75% of drugs at equilibrium in fat.

Pharmacokinetics: Excretion

Most drugs are eliminated at the kidney.

Some drugs are excreted at the liver via the biliary system into the gut.

Enterohepatic recycling: A drug or its metabolite is reabsorbed in the gut after biliary excretion and taken to the liver via hepatic portal vein. Thus drug can persist for longer which can lead to toxicity problems.

Sodium bicarbonate causes increased urine pH ionizing the drug making it less lipid soluble and less reabsorbed from the tubule, increasing its rate of excretion

Some more definitions

Bioavailability (linked to absorption)

Proportion of the administered drug that is available within the body to exert its pharmacological effect

Apparent volume of distribution (linked to distribution)

The volume in which a drug appears to be distributed

- an indicator of the pattern of distribution

Biological half-life (linked to metabolism/excretion)

Time taken for the concentration of drug (in blood/plasma) to fall to half its original value

Clearance (linked to excretion)

Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time.

(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)

Drug Elimination Kinetics

First order kinetics (most drugs)

Amount of drug decreases at a rate that is proportional to the concentration of drug remaining in the body.

Zero order kinetics (some drugs)

Amount of drug decreases at a rate that is independent of the concentration of drug remaining in the body.

pKa

EliminationFrusemide -Loop diuretic3.8Renal 66% Biliary 33%Bendroflumethiazide – Thiazide diuretic8.460% non renal

2.

a. Which drug has the higher bioavailability if they are both given by oral route? Explain in terms of

pKa

(4)

b. Think about the MOA of the drugs, what is the significance of how they are eliminated? (based on the table) (3)

c.  Give the drug target sites for both loop diuretics & thiazides (1) and explain why loop diuretics are more effective than thiazide diuretics (2)

a. State which is the : - full opioid agonist

                                   - partial opioid agonist                                    - full opioid antagonist (3)b. Compare the affinity and efficacy of drug A & drug B (4)c. how do opioids suppress the cough reflex by their peripheral presence in the airways? (3)

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