Lecture 2 Dr. Mohamed Dawood

PHRMACODYNAMICS

Deals with effects of drugs on biological systems, and it is concerned with targets, mechanism of drug action, and nature of drug action (beneficial & side effects).

Mechanism of drug action1-On cell membrane: a-Action on specific receptor e.g. agonists and antagonists on adrenoceptor. b-Interference with selective passage of ions across membranes e.g. calcium channel blockers. c-Inhibition of membrane bound enzymes and pumps e.g. membrane bound ATPase by cardiac glycoside.

2- Within the cell:a- Intracellular Enzyme inhibition e.g. platelet cyclo-oxygenase by aspirin.

b-Incorporation into large molecules e.g. 5-fluorouracil is incorporated into messenger-RNA within the cell. c-Altering metabolic processes within the cell. e.g. penicillin interferes with formation of bacterial cell wall.

3- Outside the cell: a-Direct chemical interaction e.g. chelating agents, antacids b-Osmosis, as with purgatives e.g. magnesium sulphate and diuretics e.g. mannitol

*Receptors: Is a macromolecule whose biological function changes when a drug bind to it. -Most drugs produce their pharmacological effects by binding to specific receptor in target tissues. -Affinity :Is the measure of ability of a drug to bind receptor; the force of attraction between drug and receptor. -Drug-receptor binding triggers a cascade of events known as signal transduction, through which target tissue responds.

Major receptor families (signal transduction mechanisms)*لالطالع

1-Ligand-gated channels: -The activity of these channels is regulated by binding of a ligand to the channel which will lead to flow of ions across cell membranes. -Duration of response (few milliseconds) - E.g nicotinic and GABA receptors. -Stimulation of nicotinic receptor by Ach results in Na influx and activation of contraction in skeletal muscle.

2-G protein-coupled receptors: -It is the most important mechanisms and half of drugs act through this mechanism e.g.β receptor agonist and antagonist. -These receptors are liked to G protein (Gs) having 3 subunits, an α subunit that bind GTP ,and β, γ subunits .

-Binding of a ligand to receptor activate the G protein so that GTP replace GDP on the α subunit . -Dissociation of the G protein occurs, and both α-GTP and βγ subunits interact with other cellular effectors. -These effectors include: cAMP, ionsitol 1,4,5 triphosphate(IP3), and diacylglycerol and they are responsible for the regulation of free ca++ concentrations within the cell. -Response duration (several seconds-minutes)

3- Enzyme linked receptors: -The receptor consist of a pair of protein molecules(monomers) that are separate when inactive, and an agonist causes them to interact and form a dimmer. -The interaction phosphoreylate tyrosines in the intercellular region of receptor and the receptor becomes an active enzyme. -The active receptor enzyme then activate a number of other enzymes that interact with active tyrosine of the receptor. -Duration of responses to stimulation of these receptors (min. to hrs) -e.g. insulin receptor, growth factor receptors.

4-Intracellular (nuclear) receptors: -These receptors are in the cell cytosol, an agonist enters the cell and bind to the receptor. -The drug-receptor complex then enters the nucleus and stimulate gene transcription. -This will lead to synthesis of new protein and enzymes. -e.g. receptors for steroid, retinoids and thyroid hormones .

مطلوب

*Receptor agonist and antagonist: -Agonist: Is a drug which binds to the receptor and produces an effect, thus it has affinity and intrinsic activity (action). Drug acting as agonist because it resemble natural transmitter or hormone, but the duration of agonist drug is longer than the natural agents because it resist degradation . e.g. brochodilation produced by sulbutamol is longer than that produced by adrenaline

-Antagonist: Antagonist drug will occupy(block)the receptor without activating a response, thereby preventing the natural agonist from excreting its effects, thus It has affinity for a receptor but no intrinsic activity (no action). e.g. Propranolol (B-adrenoceptor blocker)

-Partial agonist: It has affinity for a receptor but less intrinsic activity (action) {lower efficacy compared to an agonist acting at the receptor}, so, these drugs in addition to blocking access of natural agonist to the receptor, are capable of a low degree of activation of the receptor. e.g. pindolol (B-adrenoceptor blocker)

*Competitive antagonist: -Agonist and antagonist compete to occupy the same receptor.

-In the presence of antagonist a higher dose of agonist is required to produce the same effect. -e.g. Ach -agonist Atropine -competitive antagonist at muscarinic receptor

*Non-competitive antagonist: It bind irreversibly to receptor , so, even higher doses of agonist cannot produce maximal effects. e.g. nor adrenaline -agonist phenoxybenzamine -noncompetitive antagonist at α receptor.

*Receptor regulation: -Down regulation: The number of receptor decreases due to continuous exposure to an agonist and this will lead to tachyphylaxis (loss of efficacy with frequent repeated doses) e.g. sulbutamol (adrenoceptor agonist bronchodilator) in asthma.

-Upregulation:The number of receptor increases due to prolonged contact with antagonist e.g. worsening of angina pectoris due to sudden withdrawal of B blocker.

*Physiological antagonism. The antagonist is acting on different type of receptors (different from agonist receptor) , e.g. extreme bradycardia due to B adrenoceptor blocker can be overcomes by given atropine which block the parasympathetic branch of autonomic N,S.

*Efficacy: Often called maximal efficacy, is the greatest effect(Emax) an agonist can produce in high dose . -Partial agonists have lower maximal efficacy than full agonist.

*Potency : Is the amount of drug in relation to its effect e.g. Lorazepm 2 mg induce equal or even more effect than diazepam 5mg although the maximum therapeutic effect may be similar with both drugs.

*Variation in drug responsiveness. Individuals may vary considerably in their responsiveness to drug and even a single individual may respond differently to the same drug during the course of treatment."Idiosyncratic drug response: Response which is unusual and caused by genetic difference in metabolism of the drug (pharmacogenetics) or by immunological mechanism including allergic reaction.

"Tolerance and tachyplaxis:The intensity of response to a given dose may change during course of therapy; in those cases , responsiveness usually decreased as a consequence of continued drug administration , producing a state of tolerance to drug effect. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subjected to Tachyplaxis

*Mechanism of variation in drug responsiveness:

A-Alteration in the concentration of drug that reaches the receptor:Patients may differ in the rate of absorption, distribution, and clearing of the drug from blood and these pharmacokinetic differences may alter the clinical response.

B-Variation in receptor structure:This mechanism contribute greatly to variability in response to antibiotic , e.g: resistance by microorganism to antibiotic.

C-Alteration in number or function of receptors:

-e.g: Some time, the change in number of receptor is caused by hormones e.g. thyroid hormone increase the number of β-receptor and cardiac sensitivity to catecholamines which cause tachycardia in thyrotoxicosis.-e.g; Down regulation & Upregulation of receptors ; as discussed above.-Also tolerance, Tachyplaxis and genetic factors play a role in this mechanism.

D-Change in component of response distal to the receptor:-Clinically , it is the most important mechanism.-Age, general health of the patient, and pathophysiological status of the disease play a role in this mechanism.-e.g. old aged compared to young aged; race difference.

Therapeutic window: A well-defined range of a drug’s serum concentration at which a desired effect occurs, below which there is little effect, and above which toxicity occurs.

Therapeutic drug monitoring :The regular measurement of serum levels of drugs requiring close 'titration' of doses in order to ensure that there are sufficient levels in the blood to be therapeutically effective, while avoiding potentially toxic excess.

The therapeutic index (TI) (also referred to as therapeutic ratio): is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity.

A high Therapeutic Index (TI) is preferable for a drug to have a favorable safety profile. Narrow therapeutic index (NTI-drugs) are drugs with small differences between therapeutic and toxic doses.

*Dosing schedule:

A-Loading dose (L): A dose of drug sufficient to produce plasma concentration of drug that will fall within therapeutic window after only one or very few doses over a very short time. If we know the target plasma concentration(Cp)and Vd, we calculate the loading dose.

L= Cp× Vd

e.g. digoxin in heart failure

If only maintenance dose is given it will take 10 days to reach effective plasma concentration. So, we calculate the loading dose: L = 1.5 ng (1500 mic) /ml × 580/0.7 =1243 mic.g = 1.25mg and this can be divided in to 4 doses to avoid toxicity.

*Maintenance dose (M): The dose needed to maintain the concentration within the therapeutic window when given repeatedly at constant interval.

M = steady state plasma concentration(Cp) × clearance(Cl)

*Fixed – dose drug combination: Is appropriate in the fallowing cases:

1-Convenience: To improve patient compliance. e.g. kits to treat gastric ulcer. 2-Enhanced effect: e.g. Single drug treatment of TB lead to emergence of resistant cases, this effect is prevented by using 2 or more drugs. 3-Minimisation of unwanted effects: e.g. Combining levodopa with carbidopa (sinemet) slow its metabolism outside the CNS so that smaller amounts of levodopa can be used; this will reduce the adverse effects. *Drug interaction :

When a drug is administered , a response occurs; if a second drug is given and the response to first drug is altered, a drug interaction is said to have occurred.Clinically important adverse drug interactions become likely with the fallowing:1-Drugs that have small or narrow therapeutic window. e.g. digoxin, lithium2-Drug that are known enzyme inducers or inhibitors.3-Drugs that exhibit zero – order kinetics e.g. phenytoin, theophylline.4-Drugs that are used for long term, where precise plasma concentration are required e.g. antiepileptic drug, drugs for arrhythmia.5-In severely ill patient , because they receive many drugs.6-In patients with significantly impaired liver or kidney function.7-In the elderly, for they tend to have multiple pathology, may receive several drugs.

*Adverse drug reactions

-Definition of commonly used terms

1-Side effects: Reaction due to excess of normal, predictable, dose related (also called type A reaction)

2-Adverse reaction: Harmful effects occurring at doses intended for therapeutic effect which necessitate reduction of dose or withdrawal of the drug.3-Secondary effect: e.g. Superinfection or vitamin deficiency during chemotherapy.4-Intolerance: Low threshold to pharmacological action of the drug.5-Iatrogenic diseases: Drug – induced diseases e.g. Parkinsons disease due to phenothiazine.

-Classification of adverse drug effects:+Type A(Augmented)reaction = Side effect+Type B(Bizarre) reaction will occur only in some people, they are not dose related but due to abnormal reaction to the drug e.g. idiosyncrasy.+Type C(Chronic)reaction due to long term exposure e.g. analgesic nephropathy.+Type D(Delayed) effects fallowing prolonged exposure e.g. carcinogenesis.+Type E(Ending of dose)reactions, where discontinuation of therapy is too abrupt e.g. of opioid causing the withdrawal syndrome.

* Pregnancy Risk Categories:

Category AAdequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Example drugs or substances: levothyroxine, folic acid, liothyronine

Category BAnimal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Example drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole

Category CAnimal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Example drugs: tramadol, gabapentin, amlodipine, trazodone

Category DThere is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Example drugs: lisinopril, alprazolam, losartan, clonazepam, lorazepam

Category XStudies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Example drugs: atorvastatin, simvastatin, warfarin, methotrexate, finasteride