Pharmacodynami cs

Dr. Lukshmy Menik Hettihewa Senior lecturer Department of Pharmacology Faculty of Medicine University of Ruhuna 26 09 07

Pharmacodynamics

Objectives Should be able to describe different mechanisms of drug actions. Should be understand second messenger system and signal transduction. Should be able to describe the dose response relation ship Should be able to recall the type of drug effects.

WHY BE CONCERNED ABOUT HOW DRUGS WORK?

The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patients body. A patient who understands his/her therapy is more inclined to become an active participant in the management of the patients disease.

Different mechanisms of actions of drugs

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS?

1. Antagonists of Cell Surface receptors 3. Antagonists of Nuclear Receptors 4. Enzyme Inhibitors 5. Ion Channel Blockers 6. Transport Inhibitors 7. Inhibitors of Signal Transduction gdproteins

1. Drug effect by receptors

Definition of RECEPTOR:

A macromolecular component of the a cell of a organism that binds the drug and initiates its effect. Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? KEY CONCEPTS:

Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell. Some compounds bind to cell surface receptors, yet do not activate the receptors to trigger a response. When cell surface receptors bind the molecule, the endogenous chemical cannot bind to the receptor and cannot trigger a response. The compound is said to antagonize or block the receptor and is referred to as a receptor antagonist.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Extracellular Compartment Cell Membrane

Unbound Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Extracellular Compartment Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Intracellular Compartment Cellular Response

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular Compartment Cell Membrane

Bound Antagonist of Receptor (Drug)

Inactive Cell Surface Receptor

Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular Compartment Cell Membrane Intracellular Compartment

Active Receptor

Bound Antagonist of Receptor

Inactive Receptor

Allosteric Inhibitor

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Displaced Endogenous Activator (Agonist) of Nuclear Receptor Bound Antagonist of Receptor (Drug)

Inactive Nuclear Receptor In Cytosolic Compartment

DNA Nucleus

Intracellular Compartment

Inactive Nuclear Receptor In Nuclear Compartment

2. Drugs by enzymes

HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate

Product

Cellular Function
Inactive Enzyme

Substrate
Bound Enzyme Inhibitor (Drug)

 Enzymes catalyze the biosynthesis of products from substrates. Some drugs bind to enzymes and inhibit enzymatic activity. Loss of product due to enzyme inhibition mediates the effects of enzyme inhibitors.

Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and chronic renal insufficiency (captopril [Capoten]; ramipril [Altace])

3. Effects of drugs on iron channels

Calcium Channel Blockers (CCBs) for angina and high blood pressure.

Sodium Channel Blockers to suppress cardiac arrhythmias eg amioderone

4. Transport inhibitors

 Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine [Prozac]; fluvoxamine [Luvox])

Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal epithelial cells to increase urine and sodium output for the treatment of edema (furosemide [Lasix]; bumetanide [Bumex])

5. Signal transduction protein inhibitors

 Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib [Gleevec])

Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil [Viagra])

dosing schedules

Doses are scheduled according to pharmacokinetic properties. Priming dose/loading dose to achieve the desired drug concentration in the body. Maintain dose is usually equal to the amount of drug that is eliminated at dosing interval.

Calculation of the dose

According to the weight. With clinical practice do in the light of experience. There are five main kinds of drug dosages;

1. fixed dose- therapeutic dose is well below the toxic dose. 2. variable dose with crude adjustmentcan do minor adjustments. May do slowly. Make insignificant differences and hard to measure the therapeutic outcome. 3. variable dose with fine adjustmentresponse change with dose. Should do accurate changes with measuring responses. Eg BP, blood sugar.

 4.

maximum tolerated dose

Use when therapeutic effects cannot be obtained because of unwanted effects ( anticancer drugs). 5. minimum tolerated doseNot so usually practiced. But apply when you use long term corticosteroids.

Dose response relationship

To decide the proper dose of drug to get the desired effect You need to know the dose response relationship Effect of drug on the logarithm of the corresponding dose can be plotted. It is called log-dose response ( LDR) or graded dose response curve.

LDR curves are s shaped. LDR response depends on the intensity of drug action and occupancy of the receptors hence the concentration of the drug-receptor complex. Slight increase of the dose can bring the small increase of the response. But not always. It is called all or none effect Eg. convulsions

Evaluation of drug safety

Drug can have one or more additional effects Drug is safe if the LDR region of the harmful side effects is much higher than the therapeutic dose range.

LD50 - the dose that give rise to 50% of the death of subjects ED50 the dose that give the desired response in the 50% of the subjects. (potency) TD50 harmful side effect is manifested in 50% of the subjects Read about the therapeutic index and its application in clinical practice (LD50 /ED50 )

How drugs act?

1. Through receptors 2. Ion channels simple interaction induces effect. 3.enzymes drugs block or stimulate. Block can be competitive or can be a false substrate 4.carrier molecule

Drug receptors

Drugs act through receptor mechanism. (channel linked, G protein coupled, kinase linked and nuclear receptors). Regardless of the route of administration Non specific binding Any drug can bind to these sites without an effect. Eg. Albumin If binds to a place causing an effect, that component is called as a receptor

Most of the drugs can bind to several receptors This leads to greater diversity of the biological responses Ideal drug should bind to a single receptor. But most of the therapeutic agents are not so selective

Potency and efficacy

Potency - How much of drug needed to elicit given response. Relationship between the concentration and the its ability to induce an effect. 5 mg with drug A and 50 mg with drug B. Efficacy Maximum response produced by a drug.

Kinetics of intravenous infusions

Rate of drug entry into the body is constant. Start Input = drug output Stop drug infusion 100 In=out
75
Drug con.

50

t/2

Wash out of drug similar to the rate of administrat ion 2.t/2

t/2

2.t/2

Time

Kinetics of fixed dose, fixed time interval regimens

Single iv injections- rapid distribution. And exponential decrease with time. 100
Plasma concentration
100mg dose 50 Half life is not depend on the amount of the drug administer ed

50 mg dose 0 t/2 time

Multiple iv injections

2u

Injection 2 units once daily

Injection 1 unit twice daily Conti. infusion

1u

Time

Oral administration
Repeated fixed dose administrati on

con of drug.

single fixed dose administrati on time

Agonist and antagonist activity

PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. Full Agonist 1.0

% Maximal Effect

0.8 0.6 0.4 0.2 0.0 0.01

Partial agonist

Partial agonist

0.10

1.00

10.00

100.00

1000.00

[D]

(concentration units)

antagonist

Therapeutic agents that inhibit the receptor activity are called antagonist Antagonist binds to receptors and do not change the active state of the receptor. Therefore they have zero efficacy. They block the response induced by the endogenous agonist. Therefore it has a clinical utility.

Two types Reversible competitive Irreversible non competitive Reversible compete with the agonist for binding Dose response curve is shifted to right in the presence of antagonist.

antagonists

Irreversible

Compete with the agonist for receptor binding either by forming covalent bonds irreversibly Eg. Phenoxybenzamine bind with alfa adrenergic receptors Effect depends on the dose and the receptor occupancy

Types of Receptor Antagonists

Competitive Noncompetitive

Signal transduction

cAMP is the intracellular signal First messenger (hormones or neurotransmitters) second messenger (phospholipids, cyclic nucleotides ions)

Signaling mechanisms

Four basic mechanisms 1. G protein coupled receptor (metabotropic) component that has trans membrane receptor having connections with external cellular surface and the internal G proteins. 2.Tyrosine kinase and guanylyl cyclase - has enzymatic activity by phosphorylation.

3. ligand gated ion channels (ionotropic) opening of the trans-membrane ion channels leads to convey the message. 4. intracellular receptors some ligands are lipid soluble and can penetrate and bind with the intracellular receptors . This complex moves inside the cell and bind to the regulator genes of the protein expression.

Selectivity of the drug action

Different drugs have different selectivity Therapeutic efficacy is related to the drug selectivity Selectivity is important why..? Eg. Anticancer drugs. antibacterial drugs

Stereospecificity

Drugs have optical isometric forms But only one is active. It is important for the receptor selectivity Eg. Atropine is a mixture of d- and l -hyoscyamine of which only the l form is active as a muscarinic blocker. Morphine - has both l and d forms but only the l form is the active part as an analgesic