Antagonist : Drugs that interact with receptors to interfere with their activation by agonists.

Can be classified as:

·         Competitive

·         Non competitive

Can be classified as:

·         Pharmacologic : same receptors

·         Physiologic : diff receptors

·         Chemical

·         Competitive antagonists cause a parallel shift to the right and can be reversed completely by increasing the dose of agonist drug.

In effect ,such antagonists appear to decrease the potency of the agonist drug.

Most receptor antagonists used in medicine are competitive.

Examples include atropine blocksà acetylcholine at M receptors and propranolol blocksànor epinephrine at beta receptors.

·         Noncompetitive/Irreversible  antagonists cause a nonparallel shift to the right and can be reversed only partially by increasing the dose of agonist drug.

Such antagonists appear to decrease both the potency and efficacy of agonists.

One example is phenoxybenzamine , which irreversibly blocks the effects of nor epinephrine at alpha receptors by the formation of covalent bond. Phenoxybenzamine makes a co-valent bond with alpha receptor in the vasculatures.

Diazoxide binds with alpha receptors.

Pharmacologic antagonism (same receptor)

·         An agonist and antagonist compete for a single receptor type.

Ach + M receptor= effects

Atropine + M receptor= blocks the effect of ACH on M receptor

Physiologic antagonism (Different Receptors).

·         Occurs when an agonist response mediated through one receptor is antagonized by an opposing agonist action at different receptor.

·         E.g. acetylcholine causes àbradycardia through M receptor activation, which  may be antagonized by NE via beta receptor activation.

Histamine H1 receptorà bronchospasm

Epinephrine beta 2 receptorà bronchodilatation

Chemical antagonism:

·         Occurs when drug effect is antagonized by the formation of a complex between the effector drug and another compound.

E.g. protamine binds to heparin to reverse its actions.

Dimercaprol, a chelator of lead poisoning

·         In this case, a given quantal effect (a condition that can be expressed only as occurring or not occurring) is chosen , and the concentration of the drug is plotted against the percentage of a specific population in which the drug produces the effect.

·         These curves plot the percentage of a population responding to a specified drug effect versus dose.

Use to estimate ED50, TD50, LD50

·         ED50 (median effective dose) : The amount of a drug required to produce a response in 50% of the subjects to whom the drug is given.

 ·         TD50 (median toxic dose):  the dose that produces a toxic effect in 50 per cent of the population.

·        





LLD50 (median lethal dose) the quantity of an agent/drug that will kill 50 per cent of the test subjects/population

Toxicity and the Therapeutic Index:

·         Comparisons between ED 50 and TD 50 values permit evaluation of the relative safety of a drug (the therapeutic index)

·         TI = TD50/ED50

·         Also comparison between ED50 and LD50 if the latter is known.

·         TI = LD50/ED50

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Pharmacodynamics  described as what a drug does to the body, involves….

•       receptor binding

•      postreceptor effects

•      chemical interactions

Receptor: is the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug's observed effects.

Drug  +  Receptor à Drug-receptor complex-àResponse

The magnitude of drug effect depends on its concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug such as

▪Rate of absorption

▪Distribution and

▪Metabolism.

Pharmacodynamic characteristics of drug:

Agonist: Is defined as an agent that can bind to a receptor and elicit a response.

2 types:

·         Full agonist

·         Partial agonist

Full agonists: produce a maximal response, they have maximal efficacy.Partial agonists are incapable of eliciting a maximal response and are less effective than full agonists.

Antagonist: they interfere with the ability of an agonist to activate the receptor and blocking their biologic actions.

Efficacy: Is the maximum response produced by the drug.It depends on the number of drug-receptor. Efficacy is a Measure of how well a Drug produces a response (Effectiveness), shown by the Maximum Height reached by the Curve on X Axis.complexes formed.

Potency: potency is measured of how much drug is required to elicit a given response.The lower the dose is required for a given response, the more potent the drug.

The primary determinant of potency  is the affinity of the drug for the receptor.

Dose-response relationship:

Dose:  the amount of drug required to elicit a biologic response.

Dose-response relationship:  the intensity of the response elicited by a drug is proportional to the dose administered.

Two types :

Graded dose-response curve : for maximum response.

Quantal dose-response curve : for specific responses, e.g.ED50, LD50, TD50

Affinity: Ability of the drug to bind to the receptor, shown by the  proximity of  the curve to

the y axis; the nearer  the y axis, the greater  the affinity.

When two drugs interact with the same receptor, the D-R curves will have parallel slopes.

Affinity (ability of the drug to bind to the receptor) can be compared only when two drugs bind to the same receptor.

Duality of Partial Agonists:

In the presence of full agonist , partial agonist will act as antagonist. As the partial agonist displaces the full agonist from the receptor,the response is reduced-the partial agonist is acting as an Antagonist.

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Systemic lupus erythematosus (SLE):

·         SLE is a chronic autoimmune connective tissue disease that can affect any part of the body.

·         In SLE the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.

·         SLE affects the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system.

• The course of the disease is unpredictable, with periods of illness (called flares) alternating with remissions.
• The disease occurs nine times more often in women than in men, especially between the ages of 15 and 50, and is more common in those of non-European descent
• Survival for patients with SLE in the United States, Canada, and Europe is approximately 95% at five years, 90% at 10 years, and 78% at 20 years.

Causes:

·         There is no one specific cause of SLE. There are however a number of environmental triggers and a number of genetic susceptibilities.

Genetics

·         SLE may have a genetic link. SLE does run in families.

·         The most important genes are located in the HLA region on chromosome 6, where mutations may occur randomly or may be inherited.

Environmental triggers

·         They include extreme stress, exposure to sunlight, hormones, and infections. UV radiation has been shown to trigger the photosensitive lupus rash and some evidence suggests that UV light might be capable of altering the structure of the DNA, leading to the creation of autoantibodies. Sex hormones such as estrogen play an important role in the occurrence of SLE and it is observed that during reproductive years, the frequency of SLE is 10 times greater in females than in males.

Drug reactions

·         Symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped.

·         There are about 400 medications that can cause this condition, the most common of which are INH, procainamide, hydralazine, quinidine, d-penicillamine and phenytoin

·         These drugs are known to stimulate the immune system (by drugs with slow acetylation reactions) and cause SLE.

Signs and Symptoms:

Common initial and chronic complaints include :fever, malaise, joint pains, myalgias, fatigue.

·         Dermatological manifestations : Most common is the skin rash: malar rash (or butterfly rash)

·         Some may exhibit thick, red scaly patches on the skin (referred to as discoid lupus)

·         Anemia

·         mouth, nasal, and vaginal ulcers

·         Cardiac manifestation: pericarditis, myocarditis, and endocarditis. The endocarditis of SLE is characteristically noninfective (Libman-Sacks endocarditis) and involves either the mitral valve or the tricuspid valve.

·         Pulmonary manifestations: Lung and pleura inflammation can cause pleuritis,  pleural effusion, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli,  pulmonary hemorrhage.

·         Renal involvement : Painless hematuria or proteinuria

·         A histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding  is due to immune complex deposition along the glomerular  basement membrane, leading to a typical granular appearance  in immunofluorescence testing.

·         CNS manifestations of SLE include:  headache, cognitive dysfunction, mood disorder, cerebrovascular disease, seizures, polyneuropathy, anxiety disorder, and psychosis.

·         Patients with SLE may have an association with antiphospholipid antibody syndrome (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum.

·         Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged PTT and a positive test for antiphospholipid antibodies.

·         Another autoantibody finding in SLE is the anticardiolipin antibody, which can cause a false positive test for syphilis.

How is lupus diagnosed?

CBC: anaemia, sedimentation rate and C-reactive protein

For autoimmune SLE:

·         anti-dsDNA antibodies

·         anti-Sm [Smith] antibody

·         antinuclear antibody

For drug induced SLE:

·         Anti-histone antibody

·         Low level of C3, C4 and high level of anti-dsDNA 

·         antibody associated with relapse(flare up) and poor prognosis.

Treatment:

·         There is no cure for SLE. Treatment is aimed at controlling symptoms

·         NSAIDs (Nonsteroidal anti-inflammatory medications) are used to treat arthritis and pleurisy.

·         An anti-malaria drug (hydroxychloroquine) and low dose corticosteroids are sometimes used for skin and arthritis symptoms

·         Immunosuppressive : azathioprine and cyclophosphamide for renal and cerebral involvement

·         For drug induced SLE: withdrawal of medication

·         Patients should wear protective clothing, sunglasses, and sunscreen when in the sun

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How does smooth muscle contraction occur?
Smooth muscle contractile mechanism is slightly different form the cardiac and skeletal muscle. They all need the interaction between myosin and actin but one important difference is, smooth muscle does not have troponin and tropomyosin. So in smooth muscle for myosin to interact with actin, myosin must be phosphorylated.
who phosphorylate the myosin?
We all know phosphorylation is done by an enzyme called kinase, so here the enzyme is called myosin light chain kinase. That means if the myosin light chain kinase is inhibited then it won’t be able to phosphorylate myosin and then there is no interaction between the myosin and actin, hence we have relaxation of smooth muscle.
How do we inhibit myosin light chain kinase?
As we all know, phosphorylation of an enzyme will either activated or inhibit the enzyme, so here phosphorylation of myosin light chain kinase will result in inactivation.
How do we phosphorylate myosin light chain kinase?
There are several mechanisms. Increasing cAMP will result in increased level of Protein kinase A. the kinase will phosphorylate the myosin light chain kinase. This is how beta-2 adrenergic causes relaxation of bronchial smooth muscle and blood vessels.
How does nitric oxide dilate blood vessels?
Nitric oxide dilate blood vessels by binding to intra cytoplasmic Guanylate cyclase, which will convert GTP to cGMP and it in turn activates Protein Kinase G. the PKG will phosphorylate the Myosine light chain kinase and inactivate it.
How does milrinone cause blood vessels to dilate?
Milrinone is phosphodiestrase inhibitor. Phosphodiesterase inhibit cAMP. so if you inhibit Phosphodiesterase then cAMP is free to activate PKA. PKA will phosphorylate myosine light chain kinase and inactivate it. If myosin is not phosphorylated it cannot interact with actin, which means relaxation of smooth muscle.

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Cytochrome P450 Isozymes (CYP)

These are major enzyme systems involved in Phase I reactions. Localized in the smooth endoplasmic reticulum (microsomal fraction) of cells ( especially liver , but including GI tract, lungs ,and kidney)

·         P450s have an absolute requirement for molecular oxygen and NADPH.

·         Reactions include hydroxylation’s, oxidation,  and dealkylations.

·         Multiple CYP families differing by amino acid(AA) composition , by substrate specificity, and by sensitivity to inhibitors and to inducing agents.

Cytochrome P450 Isozymes:  3 types

• CYP1A
• CYP2D6

·         CYP3A4

CYP1A

·         Main substrate is theophylline; inhibited by fluoroquinolones and macrolides; induced by aromatic hydrocarbons.

CYP2D6

·         Genotypic variations in hydroxylation(fast and slow);substrates include codeine,and metaprolol; inhibited by haloperidol and quinidine; not inducible.

CYP3A4

·         Most abundant isoform; wide substrate range ; inhibited by cimetidine, macrolides, azoles, and ethanol(acute); induced by general P450 inducers such as carbamazepine, phenobarbital(Barbiturates), phenytoin, and rifampin and by ethanol(chronic).

Cytochrome P450 Isozymes:

·         These are major enzyme systems involved in Phase I reactions. Localized in the smooth endoplasmic reticulum (microsomal fraction) of cells (especially liver , but including GI tract, lungs ,and kidney)

·         Inhibited by : Cimitidine, Macrolides, Azoles (Miconazole, Ketoconazole), Alcohol (acute), grapefruit juice

·         Induced By : Carbamazepine, Barbiturate, Phenytoin, Rifampin, Alcohol (Chronic intake)

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General Pharmacology

Elimination of drugs:

Concerns the processes involved in the elimination of drugs from the body (and/or plasma) and their kinetic characteristics. The major modes of drug elimination are:

·         Bio-transformation to inactive metabolites

·         Excretion via the kidney.

·         Excretion via other modes including the bile duct (HBS), lungs and sweat.

2 types of elimination

• Zero Order elimination Rate
• First-Order elimination Rate

Zero Order elimination Rate

·         Rate of elimination is independent of plasma concentration (or the amount in the body).

·         A constant amount of drug is eliminated per unit time

·         for example, if 80 mg is administered and 10 mg is eliminated every 4 hrs, the time course of drug elimination is: 80 mgà 70 mgà60 mgà50mgà40mg(each 10 mg in 4 hrs.)

• Drugs with zero order elimination have no fixed half-life. Graphically ,  zero order elimination follows a straight-line  decay versus time.

Drugs with zero order elimination include

·         Ethanol (except for low doses),

·         Phenytoin (high therapeutic dose),

·         Salicylates (toxic doses).

ELIMINATION KINETIC

·         Zero order is due to saturation of elimination mechanisms; e.g, drug-metabolizing reactions have reached Vmax.

Most drugs follow first order kinetic

First-Order Elimination Rate

·         Rate of elimination is directly proportional to plasma level. The higher the amount, the more rapid the elimination.

·         A constant fraction of the drug is eliminated per unit time. Graphically , first order elimination follows an exponential decay versus time.

• For example, if 80 mg of a drug is administered and its elimination half-life = 4 hrs, the time course of its elimination is:80 mg à40 mgà20mgà10 mgà5 mg(each step 4 hrs)

Clearance is defined as the volume of blood cleared of the drug in unit time.

OR

Volume of plasma from which all drugs are removed in a given time.

·         Drug clearance is concerned with the rate at which  drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output.

·         It represents the relation-ship between the rate of drug elimination and its plasma level.

For drugs with first-order elimination, clearance is constant because the rate of elimination is directly proportional to the plasma level.

·         Total body clearance may involve several processes, depending on different routes of drug elimination.

·         CL= CLr + CLnr

Where CLr = renal clearance and  CLnr = non renal clearance.

·         With no active secretion or reabsorption, the renal clearance is same as glomerular filtration rate(CLr =GFR)

• Half life of drug : Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level) is called the elimination half-life (t ½).

T ½ = 0.7 x Vd/CL

Steady state(Css):

·         Css is the desired plasma concentration of drug required for optimal activity.

·         Steady rate is reached either when rate in (Rate of infusion) = rate out (Rate of elimination) or when values associated with a dosing interval are same as those in succeeding interval.

• Css is achieved in which plasma conc of drug remains constant.

The time to reach steady state is dependant on the elimination half-life of a drug

·         Although it takes > 7 t ½ to reach mathematical steady state , by convention clinical steady state is accepted to be reached at 4 t ½.

• Css = Ro/CLt

Ro- infusion rate, CLt - total body clearance e.g Css of plasma conc is directly proportional to infusion rate. If infusion is doubled the plasma conc ultimately achieved at the Css is doubled.

·         Css inversely proportional to clearance of the drug. In CRF decreases CL, so increase Css of an infused drug.

·         If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled.

·         Irrespective of the rate of infusion, it takes the same amount of time to reach steady state.

·         A similar relationship can exist for the other forms of drug administration (e.g, per oral)- doubling oral doses can double the average plasma levels of  a drug.

Maintenance Dose:

In most clinical situations, drugs are administered in such way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated .

·         At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out").

 IN Css, 

Dosing rate (rate of infusion) = Rate of elimination

                             = CL x target plasma conc

If intermittent doses are given, the maintenance dose is calculated from:

Maintenance dose (MD) = Dosing rate(rate of infusion) x Dosing interval                   

Loading Dose: A single dose of drug injected to achieve the desired plasma level rapidly

·         Loading dose (LD): LD =Vd  x  Css , where  Css = plasma at steady state , the desired plasma concentration of drug required for optimal activity.

·         Adjustment may be needed in calculations with bioavailability < f =1 ; for example, if f = 0.5 , the LD must be doubled.

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