Atropine's anti muscarinic effects:

Anticholinergic properties jimson weed and Atropine poisoning similarities:

jimson Weed (Datura stramonium) poisoning -This condition is also called as "Gardener's mydriasis" jimson Weed produce toxins (belladonna alkaloids) that possess strong anticholinergic properties jimson weed and atropine poisoning are strikingly similar. Blockade of visceral muscarinic receptors produces the following effects

1 Heart -diminished vagal tone at the SA node causes relative tachycardia

2 Blood vessels- vasoconstriction via muscarinic receptor blockade in endothelial cells results in decreased nitric oxide synthesis In spite of this effect, atropine poisoning is associated with cutaneous flushing: the pathogenesis of this effect is unknown

3 GI- delayed gastric emptying, decreased intestinal motility, and secretion 4 Respiratory bronchodilatation

5 GU- urinary retention vi a detrusor relaxation and contraction of the external urethral sphincter

6 Secretions decreased lacrimation (dry eyes), salivation (dry mouth) and sweating (dry and hot skin) Atropine decreases one's ability to sweat, contributing to hyperthermia

7 Eye- mydriasis (dilated pupils) and cycloplegia (inability to focus on the near objects, blurry vision)

8 CNS -hallucinations, agitation and delirium

Atropine's anti muscarinic effects can be counteracted by increasing the concentration of acetylcholine in the synaptic cleft increased acetylcholine concentrations are produced by cholinesterase inhibitors that suppress acetylcholine degradation Physostigmine, a cholinesterase inhibitor, can be used for treatment of atropine overdose

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The renin-angiotensin-aldosterone system (RAAS) is one of the most important neurohormonal systems that regulate arterial blood pressure and sodium and fluid content in the body In response to decreased sodium, fluid volume, or arterial blood pressure, renin is released from the kidneys converting angiotensinogen to angiotensin I Subsequently, angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II Angiotensin II then increases aldosterone secretion from the adrenal cortex leading to increased sodium and fluid retention in the collecting tubules of the kidneys Angiotensin II is also a potent vasoconstrictor that ultimately increases systemic vascular resistance and arterial pressure

Angiotensin II itself is involved in two negative feedback mechanisms that help regulate the RAAS In short loop negative feedback, elevated angiotensin II stimulates the angiotensin receptors on juxtaglomerular cells to inhibit renin release In long loop negative feedback, elevated blood pressure and sodium levels secondary to angiotensin II eventually decrease renin release via intrarenal baroreceptor and maculadensa pathways, respectively

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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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 Tricyclic antidipressents (TCA): side effects
TCA'S:
Thrombocytopenia
Cardiac (arrhymia, MI, stroke)
Anticholinergic (tachycardia, urinary retention, etc)
Seizures

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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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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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