Lecture notes, lecture 3 - Pharmacodynamics PDF

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Pharmacodynamics...

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Lecture Three: Pharmacodynamics Pharmacodynamics: the mechanism whereby drugs exert their effect on the body. Chemical Actions    

Agents that act on simple chemical processes in the body. For example, magnesium hydroxide (used in antacids) reacts with HCl in stomach to = magnesium chloride and water. Aluminium and magnesium tend to be used together in antacids, as one is a laxative and the other causes constipation. Acetylcysteine and Methionine – stimulates glutathione in liver which conjugates with the toxic metabolite of paracetamol, making it water soluble and allowing it to be cleared by the renal system.

Physical Actions    

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Drugs that act by a physical mechanism. Not many do this, as there are few purely physical processes that occur in the body. Drugs can be taken to correct osmotic imbalances, or disrupt normal osmotic balances to produce a therapeutic effect. Surfactant (surface-active agent): lungs. Synthetic versions of palmitoyl lecithin is used for lung function in premature infants – provides a physical surface tension. Simethicone: used to relieve conditions in which excess GI gases are causing problems. Lowers surface tension of GI fluids, destabilizing mucus bubbles and allowing gas (CO2) to aggregate and be expelled. Activated charcoal: relieves flatulence, and is used in cases of poisoning. Adsorbent – large surface area which binds to many materials, facilitating their removal from the body.

Enzymatic Actions  

Enzymes facilitate biochemical reactions in body, and are specific for a certain molecule/ task. Many drugs act on enzyme function producing altered biochemistry.

Competitive inhibition:  

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Drug competes with natural substrate for active centre of enzyme. Drug is a look-alike substrate which DOES NOT react. Additional time is taken up until the correct substrate reacts with the enzyme. Reaction is slowed down. Can be countered by increasing the substrate concentration – basis of some antidotes. Sulphonamide drugs interfere with folic acid synthesis in bacteria. They are competitive inhibitors of the compound 4-aminobenzoic acid. Acetylcholinesterase inhibitors used in treatment of Myasthenia gravis.

Non-competitive inhibition:

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Drug produces an irreversible change in the enzyme chemistry, changes its 3D shape and therefore renders it incapacitated. The competitive inhibitor binds to a site that is distinct and generally remote from the active centre. Rate of product formation declines. Reaction cannot be countered by increasing substrate concentration. Aspirin – anti-platelet function. MAOI’s (some) – phenelzine. MAO enzymes in liver/ gut are different to MAO enzymes in CNS. MAOI’s will target only one type of tissue due to differences in enzyme structure – eg. Anti-depressant MAOI’s specific for brain enzymes. Acetylcholinesterase inhibitors – Neostigmine and industrial/ military insecticides.

Receptor Actions 

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All natural bodily chemicals react with a specific chemical receptor on their ‘target cells’. Receptors are highly modified proteins with CHO and other groups attached, which are found on both cell membranes and in the cytoplasm. Many cellular functions are controlled by whether or not the cell’s receptors are being activated. Many drugs similar to, or have similar chemical groups to the naturally occurring chemical and have ability to bind to receptor. Can activate receptor – agonist. This mimics the endogenous action of the body’s own chemical. Can block receptor – antagonist. This blocks the action of the body’s own chemical. Both agonist and antagonist actions are competitive with the natural endogenous neurotransmitter. Competitive inhibition - similar to enzymes. Antagonism can be non-competitive – drug binds firmly and irreversibly to receptor until drug is destroyed. There is no antidote to this type of antagonism. Partial agonist – partial chemical fit to receptor resulting in partial activation of receptor action. Suxamethonium – neuromuscular blocking agent with a very strong affinity for receptors – cannot be removed from receptors and is eventually broken down (noncompetitive). It is an antagonist, as it binds to cell receptors at neuromuscular junction causing paralysis. However, it has an agonist effect as it actively ‘depolarizes’ NMJ paralysis agent – does not just block receptor. This type of drug is called an inverse agonist. Stimulates receptor to produce a reaction opposite to what the natural chemical would produce. Atropine – cholinergic antagonist. Actions occur at any cholinergic synapse. Blocks acetylcholine receptor = decreased acetylcholine. Can be overcome by the addition of more acetylcholine. Affinity: the bond strength between the drug and the receptor. Specificity: “lock and key” – some drugs may only activate one receptor type, others several. Efficacy: ability of drug to mediate a therapeutic effect. Potency: the measure of the quantity/ concentration of a drug needed to mediate a therapeutic effect.

Ion Channel Blockers

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Drugs may affect enzymes or receptors associated in gating of ion channels. Sodium, potassium and calcium channels are often affected. Local anaesthetic agents often act by blocking Na+ and K+ channels. Ca+ channel blockers are used to change cardiac output, for example, Nifedipine. This is because calcium is needed for heart to pump. Decreasing calcium in cardiac tissue = dilation of smooth muscle, slowing of heart beat.

Second Messenger Alteration  

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Receptor stimulation produces a conformational structure change in the receptor, which then initiates sequences of other biochemical changes. When a ‘first messenger’ acts on a receptor, it sometimes acts on G-Proteins. One type of G-Protein stimulates (and sometimes inhibits) adenylate cyclase. This converts ATP to cyclic AMP. cAMP then goes on to activate many cellular functions, including activation of enzymes involved in ion channel function. As cAMP causes the effect, it is known as a second messenger. Theophylline – directly affects second messenger function by inhibiting cAMP metabolism. Used in treatment of asthma, as increases areolar ventilation.

Drug Development, Evaluation and Safety      

Screening/ isolation of chemicals with potential therapeutic uses: 1 – 5 years. Pre-clinical testing (in vitro, on animals) – looks at agents chemistry, mechanism of action, therapeutic uses, potency, efficacy and toxicity. Australian Drug Evaluation Committee (of the Therapeutic Goods Administration) – assesses the case for clinical trials. Clinical trials may commence – 7- 10 years later. Many drugs have a low TI, and therefore must be administered carefully and monitored. Examples: Gentamicin, Digoxin, Lithium and Warfarin. Each drugs margin of safety is a measure of the TI.

Side Effects   

An alteration of similar physiological processes at sites distant to the primary site of action. Usually predictable. For example, Atropine (anti-cholinergic drug, can be prescribed for bradycardia). Side effects are urinary retention and reduction in gastric motility. Sometimes the ‘side effects’ are the primary reason for prescribing the drug.

Idiosyncrasies  

Non-predictable reactions to drugs, often involving an inappropriate immune response. Type I hypersensitivity reactions are the most common. Drug binds to proteins in plasma and acts like an antigen. Immune response is triggered by its interaction with specific IgE antibodies. Excess IgE antibodies bind to basophils and mast cells. On re-exposure to the antigen, the membranes of the basophils and mast cells rupture,

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resulting in systemic release of chemical mediators (histamine, serotonin, chemotaxins, MAF) from these cells. This induces a widespread vasodilator response = circulatory shock called Anaphylaxis. Also causes bronchospasm due to constriction of bronchial smooth muscle. Antidote: adrenaline (adrenergic agonist) – causes vasoconstriction, bronchodilation and relaxation of GI smooth muscle.

Pharmacogenetics   

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From 1950’s: patterns of inheritance in relation to drug effects were studied. N-acetyltransferase, methyltransferase and the cytochrome 450 group – affected enzymes. Genetic polymorphism: when a genetic trait can be expressed within the population in two or more different forms. Over 20 enzymes involved in drug metabolism have different variations. This can have a profound significance for drug treatment for members of the population classified as non-responders. Poor and extensive metabolisers (non-responders and responders). Most drugs display a normal distribution curve. Many, however, display a ‘bimodal’ response curve (there are two peak frequencies of responsiveness).

Significant polymorphisms:    

Acetylation – N-acetyltransferase is involved in the acetylation of sulphonamides, some anti-depressants and caffeine. Methylation – penicillins, catecholamines and cytotoxic agents. Cytochrome p450 – benzodiazepines, codeine and derivatives. Other – suxamethonium, warfarin, chloramphenicol and corticosteroids.

Erythrocyte reactions:  

Sulphonamides, anti-malarial drugs, some NSAID’s and Chloramphenicol may induce changes in erythrocytes – may kill them, change their number or change structure. Inherited polymorphism in enzymes are involved in erythropoiesis....