NEET MDS Lessons
Pharmacology
Antiplatelet Drugs:
Whereas the anticoagulant drugs such as Warfarin and Heparin suppress the synthesis or activity of the clotting factors and are used to control venous thromboembolic disorders, the antithrombotic drugs suppress platelet function and are used primarily for arterial thrombotic disease. Platelet plugs form the bulk of arterial thrombi.
Acetylsalicylic acid (Aspirin)
• Inhibits release of ADP by platelets and their aggregation by acetylating the enzymes (cyclooxygenases or COX) of the platelet that synthesize the precursors of Thromboxane A2 that is a labile inducer of platelet aggregation and a potent vasoconstrictor.
• Low dose (160-320 mg) may be more effective in inhibiting Thromboxane A2 than PGI2 which has the opposite effect and is synthesized by the endothelium.
• The effect of aspirin is irreversible.
Kinins
Peptide that are mediated in the inflammation.
Action of kinin:
On CVS: vasodilatation in the kidneys, heart, intestine, skin, and liver. It is 10 times active than histamine as vasodilator.
On exocrine and endocrine glands: kinin modulate the tone of pancreas and salivery glands and help regulate GIT motility, also affect the transport of water and electrolytes, glucose and amino acids through epithelial cell transport.
Excretion
Routes of drug excretion
The most important route of drug elimination from the body is via the kidney
Renal Drug Excretion
- Glomerular Filtration
- Passive Tubular Reabsorption: drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood.
- Active Tubular Secretion
Factors that Modify Renal Drug Excretion
- pH Dependent Ionization: manipulating urinary pH to promote the ionization of a drug can decrease passive reabsorption and hasten excretion.
- Competition for Active Tubular Transport
- Age: Infants have a limited capscity to excrete drugs.
Nonrenal Routes of Drug Excretion
Breast Milk
Bile, Lungs, Sweat and Saliva
The kidney is the major organ of excretion. The lungs become very important for volatile substances or volatile metabolites.
Drugs which are eliminated by the kidney are eliminated by:
a) Filtration - no drug is reabsorbed or secreted.
b) Filtration and some of the drug is reabsorbed.
c) Filtration and some secretion.
d) Secretion
By use of the technique of clearance studies, one can determine the process by which the kidney handles the drug.
Renal plasma clearance = U x V ml/min U / Cp = conc. of drug in urine
Cp = conc. of drug in plasma
V = urine flow in ml/min
Renal clearance ratio = renal plasma clearance of drug (ml/min) / GFR (ml/min)
Total Body Clearance = renal + non-renal
COAGULANTS
An agent that produces coagulation (Coagulation is a complex process by which blood forms clots).
ANTICOAGULANTS
An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting.
Anticoagulants:
Calcium Chelators (sodium citrate, EDTA)
Heparin
Dalteparin Sodium (Fragmin) -Low molecular-weight heparin
Enoxaparin - Low molecular-weight heparin
Tinzaparin Sodium - Low molecular-weight heparin
Warfarin
Lepirudin - recombinant form of the natural anticoagulant hirudin: potent and specific Thrombin inhibitor
Bivalirudin - analog of hirudin: potent and specific Thrombin inhibitor
Procoagulants:
Desmopressin acetate
Antiplatelet Drugs:
Acetylsalicylic Acid, Ticlopidine, Sulfinpyrazone, Abciximab , Clopidogrel bisulfate
Fibrinolytic Drugs:
Tissue Plasminogen Activator (t-PA, Activase), Streptokinase (Streptase),
Anistreplase, Urokinase
Antagonists:
Protamine sulfate, Aminocaproic acid
Pharmacological agents used to treat blood coagulation disorders fall in to three major categories:
1. Anticoagulants: Substances that prevent the synthesis of a fibrin network which inhibits coagulation and the formation of arterial thrombi and thromboembolic clots.
2. Antiplatelet agents: Substances that reduce the adhesion and aggregation of platelets.
3. Fibrinolytic agents: Substances that promote the destruction of already formed blood clots or thrombi by disrupting the fibrin mesh.
Sympathomimetics -Adrenergic Agents
The sympathomimetic or adrenergic or adrenomimetic drugs mimic the effects of adrenergic sympathetic nerve stimulation.
These are the important group of therapeutic agents which may be used to maintain blood pressure and in certain cases of severe bronchial asthma.
Mechanism of Action and Adrenoceptors
The catecholamines produce their action by direct combination with receptors located on the cell membrane. The adrenergic receptors are divided into two main groups – alpha and beta.
alpha receptor - stimulation produces excitatory effect and
beta receptor -stimulation usually produces inhibitory effect.
Alpha receptors: There are two major groups of alpha receptors, α1 and α2.
Activation of postsynaptic α1 receptors increases the intracellular concentration of calcium by activation of a phospholipase C in the cell membrane via G protein.
α2 receptor is responsible for inhibition of renin release from the kidney and for central aadrenergically mediated blood pressure depression.
Beta receptors:
a. Beta 1 receptors have approximately equal affinity for adrenaline and noradrenaline and are responsible for myocardial stimulation and renin release.
b. Beta 2 - receptors have a higher affinity for adrenaline than for noradrenaline and are responsible for bronchial muscle relaxation, skeletal muscle vasodilatation and uterine relaxation.
c. Dopamine receptors: The D1 receptor is typically associated with the stimulation of adenylyl cyclase. The important agonist of dopamine receptors is fenoldopam (D1) and bromocriptine (D2) and antagonist is clozapine (D4) .
Adrenergic drugs can also be classified into:
a. Direct sympathomimetics: These act directly on a or/and b adrenoceptors e.g. adrenaline, noradrenaline, isoprenaline, phenylephrine, methoxamine salbutamol etc.
b. Indirect sympathomimetics: They act on adrenergic neurones to release noradrenaline e.g. tyramine.
c. Mixed action sympathomimetics: They act directly as well as indirectly e.g. ephedrine, amphetamine, mephentermine etc.
Pharmacological Action of Sympathomimetics
Heart: Direct effects on the heart are determined largely by β1 receptors.
Adrenaline increases the heart rate, force of myocardial contraction and cardiac output
Blood vessels: Adrenaline and noradrenaline constrict the blood vessels of skin and mucous membranes.
Adrenaline also dilates the blood vessels of the skeletal muscles on account of the preponderance of β2 receptor
Blood pressure: Because of vasoconstriction (α1) and vasodilatation (β2) action of adrenaline, the net result is decrease in total peripheral resistance.
Noradrenaline causes rise in systolic, diastolic and mean blood pressure and does not cause vasodilatation (because of no action on β2 receptors) and increase in peripheral resistance due to its a action.
Isoprenaline causes rise in systolic blood pressure (because of β1 cardiac stimulant action) but marked fall in diastolic blood pressure (because of b2 vasodilatation action) but mean blood pressure generally falls.
GIT: Adrenaline causes relaxation of smooth muscles of GIT and reduce its motility.
Respiratory system: The presence of β2 receptors in bronchial smooth muscle causes relaxation and activation of these receptors by β2 agonists cause bronchodilatation.
Uterus: The response of the uterus to the atecholamines varies according to species
Eye: Mydriasis occur due to contraction of radial muscles of iris, intraocular tension is lowered due to less production of the aqueous humor secondary to vasoconstriction and conjunctival ischemia due to constriction of conjunctival blood vessels.
a. Urinary bladder: Detrusor is relaxed (b) and trigone is constricted (a) and both the actions tend to inhibit
micturition.
b. Spleen: In animals, it causes contraction (due to its a action) of the splenic capsule resulting in increase in number of RBCs in circulation.
c. It also cause contraction of retractor penis, seminal vesicles and vas deferens.
d. Adrenaline causes lacrimation and salivary glands are stimulated.
e. Adrenaline increases the blood sugar level by enhancing hepatic glycogenolysis and also by decreasing the uptake of glucose by peripheral tissues.
Adrenaline inhibits insulin release by its a-receptor stimulant action whereas it stimulates glycogenolysis by its b receptor stimulant action.
f. Adrenaline produces leucocytosis and eosinopenia and accelerates blood coagulation and also stimulates platelet aggregation.
Adverse Effects
Restlessness, anxiety, tremor, headache.
Both adrenaline and noradrenaline cause sudden increase in blood pressure, precipitating sub-arachnoid haemorrhage and occasionally hemiplegia, and ventricular arrhythmias.
May produce anginal pain in patients with ischemic heart disease.
Contraindications
a. In patients with hyperthyroidism.
b. Hypertension.
c. During anaesthesia with halothane and cyclopropane.
d. In angina pectoris.
Therapeutic Uses
Allergic reaction: Adrenaline is drug of choice in the treatment of various acute allergic disorders by acting as a physiological antagonist of histamine (a known mediator of many hypersensitivity reactions). It is used in bronchial asthma, acute angioneurotic edema, acute hypersensitivity reaction to drugs and in the treatment of anaphylactic shock.
Bronchial asthma: When given subcutaneously or by inhalation, adrenaline is a potent drug in the treatment of status asthmaticus.
Cardiac uses: Adrenaline may be used to stimulate the heart in cardiac arrest.
Adrenaline can also be used in Stokes-Adam syndrome, which is a cardiac arrest occurring at the transition of partial to complete heart block. Isoprenaline or orciprenaline may be used for the temporary treatment of partial or complete AV block.
Miscellaneous uses:
a. Phenylephrine is used in fundus examination as mydriatic agent.
b. Amphetamines are sometime used as adjuvant and to counteract sedation caused by antiepileptics.
c. Anoretic drugs can help the obese people.
d. Amphetamine may be useful in nocturnal enuresis in children.
e. Isoxsuprine (uterine relaxant) has been used in threatened abortion and dysmenorrhoea.
Dextromethorphan �
O-methylated dextrorphan,� Excellent oral antitussive,� No analgesic effect,� No GI effects,� No respiratory depression
Ketoprofen
It acts by inhibiting the body's production of prostaglandin.