Cholinergic system and drugs

• Acetylcholine (Ach) is a neurotransmitter.
• It has got 2 receptors-muscuranic and nicotinic receptors
• Muscuranic receptors are of three types-M1,M2,M3
• Nicotinic receptor is of two types Nm & Nn
• M2,M3 receptors are of more significance and would be discussed in this article.
• M2 receptors are present on heart and they cause bradycardia,marked decrease in force of contraction and rate of conduction.
• M3 receptors are present on glands and regulate there secretion.They are also present on vessels and causes vasodilatation by releasing EDRF.
• Actions-

1. Ach causes bradycardia,slow conduction and reduced contraction
2. Ach causes vasodilatation.Although they supply only vessels of face and neck,so flushing is seen on face.
3. Ach causes constriction of smooth muscles.They are potent broncho constrictor  
4. Ach increases secretion from all glands like salivary,lacrimal,sweat glands

• Cholinesterase is the enzyme that causes lysis of Ach.Anticholinesterase drugs mimic the action of Ach.
• Some anticholinesterase drugs are - Physostigmine;Neostigmine

Adrenergic System and Drugs(catecholamines)

• Understanding Nervous system-

                                 CNS-Central Nervous System.Consist of Brain and Spinal cord

                                 PNS-Peripheral Nervous System.Consist of ganglia and nerves.Connect CNS to other 

                                           parts of body.It consist of two systems-

                                           Somatic nervous system & Autonomic nervous system

                                           Somatic nervous system is related to voluntary muscles like that of limbs 

                                           Autonomic nervous system is related to involuntary muscle and it further divided 

                                           into two systems as sympathetic and para sympathetic systems. 

                                 Sympathetic system-Its a thoracicolumbar system.It consist of spinal nerves only.This

                                           system uses nor adrenaline and acetylcholine as neurotransmitter.Acetylcholine is 

                                           released by the presynaptic neuron.Noradrenaline is relaesed by the post 

                                           synaptic neurone.

                                 Parasympathetic system-Its a cranisacral system.It consist of spinal and cranial nerves

                                    III,VII,IX & X.This system utilizes acetylcholine as a nurotransmitter.

• Adrenaline has got two receptors for conducting its action-Alpha receptors and Beta receptors.Alpha receptors are further of two types-Alpha 1 & Alpha 2.Beta receptors are of three types-Beta 1,Beta 2 & Beta 3.Each receptor is present on a specific site,for eg: Beta 1 is present heart;Beta 2 is present on bronchi,blood vessels,uterus; alpha 1 is present on blood vessels.
• At large doses of adrenaline alpha response predominates.
• Adrenaline cause increase in heart rate,force of contraction and conduction velocity.This response is due to beta 1 receptor action.
• Adrenaline can cause both vasoconstriction and vasodilatation.Adrenaline causes vasoconstriction in cutaneous,mucous membrane and renal beds.Its due to alpha 1 receptors.Vasodilatation occurs in skeletal and coronaries vessels.Its due to beta 2 receptors.
• When adrenaline is given slowly S.C. than it causes increase in systolic blood pressure(due to increase in cardiac output) but decrease in diastolic blood pressure(due to decrease in peripheral vascular resistance).Mean B.P. generally rises.
• When adrenaline is given rapidly through I.V. than adrenaline concentration increases rapidly in blood and as such alpha receptors become more active towards adrenaline.This leads to increase in both the systolic and diastolic blood pressure( due to increase in cardiac output as well as vasoconstriction even in skeletal muscles).But this increase is just for a short period of time.As the concentration of adrenaline decreases Diastolic Blood pressure drops again.
• Adrenaline causes broncho dilatation.This action is due to beta 2 receptor.
• Adrenaline increases blood flow to skeletal muscles and coronaries arteries.
• Adrenaline should not be given in cases of hyperthyroidism,Angina & hypertension.
• Should be cautiously used in pregnant ladies.
• Dose:0.2-0.5 mg S.C/I.M

                       

Corticosteroids

• Adrenal Cortex produces glucocorticoid and mineralocorticoids.They both are termed as corticosteroids.
• Produced from cholesterol
• At the time of stress,adrenaline is released directly from adrenal medulla.At the same time stress and adrenaline also stimulate higher centers, hypothalamus and anterior pituitary to releases releasing factors,which acts on adrenal cortex provoking the production of coticosteroids.Its must to understand that adrenaline manage stress for short time,where as corticosteroids manage it for longer terms.
• Glucocorticoid increases blood glucose level
• Also causes protein break down, muscle wasting is seen
• Glucocorticoid increases myocardial contractility,maintain tone of arterioles and restrict membrane permeability.They have permissive effect on pressor action of adrenaline and angiotensin.In a cyclic manner glucocorticoid stimulates kidney to release angiotensin & this angiotensin acts on adrenal cortex to release coticosteroids.Angiotensin causes sodium retention and has a vasopressor action.
• Inflammatory Responses-Causes reduction of:capillary permeability,local exudation,cellular infiltration,phagocytic activity,scar formation and healing.Cardinal signs of inflammation are suppressed.
• Corticosteroids favour spread of infections as capacity of defensive cells to kill microorganisms is impaired.
• Coticosteroids suppress all types of allergic and hypersensitivity reactions.
• Steroids are powerful drugs.They can be life saving and at the same time they can be life threatening

1. Single dose is not harmful.can be used in mortal crisis
2. Short courses of heavy doses are not harmful,in the absence of contraindications
3. Don't withdraw immediately,can lead to adrenal insufficiency
4. In cases where fast action is needed like that in case of anaphylactic shock adrenaline must be preferred over steroids as they take 1 to 2 hours to show the effect.
5. If they are used in cases of high infectivity than it should be administered only when proper antibiotic coverage has been maintained.

• Should be cautiously used in cases of hypertension and Cardiac disorders.
• Dexamethasone- Anti inflammatory & allergic dose 0.5-5 mg/day oral

                                     Shock 4-20 mg/day i.v/i.m 

                                     Brand name-Dexona 0.5 mg tab, 4 mg/ml for i.v. i.m. inj.

• Betamethasone- Dose 0.5-5 mg/day oral

                                             4-20 mg/day i.v/i.m for inj.

                                    Brand name-Betnesol

• Prednisolone- Dose 5-60 mg/day oral

                                        10-40 mg i.m/i.v

NSAIDS-Non Steroidal Anti Inflammatory Drugs

• Cyclooxygenase(COX) inhibition is recognized as the most important mechanism of action.
• COX is an enzyme that is responsible for the formation of prostaglandins and thromboxane.
• Prostaglandins are the main mediators of inflammation alongwith leukotrienes
• Thromboxane is a potent vasoconstrictor,released from platelets,increases platelet aggregation.
• Leukotriene is another mediator of inflammation which is released from leukocytes,they are produced by enzyme lipooxygenase(LOX)
• NSAIDS can only inhibit COX enzyme,they cant inhibit LOX enzyme.whereas glucocorticoids can inhibit all inflammatory mediators.
• There are two types of COX enxymes,COX1 & COX 2.
• COX1 is seen in almost all tissues whereas COX 2 is found in inflammed tissues
• NSAIDS action-

1. Analgesic
2. Anti Inflammatory
3. Anti Pyretic
4. Anti Thrombotic

• NSAIDS Side effects due to PG synthesis inhibition-

1. Causes gastric erosion- * inhibit synthesis of gastroprotective PGs

                                              * Back diffusion of hydrogen ion in gastric mucosa

     2.  Bleeding tendencies- Due to inhibition of thromboxane synthesis

     3.  Exacerbation of asthmatic reactions-Asthmatic patients are more prone to leukotrienes,which are bronchoconstrictors.As NSAIDS inhibit PG synthesis all arachidonic acid is used to form leukotrienes.

     4.  Causes sodium & water retention.

     5.  Prolongation of labour

• Contraindicated in- 

1. Asthmatic patients
2. Pregnant ladies in 3rd trimester
3. Liver insufficiency
4. Gastric ulcers
5. 1 week before surgeries
6. Cautiously used in diabetics

• Piroxicam- Non selective COX inhibitor.Potent anti inflammatory and potent analgesic.Prolongs bleeding time.Causes gastric discomfort

           Dose-20 mg BD/OD 

           Brand name-Dolonex 10,20 mg caps.

• Ketorolac- Non selective COX inhibitor.Potent analgesic and modest anti inflammatory.Not to be used for more than 5days

           Dose-10-20 mg 6 hourly

           Brand name-Ketorol 10 mg tab.

• Other non selective COX inhibitors-ibuprofen;indomethacin
• Nimesulide-Preferential COX 2 inhibitor. Doesn't exacerbate asthmatic attacks, preferred NSAID in asthmatic patients.Hepatic toxic.Gastrointestinal disturbances.Not to be given to children and pregnant ladies.

          Dose-100mg BD

          Brand name-Nimegesic100mg tab.

• Paracetamol-Potent analgesic.Mild anti inflammatory.Gastric erosion is rare. Doesn't prolong bleeding time.contraindicated in liver insufficiency.

          Dose-0.5-1gm TDS

          Brand name-Crocin 0.5,1 mg tab.