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.

Antihypertensives Drugs

CATEGORIES
I.    Diuretics to reduce blood volume 
Chlorothiazide (Diuril)

II. Drugs that interfere with the Renin-Angiotensin System

A. Converting enzyme inhibitors             Captopril , enalapril, Lisinopril

B. Angiotensin receptor antagonists         Saralasin Losartan 

III. Decrease peripheral vascular resistance and/or cardiac output

A. Directly acting vasodilators
1. calcium channel blockers           Nifedipine , Diltiazem,  amlodipine

2. potassium channel activators     Minoxidil 

3. elevation of cGMP                      Nitroprusside 

4. others                                         Hydralazin e

B. Sympathetic nervous system depressants

1. α-blockers                             Prazosin, phentolamine, phenoxybenzamine

2. β-blockers                             Propranolol ,Metoprolol, atenolol

3. norepinephrine synthesis inhibitors     Metyrosine 

4. norepinephrine storage inhibitors     Reserpine
 
5. transmitter release inhibitors         Guanethidine 

6. centrally acting: decrease 
sympathetic outflow                     Clonidine , methyldopa

Histamine: 

Involved in inflammatory and anaphylactic reactions 
Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction.

Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin.

Storage: widely distributed; in tissues, primarily in mast cells; in blood- in basophils, platelets; non-mast cell sites (epidermis, CNS, regenerating cells)

Histamine Stored in complex with:
Heparin
Chondroitin Sulfate
Eosinophilic Chemotactic Factor
Neutrophilic Chemotactic Factor
Proteases

Release: during type I (IgE-mediated) immediate hypersensitivity rxns, tissue injury, in response to some drugs
a.    Process: Fcε receptor on mast cell or basophil binds IgE, when Ag binds → ↑ PLC activity → histamine

Symptoms: bronchoconstriction, ↓ Pa, ↑ capillary permeability, edema

Action

H1 receptors are located mainly on smooth muscle cells in blood vessels and the respiratory and GI tracts. When histamine binds with these receptors producing the following effects.

-Contraction of smooth muscle in the bronchi and bronchioles producing bronchoconstraction.

-stimulation of vagus nerve endings to produce reflex bronchoconstraction and cough.

-Increased permeability of veins and capillaries, which allows fluid to flow into subcutaneous tissues and form edema (little lower blood pressure).

-Increased secretion of mucous glands. Mucosal edema and increased nasal mucus produce the nasal congestion characteristic of allergic rhinitis and the common cold.

-Stimulation of sensory peripheral nerve endings to cause pain and pruritus.

Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation.

H2-receptors present mostly in gastric glands and smooth muscle of some blood vessels. When receptors are stimulated, the main effects are increased secretion of gastric acid and pepsin, increased rate and force of myocardial contraction.

The H3-receptor functions as a negative-feedback mechanism to inhibit histamine synthesis and release in many body tissues. Stimulation of H3 receptors opposes the effects produced by stimulation of H1 receptors.

The H4- receptor is expressed in only a few cell types, and their role in drug action is unclear.

Drugs cause release of histamine: 

Many drugs can cause release of histamine in the body.
-Intracutaneouse morphine injection in humans produced localized redness, localized edema and a diffuse redness. This is due to release of histamine.

-I.V. inj of curare may cause bronchial constriction due to release of histamine.

-codeine , papaverine, meperidine (pethedine), atropine, hydralizine and sympathomimetic amines, histamine releases by these drugs may not be significant unless they are administered I.V in large doses

Pharmacological effects

-  If injected I.V. (0.1 mg of histamine) causes a sharp decline in the blood pressure, flushing of the face and headache. 
- There is also stimulation of gastric acid secretion. 
- If this injection is given to an asthmatic individual, there will be a marked decrease in vital capacity and a sever attack of asthma. 

Circulatory effects of histamine:

The two factors involved in the circulatory action of histamine are:
Arteriolar dilatation and
Capillary permeability
So it leads to loss of plasma from circulation

Effect on gastric secretion:
Histamine is a potent stimulant of gastric Hcl secretion. 

Carbenicillin

Antibiotic that is chemically similar to ampicillin. Active against gram-negative germs. It is well soluble in water and acid-labile.

Ciclopirox:Ciclopirox is a synthetic antifungal agent for topical dermatologic use.

Gabapentin (Neurontin): newer; for generalized tonic-clonic seizures and partial seizures (partial and complex)

Mechanism: unknown but know doesn’t mimic GABA inhibition or block Ca currents

Side effects: dizziness, ataxia, fatigue; drug well-tolerated and no significant drug interactions