Operator position

For the right-handed operator, the 8 and 10 o’clock position and for left-handed operators, the corresponding 2 and 4 o’clock position almost always allows for optimal visualization of the injection field.

Mechanism of Action

When a local anesthetic is injected, it is the ionized [cation] form of the local anesthetic that actually binds to anionic channel receptors in the sodium channel, thus blocking the influx of sodium ions which are responsible for lowering the -70mv resting potential towards the firing threshold of -55mv which then results in depolarization of the nerve membrane. However, only the lipid soluble nonionized [base] form of the local anesthetic can penetrate the various barriers [e.g., nerve membrane, fibrous tissue] between the site of injection and the targeted destination which is the sodium channel.

RENIN-ANGIOTENSIN SYSTEM INHIBITORS

The actions of Angiotensin II include an increase in blood pressure and a stimulation of the secretion of aldosterone (a hormone from the adrenal cortex) that promotes sodium retention. By preventing the formation of angiotensin II, blood pressure will be reduced. This is the strategy for development of inhibitors. Useful inhibitors of the renin-angiotensin system are the Angiotensin Converting Enzyme Inhibitors 

First line treatment for: Hypertension , Congestive heart failure [CHF] 

ACE-Inhibitor’s MOA (Angiotensin Converting Enzyme Inhibitors)

Renin-Angiotensin Aldosterone System: 
. Renin & Angiotensin = vasoconstrictor 
. constricts blood vessels & increases BP 
. increases SVR or afterload 
. ACE Inhibitors blocks these effects decreasing SVR & afterload 
 
. Aldosterone = secreted from adrenal glands 
. cause sodium & water reabsorption 
. increase blood volume 
. increase preload 
. ACE I  blocks this and decreases preload 

Types 

Class I: captopril 
Class II (prodrug) : e.g., ramipril, enalapril, perindopril 
Class III ( water soluble) : lisinopril. 

Mechanism of Action 

Inhibition of circulating and tissue angiotensin- converting enzyme. 
Increased formation of bradykinin and vasodilatory prostaglandins. 
Decreased secretion of aldosterone; help sodium excretion. 

Advantages 

- Reduction of cardiovascular morbidity and mortality in patients with atherosclerotic vascular disease, diabetes, and heart failure. 
- Favorable metabolic profile. 
- Improvement in glucose tolerance and insulin resistance. 
- Renal glomerular protection effect especially in diabetes mellitus. 
- Do not adversely affect quality of life. 

Indications 
- Diabetes mellitus, particularly with nephropathy. 
- Congestive heart failure. 
- Following myocardial infraction. 

Side Effects  

- Cough (10 - 30%): a dry irritant cough with tickling sensation in the throat. 
- Skin rash (6%). 
- Postural hypotension in salt depleted or blood volume depleted patients. 
- Angioedema (0.2%) : life threatening. 
- Renal failure: rare, high risk with bilateral renal artery stenosis. 
- Hyperkalaemia 
- Teratogenicity. 

Considerations 
- Contraindications include bilateral renal artery stenosis, pregnancy, known allergy, and hyperkalaemia. 
- High serum creatinine (> 3 mg/dl) is an indication for careful monitoring of renal function, and potassium. Benefits can still be obtained in spite of renal insufficiency. 
- A slight stable increase in serum creatinine after the introduction of ACE inhibitors does not limit use. 
- ACE-I are more effective when combined with diuretics and moderate salt restriction. 
 

ACE inhibitors drugs

Captopril 50-150 mg       
Enalapril 2.5-40 mg
Lisinopril 10-40 mg
Ramipril 2.5-20  mg        
Perindopril 2-8  mg

Angiotensin Receptor Blocker  

Losartan    25-100 mg 
Candesartan 4-32  mg
Telmisartan 20-80 mg

Mechanism of action 

They act by blocking type I angiotensin II receptors generally, producing more blockade of the renin -angiotensin - aldosterone axis. 

Advantages 

• Similar metabolic profile to that of ACE-I. 
• Renal protection. 
• They do not produce cough. 

Indications 

Patients with a compelling indication for ACE-I and who can not tolerate them because of cough or allergic reactions. 

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.

Antidepressant Drugs

Drug treatment of depression is based on increasing serotonin (5-HT) or NE (or both) at synapses in selective tracts in the brain. This can be accomplished by different mechanisms.

Treatment takes several weeks to reach full clinical efficacy.

1. Tricyclic antidepressants (TCAs)
a. Amitriptyline
b. Desipramine
c. Doxepin
d. Imipramine
e. Protriptyline

2. Selective serotonin reuptake inhibitors (SSRIs)
a. Fluoxetine
b. Paroxetine
c. Sertraline
d. Fluvoxamine
e. Citalopram

3. Monoamine oxidase inhibitors (MAOIs)
a. Tranylcypromine
b. Phenelzine

4. Miscellaneous antidepressants

a. Bupropion
b. Maprotiline
c. Mirtazapine
d. Trazodone
e. St. John’s Wort

Antimania Drugs

These drugs are used to treat manic-depressive illness.

1. Lithium
2. Carbamazepine
3. Valproic acid

Benzodiazepines
All metabolites are active sedatives except the final glucuronide product. Elimination half-life varies a great deal from drug to drug.

?-Hydroxylation is a rapid route of metabolism that is unique to triazolam, midazolam, and alprazolam.
This accounts for the very rapid metabolism and short sedative actions of these drugs.

Pharmacological effects of benzodiazepines

- Antianxiety.
- Sedation.
- Anticonvulsant (including drug-induced convulsions).
- Amnesia, especially drugs like triazolam.
- Relax skeletal muscle (act on CNS polysynaptic pathways).

Indications

- IV sedation, (e.g., midazolam, diazepam, lorazepam).
- Antianxiety.
- Sleep induction.
- Anticonvulsant (e.g., diazepam, clonazepam).
- Panic disorders.
- Muscle relaxation.


Adverse effects

- Ataxia, confusion.
- Excessive sedation.
- Amnesia (not a desired effect with daytime sedation).
- Altered sleep patterns (increase stage 2 and decrease stage 4 sleep).