Codeine

Codeine is methyl morphine, with a methyl substitution on the phenolic hydroxyl group of morphine. It is more lipophilic than morphine and thus crosses the blood–brain barrier faster.

• classified as a simple, or mild analgesic, codeine is often used in low doses as an oral analgesic has a much better oral/parenteral absorption ratio than morphine.
• Effective for mild to moderate pain.
• Constipation occurs
• Dizziness may occur in ambulatory patients.
• More potent histamine-releasing action than does morphine.
• Should not be administered by IV injection.
• Extremely effective antitussive agent and is used therapeutically for suppressing cough.
• In contrast to morphine, codeine overdose can occasionally lead to the production of seizures.
• Seizures can be treated with barbiturates.
• Respiratory depression can be counteracted with Naloxone.
• orally, 30 mg of codeine is equi-analgesic to 600 mg of aspirin, however, the effects of the two are additive, and occasionally synergistic

ANTIASTHMATIC AGENTS

 Classification for antiasthmatic drugs.
 
I. Bronchodilators

i. Sympathomimetics (adrenergic receptor agonists)

Adrenaline, ephedrine, isoprenaline, orciprenaline, salbutamol, terbutaline, salmeterol, bambuterol

ii. Methylxanthines (theophylline and its derivatives)

Theophylline 
Hydroxyethyl theophylline 
Theophylline ethanolate of piperazine

iii. Anticholinergics

Atropine methonitrate 
Ipratropium bromide

II. Mast cell stabilizer

Sodium cromoglycate
Ketotifen 

III. Corticosteroids

Beclomethasone dipropionate 
Beclomethasone (200 µg) with salbutamol

IV. Leukotriene pathway inhibitors 

Montelukast 
Zafirlukast

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.

Lamotrigine (Lamictal): newer; broad spectrum (for most seizure types)

Mechanism: ↓ reactivation of Na channels (↑ refractory period, blocks high frequency cell firing)

Side effects: dizziness, ataxia, fatigue, nausea, no significant drug interactions

Angiotensin

It is generated in the plasma from a precursor plasma globulin. It is involved in the electrolyte balance, plasma
volume and B.P

Angiotensin I:
Renin is an enzyme produced by the kidney in response to a number of factors including adrenergic activity (β1-
receptor) and sodium depletion. Renin converts a circulating glycoprotein (angiotensinogen) into an inactive material angiotensin-I. It gets activation during passage through pulmonary circulation to angiotensin II by (ACE). ACE is located on the luminal surface of capillary endothelial cells, particularly in the lungs & also present in many organ (e.g brain).

Angiotensin II:
Is an active agent, has a vasoconstrictor action on blood vessels & sodium and water retention

Pharmacodynamics

Pharmacodynamics is the study of what drugs do to the body and how they do it.

Dose-Response Relationships

- Basic Features of the Dose-Response Relationship:  The dose-response relationship is graded instead of all-or-nothing (as dose increases, response becomes progressively larger).

- Maximal Efficacy and Relative Potency

- Maximal Efficacy: the largest effects that a drug can produce

- Relative Potency:  Potency refers to the amount of drug that must be given to elicit an effect.

- Potency is rarely an important characteristic of a drug.

- Potency of a drug implies nothing about its maximal efficacy.