Morphine

Morphine is effective orally, but is much less effective than when given parenterally due to first-pass metabolism in the liver. Metabolism involves glucuronide formation, the product of which is excreted in the urine.

1. Central Nervous System Effects

• Morphine has mixed depressant and stimulatory actions on the CNS.

• Analgesia:

• Dysphoria – Euphoria

- morphine directly stimulates the chemoreceptor trigger zone, but later depresses the vomiting center in the brain stem. This center is outside the blood/brain barrier.

- opiates appear to relieve anxiety

• Morphine causes the release of histamine and abolishes hunger.

- causes the body to feel warm and the face and nose to itch.

• Pupils are constricted.- due to stimulation of the nuclei of the third cranial nerves.

- tolerance does not develop to this effect.

• Cough reflex is inhibited. - this is not a stereospecific effect.

- dextromethorphan will suppress cough but will not produce analgesia.

• Respiration is depressed

- due to a direct effect on the brain stem respiratory center.

- death from narcotic overdose is nearly always due to respiratory arrest.

- the mechanism of respiratory depression involves:

• a reduction in the responsiveness of the brain stem respiratory centers to an increase in pCO₂.

• depression of brain stem centers that regulate respiratory rhythm.

- hypoxic stimulation of respiration is less affected and O2 administration can produce apnea.

2. Cardiovascular Effects

• Postural orthostatic hypotension.- due primarily to peripheral vasodilation, which may be due in part to histamine release.

• Cerebral circulation is also indirectly influenced by increased pCO2, which leads to cerebral vasodilation and increased cerebrospinal fluid pressure.

• In congestive heart failure, morphine decreases the left ventricular workload and myocardial oxygen demand.

3. Endocrine Effects

• Increases prolactin secretion

• Increases vasopressin (ADH) secretion

• Decreases pituitary gonadotropin (LH & FSH) secretion.

• Decreases stress induced ACTH secretion.

4. Gastrointestinal Tract Effects

• Constipation (tolerance does not develop to this effect).

• Several of these agents can be used in the treatment of diarrhea.

There is an increase in smooth muscle tone and a decrease in propulsive  contractions.

Adverse Reactions

Generally direct extensions of their pharmacological actions.

1. respiratory depression, apnea

2. nausea and vomiting

3. dizziness, orthostatic hypotension, edema

4. mental clouding, drowsiness

5. constipation, ileus

6. biliary spasm (colic)

7. dry mouth

8. urine retention, urinary hesitancy

9. hypersensitivity reactions (contact dermatitis, urticaria)

Precautions

1. respiratory depression, particularly in the newborn

3. orthostatic hypotension

4. histamine release (asthma, shock)

5. drug interactions (other CNS depressants)

6. tolerance:

- analgesia, euphoria, nausea and vomiting, respiratory depression

7. physical dependence (psychological & physiological)

Beta - Adrenoceptor blocking Agents

These are the agents which block the action of sympathetic nerve stimulation and circulating sympathomimetic amines on the beta adrenergic receptors. 

At the cellular level, they inhibit the activity of the membrane cAMP. The main effect is to reduce cardiac activity by diminishing β1 receptor stimulation in the heart. This decreases the rate and force of myocardial contraction of the heart, and decreases the rate of conduction of impulses through the conduction system.

Beta blockers may further be classified on basis of their site of action into following two main classes namely 

cardioselective beta blockers (selective beta 1 blockers) 

non selective beta 1 + beta 2 blockers 

Classification for beta adrenergic blocking agents.

A. Non-selective (β1+β2)

Propranolol  Sotalol  Nadolol Timolol  Alprenolol Pindolol 

With additional alpha blocking activity

Labetalol  Carvedilol  

B. β1 Selective (cardioselective)

Metoprolol  Atenolol  Bisoprolol  Celiprolol  

C. β2  Selective

Butoxamine 

Mechanisms of Action of beta blocker

Beta adrenoceptor Blockers competitively antagonize the responses to catecholamines that are mediated by beta-receptors and other
adrenomimetics at β-receptors 

Because the β-receptors of the heart are primarily of the β1 type and those in the pulmonary and vascular smooth muscle are β2 receptors, β1-selective antagonists are frequently referred to as cardioselective blockers. 

β-adrenergic receptor blockers (β blockers)
1. Used more often than α blockers.
2. Some are partial agonists (have intrinsic sympathomimetic activity).
3. Propranolol is the prototype of nonselective β blockers.
4. β blocker effects: lower blood pressure, reduce angina, reduce risk after myocardial infarction, reduce heart rate and force, have antiarrhythmic effect, cause hypoglycemia in diabetics, lower intraocular pressure.
5. Carvedilol: a nonselective β blocker that also blocks α receptors; used for heart failure.
 

Thiopental 

- A barbiturate that is generally used to induce anesthesia.
- The temporal course of effects from induction to recovery depends almost entirely upon progressive redistribution.
- Metabolic degradation or excretion during anesthesia is negligible, except in the case of methohexital.
- The barbiturates produce minimal analgesia.
- Respiratory depression may be pronounced.
- Cardiac output is reduced while total peripheral resistance is increased.
- It does not sensitize the heart to catecholamines.
- It may cause bronchiospasm, especially in asthmatics.
- It is contraindicated in acute intermittent porphyria.

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

Examples of calculations of doses of vasoconstrictors

Ratio concentrations represent grams per millilitre

1:100,000 = 0.01 mg/mL or 10 µg/mL

1:200,000 = 0.005 mg/mL or 5 µg/mL

1:50,000 = 0.02 mg/mL or 20 µg/mL

1 cartridge of epinephrine 1:200,000 = 9 µg

1 cartridge of epinephrine 1:100,000 = 18 µg

1 cartridge of epinephrine 1:50,000 = 36 µg

1 cartridge of levonordefrin 1:20,000 = 90 µg

CHOLINERGIC DRUGS

Produce actions similar to Acetylcholine (Ach)

Cholinergic Agonists
1 Acetylcholine  2 Methacholine  3. Carbachol 4 Bethnechol

Alkaloids
1.Muscarine 2 Pilocarpine 3. Arecoline

MECHANISM OF ACTION
I Heart- hyperpolarizes the SA node and decreases the rate of diastolic depolarisation. thus the frequcncy of impulse generation is decreased. bradycardia.
2 Blood vessels- vasodilatation
3. Smooth muscles - increased contraction. increased tone. increased peristalsis.
4. Glands- increased sweating. increased lacrimation.
5 Eye- contraction of the circular muscle of iris (miosis).

Nicotinic action
Autonomic ganglia - stimu1ation of sympathetic and parasympathetic system.
Skeletalmuscles - contraction of fibres.
CNS..No effect as it does not penetrate the blood-brain barrier.

Toxic effects
Flushing. sweating.salivation. cramps. belching. involuntary mictuirition. defaccation.

Contraindication
1.. Anginapectoris- decreases the coronary flow.
2 Pepticulcer - increases the gastric secretion
3 Asthma- bronchoconstriction
4 Hyperthyroidisim

Cholinomimetic Alkaloids
Pilocarpine
Prominent muscarinic actions. causes marked sweating. salivation. Increase of secretions. small doses cause fall in BP but higher doses increase in BP. Applied to the eye cause miosis. fall in intraocular tension

Uses
I. .Open angle glaucoma
2. To counteract mydriasis

Anticholinesterase
They inhibit the enzyme cholinestrase and prolong the action of Ach

Reversible 
Physostigamine, Ncostigamine, Pyridostigamine, Ambenonium, Edrophonium, Demecarium

Irreverible
Dyflos. Echothiphate.

Pharmacological Actions
I Ganglia - persistent depolarisation of ganglionic nicotinic receptors.
2 CVS - unprcdictable as Muscarinic-I receptor causes bradycardia but ganglionic stimulation
tachycardia.
3. Skeletal muscles - as Ach is not destroyed and rebinds to the same receptor or it diffuses on to the neighbouring receptors to cause repetitive firing. twitching and fasciculations.

Uses 
I As miotic
a) Glaucoma :  Acute congestive (narrow angle) glaucoma,  Chronic simple (wide angle)  glaucoma
b) Counter act  atropine mydriasis.
2) Post operative paralytic ileus
3) Myasthenia gravis
4) Postoperativedecurarization
5) Cobra bite
6) Belladona poisoning
7) Other drug overdoses