Chronic Pharmacology

·        Introduction.

·        Interference with self-regulating systems.

·        Tolerance.

·        Dependence.

·        Withdrawal.

Introduction

1.    The proportion of the population taking drugs continuously for large portions of their lives increases as tolerable suppressive and prophylactic remedies for chronic or recurrent conditions are developed.

2.    In some cases long-term treatment introduces significant hazard into patients’ lives and the cure can be worse than the disease if it is not skillfully managed.

3.    In general, the dangers of a drug are not markedly increased if therapy lasts years rather than months; exceptions include renal damage due to analgesic mixtures and carcinogenicity.

Interference with Self-regulating Systems

1.       Homeostasis: when self-regulating physiological systems are subject to interference, their control mechanisms response to minimize the effects of the interference and to restore the previous steady state of rhythm.

2.    If the body successfully restores the previous steady state of rhythm then the subject has become tolerance to the drug.

3.       Feedback Systems:

a.    The endocrine system serves fluctuating body needs.

b.    An administered hormone or hormone analogue activates the receptors of the feedback system so that high doses cause suppression of natural production of the hormone.

c.    On withdrawal of the administered hormone restoration of the normal mechanism takes time, e.g. hypothalamic/pituitary/adrenal cortex system can take months to recover sensitivity.

d.       Regulation of receptors:

a.    The number of receptors on cells, the number occupied and the capacity of the receptor to response can change in response to the concentration of the specific binding molecule or ligand.

b.    The effect always tend to restore cell function to its normal or usual state.

Tolerance

1.       Tolerance is said to have developed when it becomes necessary to increase the dose of a drug to obtain an effect previously obtained with a smaller dose.

2.       When responsiveness diminishes rapidly after administration of a drug, the response is said to be subjected to tachyphylaxis.

3.       Down-regulation of receptors: tolerant or refractory state seen in severe asthmatics who no longer respond to b₂-agonists due to decrease in receptor density following prolonged use.

4.       Physiological compensatory mechanisms: compensatory increases in fluid retention by the kidney can contribute to the tolerance to the anti-hypertensive effects of a vasodilator drug.

5.       Enzyme induction: tolerance develops with long-term phenytoin use due to its induction of its own metabolism.

6.    In the clinical setting, the dosage of a drug would have to be increased gradually over time to counter tolerance and to produce a therapeutic response.

7.    An alternative is to use various combinations of drugs to reduce tolerance to a particular drug and to maximize therapeutic effect.

Dependence

1.    Drug dependence: a state arising from repeated, periodic or continuous administration of a drug that results in harm to the individual.

2.    The subject feels a desire, need or compulsion to continue using the drug and feels ill if abruptly deprived of it (abstinence or withdrawal syndrome).

3.    Drug dependence is characterized by:

a.       Psychological dependence: the first to appear; there is emotional distress if the drug is withdrawn.

b.       Physical dependence: accompanies psychological dependence in some cases; there is a physical illness if the drug is withdrawn.

c.       Tolerance.

4.       Psychological dependence:

a.    This may occur with any drug that alters consciousness however bizarre, e.g. muscarine and to some that, in ordinary doses, do not, e.g. non-narcotic analgesics, purgatives, diuretics.

b.       Psychological dependence can occur merely on a tablet or injection, regardless of its content, as well as to drug substances.

c.    Mild dependence does not require that a drug should have important psychic effects; the subjects’ beliefs as to what it does are as important.

5.       Physical dependence:

a.       Physical dependence and tolerance imply that adaptive changes have taken place in body tissues so that the drug is abruptly withdrawn these adaptive changes are left unopposed, resulting generally in a rebound overactivity.

b.       Physical dependence develops to a substantial degrees with cerebral depressants, but is minor or absent with excitant drugs.

c.       There is commonly cross-tolerance between drugs of similar, and sometimes even of dissimilar chemical groups, e.g. alcohol and benzodiazepines.

Withdrawal

1.    A patient may suffer from withdrawal effects or symptoms after the discontinuation of a drug.

2.       Withdrawal symptoms are physical symptoms that manifest in direct association with the withdrawal of the drug.

3.    Up-regulation:

a.       Prolonged contact with an antagonist leads to formation of new receptors.

b.       When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiological concentrations of agonist.

c.       Example: worsening of angina pectoris in patients following abrupt withdrawal of a beta-blocker as normal concentrations of circulating catecholamines now have access to an increased number of receptors.

4.       Down-regulation:

a.    After discontinuation of an agonist drug, the number of receptors may decrease to too low a number for the endogenous agonist to produce effective stimulation.

b.       Example: withdrawal of adrenaline used to treat chronic obstructive pulmonary disease may result in bradycardia and hypotension.

5.       Clinical important consequences have occurred in abrupt withdrawal of the following:

a.    Anti-hypertensives.

b.    Beta blockers.

c.    All depressants: opioids, sedatives, alcohol, hypnotics.

d.    Anti-epileptics.

e.       TCAs.

f.     Anti-parkinsonian agents.

g.       Corticosteroids.

Hazards of Chronic drug use