SedativesSedativesHypnotics

Objectives: Objectives:
At the end of the chapter, the student is expected to:  Define terminologies relevant to sedativesedative-hypnotics.  Classify and describe the mechanism of action and effects of sedative-hypnotic sedativedrugs.

deFiniTions
Sedative [anxiolytic] -Reduces anxiety -Little or no effect on motor or mental functions -Suppression of responsiveness to a constant level of stimulation -Decreased spontaneous activity and ideation

Hypnotic -Produces drowsiness -Encourage onset and maintenance of sleep

SEDATIVESEDATIVE-HYPNOTIC DRUGS

Benzodiazepines
Effects Reduction of anxiety Sedative and hypnotic actions Anticonvulsant Muscle relaxant Most effects are due to action of drugs on the CNS Peripheral action: Coronary vasodilation Neuromuscular blockade

 

Mode of action Potentiate GABAergic inhibition in all levels of the neuroaxis Increases the efficiency of GABAergic synaptic inhibition Does not directly activate GABA receptors Increases the frequency of channel opening Receptors located in the gamma subunit of the GABA receptor

Organ level effects

Sedation  Suppression of responsiveness  Decreased spontaneous activity and ideation  Anterograde amnesic effect at sedative doses Hypnosis induces sleep  Latency of sleep onset is decreased  Duration of stage 2 nrem sleep is increased  Duration of rem stage is decreased  Duration of slow wave sleep [stage 3 and 4 nrem sleep] is decreased Anticonvulsant effects  Prevent development / spread of epileptiform activity Muscle relaxation  Inhibitory effect on  Polysynaptic reflexes  Internuncial neurons  Depress transmission at the neuromuscular junction Respiratory effects  Hypnotic doses, no effect in normal subjects  Higher doses, decreases the hypoxic drive  Apnea when combined with another CNS depressant Cardiovascular system  Minor effects in normal subjects  Preanesthetic dose  Increase heart rate  Decrease blood pressure GI tract  Diazepam decreases nocturnal gastric secretion

Barbiturates
     

Barbituric acid derivative NonNon-selective CNS depressants Reversibly depress the activity of all excitable tissue Weak direct effects on peripheral excitable tissue Replaced by benzodiazepines as sedative hypnotics Able to induce full surgical anesthesia  Pain perception unimpaired until unconscious  In slam doses increase the perception of pain

Mode of Action Potentiates GABA-induced increases in chloride GABAconductance Prolongs the periods of channel opening In high concentrations, GABA-mimetic GABAReduces glutamate-induced depolarizations [AMPA glutamatesubtypes of glutamate receptors] Inhibits the function of voltage dependent Na+ and K+ channels

Organ level effects

 

Sedation Hypnosis
decreases duration of REM and slow wave sleep decrease sleep latency and number of awakenings

  

Anesthesia Anticonvulsant effects Peripheral nervous structures

depresses transmission in autonomic ganglia, reduces nicotinic excitation by choline esters enhances the effect of tubocurarine and decamethonium at the neuromuscular junction

Respiration depresses the respiratory drive Cardiovascular system given orally in sedative or hypnotic doses, does not produce overt cardiovascular effects direct depression of the cardiac contractility occurs only when doses several times required to cause anesthesia is used GI tract decreases the tonus of the GI musculature and amplitude of rhythmic contraction hypnotic dose does not significantly delay gastric emptying time Liver inducing effect on the microsomal drug-metabolizing drugsystem

Drugs Used to Treat Hypertension

Objectives: Objectives:
At the end of the chapter, the student is expected to:  Classify antihypertensive drugs by their primary sites of action.  Explain the inter- and intra-group interintradifferences of antihypertensive drugs according to their effects, mechanisms of action, therapeutic uses and toxicity.  Select appropriate antihypertensive drugs for a particular patient.

Antihypertensive Therapy

Goal is to decrease elevated BP to prevent end-organ damage by: endInterfering with the normal physiologic mechanisms which regulate blood pressure.  Preventing future disease and death by lowering blood pressure.  Balancing of risk of toxicity and risk of not treating.  Combining various therapeutic agents


Clinical Management of Hypertension

    

Na+ restriction [low salt diet]. Weigh reduction. Monotherapy-beta blocker [Thiazide diuretic in Monotherapymost cases]. Combined therapy is one drug can't control hypertension. The "stepped care" approach for the pharmacologic management of primary hypertension has been advocated for over 20 years. Approximately 80% of patients who are compliant with their medications will obtain adequate blood pressure control using this treatment strategy.

PHARMACOLOGY OF ANTIHYPERTENSIVE AGENTS

All antihypertensive agents act at anatomic BP control sites

Agent 1. Diuretics Mechanism of decrease BP Decrease Na+ and leads to decrease in blood volume.

2. Sympathoplegic Agents

Decrease peripheral vascular resistance decrease cardiac function venous pooling.

3. Direct Vasodilators

Relax vascular smooth muscle dilate resistance vessels capacitance.

4. Blockers of Angiotensin

Decrease peripheral vascular resistance decrease blood volume.

Overview of Antihypertensive Agents

A. Diuretics Decrease BP by depleting body Na+. Mild or moderate hypertension: diuretics alone are sufficient [e.g., thiazides]. Severe hypertension: more powerful diuretics used in combination with sympathoplegic and vasodilators [prevent volume retention and edema]. Diuretics enhance efficacy of ACE inhibitors.

Thiazides
 Inhibit NaCl transport in distal convoluted tubule.  Absorbed well orally.  Secreted by organic acid secretory system/competes with uric acid secretion by that system low cost and effective.  Toxicity is limited at doses used in hypertension.

Toxicity: Toxicity:
Enhanced renal secretion of K+ and H+ leads to K+ depletion, which leads to hypokalemic metabolic alkalosis. Hazardous in patient taking digitalis, those with chronic arrhythmias or acute myocardial infarction. Hyperglycemia in diabetics. Increased serum cholesterol, uric acid and lipid levels. Decreased serum Na+. Allergic reactions photosensitivity or general dermatitis.

Drugs Altering Sympathetic Nervous Function

Classified according to site where sympathetic reflex arc is impaired

1.

Centrally Acting Sympatholytic Drugs

Methyldopa and Clonidine

Methyldopa is an analogue of L-dopa which is Lmetabolized to alpha-methylnorepinephrine. alpha Clonidine is a 2-imidazoline derivative. 2 Both act on alpha 2 adrenoreceptors in brain stem to decrease sympathetic outflow leading to decrease in baroreceptor reflex arc and decrease in peripheral vascular resistance. Clonidine also decreases heart rate and cardiac output. Toxicity: sedation and impaired concentration [CNS effects].

Peripherally Acting Sympatholytic Drugs

Adrenergic neuron-blocking agents neurondecrease BP by blocking release of norepinephrine [NE] from postganglionic sympathetic neurons

Reserpine [alkaloid from the root of Indian plant Rauwolfia serpentina].

   

Blocks uptake of biogenic amines by NE storage vesicles. Leads to decrease in NE, dopamine and serotonin in central and peripheral neurons. Leads to decrease in cardiac output and peripheral vascular resistance. Toxicity: Sedation, mental depression and Parkinsonism symptoms.

Guanethedine
 Depletes

NE concentrations leading o decrease in NE release.  Used for patients with severe refractory hypertension.  Side-effect is orthostatic hypotension. Side-

Adrenoceptor Antagonists [alpha and beta blockers]

Propanolol [classical beta blocker]

     

Anatgonizes catecholamines at both beta1 and beta 2 adrenoceptors. Leads to decrease heart rate and cardiac output. Leads to decrease peripheral vascular resistance [blocks beta1 receptors in j-g apparatus]. jLeads to decrease stimulation rennin production by catecholamines. Net effect: decrease BP Toxicity: Due to cardiac, vascular and bronchial beta receptor blockade patient with cardiac dysfunction, asthma, peripheral vascular insufficiency and etc. are more susceptible.

Prazosin
 Selectively

blocks alpha1 receptors in arterioles and venules.  Allows for negative feedback of norepinephrine release.  Decreases BP by dilating both resistance [arterioles] and capacitance [venules] vessels.  Few toxicities.

Vasodilators
- All vasodilators used in hypertension relax smooth muscle of arterioles and lead to decreased peripheral vascular resistance, which leads to decrease in BP. - Compensatory responses from baroreceptors and renin Angiotensin system oppose the antihypertensive effect therefore vasodilators work best in combination with other antihypertensive drugs (e.g., blockers and diuretics) that oppose the compensatory responses.

Oral Vasodilators [e.g., hydralazine, minoxidil]

Long term outpatient therapy of hypertension. Toxicity: tachycardia, palpitations, angina, sweating, headache, edema.

Parenteral Vasodilators
IV treatment of hypertensive emergencies. Toxicity: excessive hypotension.

Calcium Channel Blockers

Both long term and emergency treatment. Inhibition of Ca2+ influx arterial smooth muscle cells leading to dilation of peripheral arterioles. Toxicity: severe cardiac depression [decrease Heart Rate and Cardiac Output].

AngiotensinAngiotensin-converting Enzyme [ACE] Inhibitors

Biosynthesis of Angiotensin
Renin is produced by juxtaglomerular cells [bear afferent arterioles of glomeruli] of the kidney. Decreased ECF volume and decreased blood pressure leads to increased rennin secretion. Many conditions including CHF will stimulate rennin secretion [e.g., hypotension, hemorrhage, dehydration, diuretics, Na+ depletion etc]. Renin converts circulating angiotensin leads to angiotensin I. Angiotensin converting enzyme [ACE] [found in endothelial cells] converts angiotensin I to angiotensin II. Also inactivates bradykinin.

Angiotensin II is one of most potent vasoconstrictors known. Leads to increased systolic and diastolic blood pressure. Acts directly on adrenal cortex leads to increased secretion of aldosterone. Also increases release of norepinephrine from post-ganglionic postsympathetic neurons. Decreased BP leads to contraction of mesangial cells leads to decreased glomerular filtration rate. Also increases release of antidiuretic hormone from pituitary gland.

Mechanism: decreased Angiotensin II leads to decreased peripheral resistance leads to decreased afterload

Decreased aldosterone secretion leads to decreased salt and water retention leads to decreased preload. Decreased degradation of bradykinin leads to increased kinin activity i.e., leads to increased vasodilation Decreased sympathetic activity by decreased angiotensin-mediated angiotensinnorepinephrine release.

Clinical effect
Decreased blood pressure. No effect on heart rate and cardiac output. No reflex sympathetic activation i.e., No reflex tachycardia [unlike vasodilators], therefore safe for use in persons with ischemic heart disease.

Examples of ACE inhibitor drugs

Natural ACE inhibitor
Teprotide:

- Isolated from the venom of the South American pit viper. - Active only when given IV.

Synthetic ACE inhibitors

 Captopril: - Rapid oral absorption. - Short T 1/2 [3 hours] - Eliminated in the kidney [decreased dose with renal insufficiency]  Enapralil: - IV emergency use - T 1/2 [11 hours]

Clinical Use
 Studies

have shown ACE inhibitors to be useful first line agents in all subsets of CHF patients i.e., Asymptomatic to severe chronic failure.

Toxicity
Severe hypotension Acute Renal Failure Angioedema Dry cough

tHe eNd