Sufentanil

• A synthetic opioid related to fentanyl.
• About 7 times more potent than fentanyl.
• Has a slightly more rapid onset of action than fentanyl.

Calcium Channel Blocking Agents 

• Act on contractile and conductive tissues of the heart and on vascular smooth muscles 
• Prevent movement of extracellular calcium into the cell 
– Coronary and peripheral arteries dilate
– Myocardial contractility decreases 
– Depress conduction system

Therapeutic Actions
• Inhibit movement of calcium ions across the membranes of myocardial and arterial muscle cells. Altering the action potential and blocking muscle cell contraction 
• Depress myocardial contractility 
• Slow cardiac impulse formation in the conductive tissues 
• Cause a fall in BP 
 

VITAMIN -K

• Group of lipophilic, hydrophobic vitamins.
• Needed for the post-translational modification of coagulation proteins.
• Phylloquinone (vitamin K1) is the major dietary form of vitamin K.

• Vitamin K2 (menaquinone, menatetrenone) is produced by bacteria in the intestines.

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.

Seizure classification:

based on degree of CNS involvement, involves simple ( Jacksonian; sensory or motor cortex) or complex symptoms (involves temporal lobe)

1.    Generalized (whole brain involved): 

a.    Tonic-clonic:

Grand Mal; ~30% incidence; unconsiousness, tonic contractions (sustained contraction of muscle groups) followed by clonic contractions (alternating contraction/relaxation); happens for ~ 2-3 minutes and people don’t breathe during this time

Drugs: phenytoin, carbamazepine, Phenobarbital, lamotrigine, valproic acid

Status epilepticus: continuous seizures; use diazepam (short duration) or diazepam + phenytoin

b.    Absence:

Petit Mal; common in children; frequent, brief lapses of consciousness with or without clonic motor activity; see spike and wave EEg at 3 Hz (probably relates to thalamocorticoreverburating circuit)

Drugs: ethosuximide, lamotrigine, valproic acid

c.    Myoclonic: uncommon; isolated clinic jerks associated with bursts of EEG spikes; 

Drugs: lamotrigine, valproic acid

d.    Atonic/akinetic: drop seizures; uncommon; sudden, brief loss of postural muscle tone
Drugs: valproic acid and lamotrigine

2.    Partial:  focal

a.    Simple:  Jacksonian; remain conscious; involves motor or sensory seizures (hot, cold, tingling common)

Drugs: carbamazepine, phenytoin, Phenobarbital, lamotrigine, valproic acid, gabapentin

b.    Complex: temporal lobe or psychomotor; produced by abnormal electrical activity in temporal lobe (involves emotional functions)

Symptoms: abnormal psychic, cognitive, and behavioral function; seizures consist of confused/altered behavior with impaired consciousness (may be confused with psychoses like schizophrenia or dementia)

Drugs: carbamazepine, phenytoin, laotrigine, valproic acid, gabapentin

Generalizations: most seizures can’t be cured but can be controlled by regular administration of anticonvulsants (many types require treatment for years to decades); drug treatment can effectively control seizures in ~ 80% of patients

Ketoconazole

synthetic antifungal drug

used for infections such as  athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch.

Ketoconazole is used to treat eumycetoma, the fungal form of mycetoma.

MOA: Ketoconazole is imidazole structured, and interferes with the fungal synthesis of  ergosterol, the main constituent of cell membranes, as well as certain enzymes. It is specific for fungi, as mammalian cell membranes contain no ergosterol.

Sensitive fungi Ketoconazole inhibits growth of  dermatophytes and  yeast species (such as Candida albicans).